1. 肠道作为“第二大脑”的概念溯源与生物学基础
1.1 概念的提出与演变
“肠道是人的第二个大脑”这一说法并非空穴来风，其科学内涵植根于对肠道神经系统（Enteric Nervous System, ENS）独立性与复杂性的认知。长期以来，科学家们通过早期生理学观察逐渐认识到肠道不仅是消化器官，更具有自主调节功能。随着神经科学研究的深入，这一概念得到了更全面的阐释。
ENS是人体内最复杂的周围神经系统分支，在神经化学多样性方面表现突出 12。这些神经元分布在胃肠道壁内的两层神经丛中，能够自主调控肠道的运动、分泌和局部血流，并在没有中枢神经系统（Central Nervous System, CNS）直接指令的情况下独立运作 123。这种高度的自主性使得肠道获得了“第二个大脑”的美誉。
这一概念的演变经历了从最初的观察性描述到分子机制深入探究的过程。早期研究主要集中在肠道对食物的机械和化学刺激的响应，以及其在消化吸收过程中的关键作用。现代神经科学研究则揭示了ENS在结构和功能上与CNS的相似之处，例如两者都使用多种神经递质（如乙酰胆碱、血清素、多巴胺等），并且拥有支持性胶质细胞（肠胶质细胞）来维护神经元功能和肠道稳态 45。此外，ENS不仅能够处理局部信息，还能通过迷走神经等通路与大脑进行双向通信，形成复杂的“肠-脑轴” 67。这种双向沟通机制进一步强化了“肠道是第二个大脑”的观点，因为它强调了肠道在调节情绪、认知和行为方面的重要作用，远超传统意义上的消化功能。例如，肠道菌群通过产生神经活性物质直接影响脑功能，为这一概念增添了微生物维度 68。对ENS发育生物学的研究也表明，其起源于神经嵴细胞，并在胚胎发育早期沿着胃肠道迁移、增殖和分化，形成复杂的神经回路，这一过程的紊乱会导致先天性疾病，如巨结肠症 1910。这些发现共同构建了“肠道是第二个大脑”的科学基础，使其从一个形象的比喻逐渐发展成为一个具有深刻生物学意义的科学命题。
1.2 肠道神经系统（ENS）的解剖与功能特征
肠道神经系统（ENS）是胃肠壁内固有的、复杂的神经网络，其在解剖学和功能上展现出独特的“类脑”特性。ENS包含约2亿至6亿个神经元，数量甚至超过脊髓中的神经元总数，使其成为自主神经系统的第三个组成部分，独立于中枢神经系统（CNS）和外周自主神经系统之外1112。
解剖分布：
ENS主要分布在胃肠道壁内的两层神经丛中：
- 肌间神经丛（Auerbach’s plexus/Myenteric plexus）：位于环肌层和纵肌层之间，从食道延伸至肛门内括约肌，形成连续的网络11。它主要负责调控肠道肌肉的收缩与舒张，进而控制肠道蠕动，推动食糜和粪便的运动。
- 黏膜下神经丛（Meissner’s plexus/Submucosal plexus）：位于黏膜下层，在小肠和结肠中形成神经丛，但在胃和食道中不明显11。该神经丛主要参与调节肠道上皮细胞的分泌、吸收功能以及局部血流量。
这些神经丛通过神经纤维束相互连接，构成了一个高度整合的局部调控系统1113。肠道内的其他细胞类型，如肠嗜铬细胞（enterochromaffin cells）、间质细胞（interstitial cells of Cajal, ICCs）和免疫细胞，也与ENS紧密交互，共同维持肠道功能2。
功能特征：
ENS的核心功能在于自主调控肠道的各项生理活动，而无需CNS的直接指令，这正是其“第二个大脑”称号的由来：
- 肠道运动（Motility）：ENS包含完整的反射回路，包括感觉神经元、中间神经元和多种运动神经元，能够独立控制肠道肌肉的收缩和放松，产生蠕动、分节运动等，以实现食物消化和废物排出11。例如，局部扩张或化学刺激即可在ENS内部触发感知反应，进而调节结肠蠕动14。
- 分泌与吸收（Secretion and Absorption）：黏膜下神经丛的神经元直接或间接调控肠腺体的分泌活动，影响消化液、黏液和电解质的分泌，以及营养物质和水分的吸收效率2。
- 局部血流（Local Blood Flow）：ENS也参与调节肠壁的血液循环，确保消化吸收过程中的能量和氧气供应。
- 免疫调控（Immune Regulation）：肠道作为人体最大的免疫器官，其免疫功能受到ENS的显著影响。ENS与肠道免疫细胞相互作用，参与维持肠道屏障完整性，抵御病原体入侵，并调节局部炎症反应215。
与CNS的对比与“类脑”特性：
ENS之所以被称为“第二个大脑”，不仅因为其庞大的神经元数量和自主性，更在于其在结构和功能上与CNS的诸多相似之处：
- 神经元多样性：ENS拥有多种类型的神经元，包括兴奋性神经元（如胆碱能神经元）和抑制性神经元（如一氧化氮合酶阳性神经元），以及多种感觉神经元和中间神经元，它们释放并响应与CNS相同的多种神经递质，如乙酰胆碱（ACh）、血清素（5-HT）、多巴胺、去甲肾上腺素、γ-氨基丁酸（GABA）等131617。
- 胶质细胞支持：ENS拥有肠胶质细胞（enteric glial cells），这些细胞在功能上类似于CNS中的星形胶质细胞，为神经元提供支持、营养和保护，参与维持肠道屏障功能，并在肠道损伤和炎症中发挥作用2。
- 反射弧：ENS能够独立形成完整的反射弧，即“局部反射”，感知肠道内刺激（如食物进入、肠壁扩张），处理信息，并产生相应的效应（如肌肉收缩、腺体分泌），无需经过大脑的决策11。
- 神经可塑性：ENS的神经元具有一定的可塑性，能够适应肠道内环境的变化，并在一定程度上进行损伤修复。研究表明，在肠道炎症后，ENS的神经元数量和分布会发生改变，可能导致肠道功能障碍1819。
- 发育起源：ENS的神经元起源于神经嵴细胞，与CNS的神经元有共同的胚胎发育起源，这进一步凸显了它们之间的内在联系2021。
尽管ENS具有高度的自主性，但它并非完全独立于CNS。两者通过迷走神经、脊髓传入和传出神经以及神经内分泌通路进行复杂的双向通信，共同构成“肠-脑轴”，协同调控整个机体的生理和心理健康22。例如，大脑可以通过迷走神经调控肠道功能，而肠道状态也能通过神经信号反馈影响大脑功能和情绪11。
2. 肠道-脑轴的双向通信机制：神经、免疫与代谢的协同作用
2.1 神经通路：迷走神经与肠-脑信号传递
肠道-脑轴是一个复杂的双向通信系统，其中神经通路扮演着至关重要的角色，尤其以迷走神经（Vagus nerve）作为主要的神经桥梁。迷走神经是第十对脑神经，其传入和传出纤维直接连接脑干与内脏器官，构成了一条快速、直接的信息传递通道 2324。
2.1.1 迷走传入纤维：从肠道到大脑的信息上报
迷走神经的传入纤维（afferent fibers）是肠道向大脑传递信息的主要途径。这些传入纤维的胞体位于结状神经节（nodose ganglia）和迷走神经节，其末梢广泛分布于胃肠道壁，能够感知多种肠道内环境信号，并将这些信息传递至脑干，特别是孤束核（Nucleus Tractus Solitarius, NTS）等整合中枢 242526。
迷走传入纤维能够感知的肠道信号包括：
- 营养物质感知：肠道上皮细胞中存在特殊的“神经足细胞”（neuropod cells），这些细胞能够直接感知肠腔内的营养物质（如葡萄糖、脂肪酸）或化学刺激，并通过突触结构快速地将信号传递给迷走神经末梢，使其将信息上报至大脑 27。例如，迷走传入神经元上表达的胰高糖素样肽-1受体（GLP1R）能够感知肠道中的GLP-1信号，进而调节饱食感和血糖稳态 28。
- 机械刺激：肠壁的扩张、收缩以及食糜的移动等机械刺激，可以通过分布在肠壁肌层中的迷走传入纤维（如肌内阵列, IMAs）和肠内神经节层状末梢（IGLEs）被感知 29。这些机械感受器在消化过程中向大脑提供关于肠道充盈度和运动状态的信息 26。
- 炎症和损伤信号：当肠道发生炎症或损伤时，局部释放的细胞因子、神经肽等信号分子也能激活迷走传入神经，将异常信号传递给大脑，从而影响中枢对疼痛、不适的感知以及行为反应 30。
- 微生物代谢产物：肠道菌群产生的某些代谢产物（如短链脂肪酸、神经递质前体等）也能通过直接或间接方式激活迷走传入神经，将肠道微生物状态的信息传递至大脑 31。例如，益生菌如鼠李糖乳杆菌（Lactobacillus rhamnosus (JB-1)）能够引起迷走传入神经元的快速频率促进，影响脑部神经化学变化和行为 31。
这些肠道信号经迷走传入纤维到达脑干后，会在NTS等脑区进行整合和处理，进而影响下丘脑、边缘系统等高级脑区的活动，调节摄食行为、情绪、应激反应和代谢稳态 242832。
2.1.2 迷走传出纤维：从大脑到肠道的指令下达
迷走神经的传出纤维（efferent fibers）主要起源于迷走神经背侧运动核（Dorsal Motor Nucleus of the Vagus, DMV），负责将大脑的指令传递给肠道，调控肠道的运动、分泌和免疫功能 2433。
迷走传出纤维对肠道功能的调控机制包括：
- 调控肠道运动和分泌：迷走传出纤维主要通过释放乙酰胆碱作用于肠神经系统中的胆碱能神经元，进而影响肠道平滑肌的收缩以及腺体的分泌。例如，迷走神经能够促进胃肠道蠕动和消化液分泌，加速食物的消化吸收过程 33。研究发现，DMV中存在分子上不同的神经元亚型，它们可以选择性地支配胃的不同区域，并释放不同功能相反的神经递质（如乙酰胆碱与一氧化氮），从而实现对胃功能的精确调控，包括胃收缩和舒张 33。
- 免疫调控：迷走神经还具有抗炎作用。迷走传出神经元可以激活肠神经系统中的神经元，这些神经元进而释放神经肽（如血管活性肠肽VIP）或通过乙酰胆碱直接作用于肠道免疫细胞（如巨噬细胞、淋巴细胞），抑制促炎细胞因子的释放，从而减轻肠道炎症 3435。这种“神经炎症反射”是肠道-脑轴在免疫调节中的重要体现。
- 应激反应与肠道健康：大脑对压力的感知可以通过迷走传出通路影响肠道功能。例如，慢性应激可以激活中枢杏仁核-DMV通路，导致迷走神经活化，进而通过胆碱能肠神经元释放乙酰胆碱，作用于肠道干细胞（ISCs）上的M3毒蕈碱乙酰胆碱受体（CHRM3），激活p38 MAPK通路，加速ISCs衰老样衰退，损害肠道健康 36。这表明大脑通过迷走神经对肠道的影响是多方面且深远的。
总而言之，迷走神经作为肠道-脑轴中关键的神经通路，实现了大脑与肠道之间的高效双向通信。它不仅将肠道的生理状态、营养感知和潜在威胁信息上传至大脑，也负责将大脑对这些信息的反应和调节指令下达至肠道，从而协同维持机体的内稳态，并对情绪、行为产生重要影响 232537。
2.2 免疫与炎症调控：肠道-脑的“免疫对话”
肠道-脑轴的另一个重要通信途径是免疫系统，它介导了肠道与大脑之间的“免疫对话”。肠道作为人体最大的免疫器官，其免疫细胞能够感知肠道微环境的变化，特别是微生物或损伤信号，并通过释放多种信号分子，尤其是细胞因子，来影响大脑功能，进而介导神经炎症和行为改变，如抑郁和焦虑3839。
2.2.1 肠道免疫细胞感知与信号传导
肠道内富含各种免疫细胞，包括肠巨噬细胞、树突状细胞、T淋巴细胞和B淋巴细胞等。这些细胞持续监测肠腔内容物，识别病原体相关分子模式（PAMPs）和宿主损伤相关分子模式（DAMPs）。当肠道菌群失调（dysbiosis）或肠道屏障受损时，这些免疫细胞会被激活：
- 模式识别受体（PRRs）：肠道免疫细胞表面的PRRs，如Toll样受体（TLRs）和NOD样受体（NLRs），能够识别细菌脂多糖（LPS）、肽聚糖等微生物产物。LPS是革兰氏阴性菌细胞壁的组分，当肠道通透性增加时，LPS可能进入循环系统，引发全身性炎症3940。
- 炎性体（Inflammasome）：肠道免疫细胞，特别是巨噬细胞，在感染、应激或代谢紊乱条件下，可通过NLRP3等炎性体复合物的激活，诱导促炎细胞因子白介素-1β（IL-1β）和白介素-18（IL-18）的成熟与释放4041。
2.2.2 细胞因子与神经炎症
被激活的肠道免疫细胞会释放大量促炎性细胞因子，如肿瘤坏死因子-α（TNF-α）、白介素-6（IL-6）、白介素-1β（IL-1β）和单核细胞趋化蛋白-1（MCP-1/CCL-2）等4042。这些细胞因子可以通过多种途径影响大脑：
- 血脑屏障（BBB）的渗透：炎症状态下，血脑屏障的通透性可能增加，允许细胞因子或其诱导的信号分子进入大脑4143。
- 迷走神经激活：部分细胞因子可以激活迷走神经传入纤维，将炎症信号直接传递至中枢神经系统，进而影响大脑功能43。
- 内皮细胞与周血管细胞：细胞因子可以作用于脑血管内皮细胞，诱导其产生次级信使，间接影响脑部。
- 脑内小胶质细胞活化：到达大脑的促炎细胞因子是小胶质细胞活化的重要诱因。小胶质细胞是中枢神经系统内的主要免疫细胞，其活化后会释放更多的促炎细胞因子、活性氧自由基等，形成神经炎症循环4144。这种神经炎症被认为是多种神经精神疾病的核心病理机制之一，如抑郁症、焦虑症、阿尔茨海默病和帕金森病3841。
2.2.3 介导行为改变
神经炎症的发生与发展与多种行为改变密切相关：
- 抑郁和焦虑：肠道菌群失调引起的慢性低度炎症通过细胞因子影响大脑，可能导致抑郁和焦虑样行为。例如，IL-6和TNF-α等促炎细胞因子水平升高与抑郁症的发生发展密切相关394546。炎症可以影响神经递质的代谢，如色氨酸向犬尿氨酸途径的转化，减少5-羟色胺（5-HT）的合成，从而影响情绪调节44。应激诱导的肠道炎症和5-HT代谢紊乱在应激性肠易激综合征小鼠模型的抑郁行为中扮演重要角色47。
- 认知功能障碍：神经炎症，特别是小胶质细胞的持续活化，会损害神经元功能和突触可塑性，进而导致认知功能下降4548。例如，在化疗引起的认知障碍中，肠道菌群的改变与循环中TNF-α和IL-6的升高相关，并与客观认知能力的下降有关，这提示肠道菌群可能通过炎症途径影响认知45。
- 其他神经精神疾病：肠道免疫与大脑的对话也与自闭症谱系障碍（ASD）和多发性硬化症（MS）等疾病有关384849。肠道菌群失调可能通过免疫系统影响神经发育和神经病理过程41。
值得注意的是，应激反应也能反过来影响肠道免疫，导致肠道通透性增加和菌群失调，形成恶性循环。心理应激通过糖皮质激素应答增强肠道通透性，导致微生物依赖性IL-17A分泌，进而引起血管危象，提示应激对血管疾病的影响与肠道菌群和免疫反应有关50。因此，肠道与大脑之间的免疫对话是一个复杂的双向过程，对维持身心健康至关重要。
2.3 代谢与微生物：肠道菌群的“化学信使”作用
肠道菌群通过其丰富的代谢活动，产生多种具有生物活性的分子，这些分子充当“化学信使”，通过血液循环或直接作用于肠道内的细胞，进而深刻影响大脑功能和神经递质平衡，是肠-脑轴通信中不可或缺的一环 5152。
2.3.1 短链脂肪酸 (SCFAs) 的作用
短链脂肪酸（SCFAs），主要包括乙酸、丙酸和丁酸，是肠道菌群发酵膳食纤维和抗性淀粉等碳水化合物的产物 53。它们对宿主健康具有多方面益处，并被认为是肠道菌群与大脑沟通的关键代谢物：
- 能量供应与肠道屏障：丁酸是结肠上皮细胞主要的能量来源，对维持肠道屏障的完整性至关重要 53。健康的肠道屏障可以阻止有害物质进入循环系统，进而避免对大脑的潜在负面影响。
- 神经免疫调节：SCFAs可以通过作用于宿主细胞表面的G蛋白偶联受体（GPCRs），如GPR41和GPR43，参与免疫调节 53。它们能够调节炎症反应，影响血脑屏障的通透性，并间接影响脑内的神经炎症状态 53。研究发现，压力可导致肠道代谢物，尤其是SCFAs的显著下降 54。而丁酸已被证明可以穿过血脑屏障，直接影响大脑功能，具有神经保护作用，并可能通过调节神经递质合成或小胶质细胞功能来影响情绪和行为 53。
- 神经递质前体与调节：虽然SCFAs本身不是神经递质，但它们可以影响神经递质的合成和功能。例如，丙酸和丁酸可以调节某些神经递质的水平，并被认为与自闭症谱系障碍等神经发育疾病有关 53。补充SCFAs的干预措施已被证明可以改善应激大鼠的SCFA和多胺水平，并有助于调节肠-脑轴和改善焦虑样行为 54。
2.3.2 色氨酸代谢产物与神经递质平衡
色氨酸（Tryptophan, Trp）是一种必需氨基酸，是多种神经活性分子的前体，其代谢途径受到肠道菌群的显著影响，从而在肠-脑轴中发挥核心作用 5556。
- 5-羟色胺 (5-HT, 血清素)：肠道是体内5-HT的主要合成场所，约95%的5-HT由肠道内的肠嗜铬细胞（Enterochromaffin cells, ECs）合成和分泌 5758。肠道菌群，特别是某些产孢细菌，可以促进ECs合成5-HT，从而影响肠道蠕动、血小板功能，并最终影响情绪和行为 5759。5-HT在调节情绪、食欲、睡眠和疼痛方面至关重要 5560。一些肠道细菌（如Ruminococcus gnavus）可通过其代谢产物（如苯乙胺和色胺）直接刺激ECs的5-HT合成，进而影响肠道转运和结肠分泌，这与腹泻型肠易激综合征（IBS-D）等疾病相关 61。
- 犬尿氨酸途径：色氨酸的另一条主要代谢途径是犬尿氨酸（Kynurenine）途径，该途径的产物在调节神经活动和全身炎症中发挥作用 5556。在炎症或应激条件下，犬尿氨酸途径的活性增加，导致更多的色氨酸转化为犬尿氨酸及其代谢产物（如喹啉酸），而用于合成5-HT的色氨酸减少 6062。某些犬尿氨酸代谢物具有神经毒性，并与抑郁症等神经精神疾病有关 5562。肠道菌群可以通过调节犬尿氨酸途径中的关键酶（如IDO1）来影响脑内犬尿氨酸与5-HT的平衡 62。
- 吲哚类代谢物：肠道菌群还可以将色氨酸代谢为吲哚及其衍生物。这些吲哚类代谢物可以激活芳香烃受体（AHR），调节免疫反应，并对肠道炎症和结肠直肠癌具有保护作用 63。
2.3.3 其他神经递质和神经可塑性调节
除了5-HT和SCFAs，肠道菌群还能产生或影响其他神经递质的水平及其前体，进而调节神经可塑性：
- γ-氨基丁酸 (GABA)：一些肠道菌群衍生的代谢物，如短链脂肪酸，可能通过多种机制间接影响GABA的产生和信号传导，而GABA是一种主要的抑制性神经递质，对调节焦虑和情绪至关重要 51。
- 酪氨酸和多巴胺：肠道菌群的代谢产物能影响宿主的酪氨酸代谢，进而影响儿茶酚胺类神经递质的合成。例如，在应激条件下，肠道菌群的变化可能影响多巴胺和去甲肾上腺素的合成及代谢，而这些神经递质在奖赏、动机和运动控制中发挥关键作用 64。
- 神经可塑性：肠道菌群的代谢产物，如SCFAs和色氨酸代谢物，可以通过多种机制影响神经可塑性，包括调节脑源性神经营养因子（BDNF）的表达。BDNF对神经元的生长、分化、存活和突触可塑性至关重要。例如，一项研究发现，某些益生菌（如Roseburia intestinalis）可以显著改善慢性应激诱导的小鼠抑郁行为，并增加脑和结肠中的5-HT水平，同时抑制犬尿氨酸途径的毒性代谢物，并通过促进BDNF和PSD-95的表达来保护突触丢失和改善神经可塑性 62。同时，应激还会导致BDNF减少，而某些干预措施，如CBD脂质纳米颗粒，能够增加BDNF水平，从而增强神经可塑性 54。
- 微生物-宿主RNA相互作用：肠道内分泌细胞上的阳离子通道Piezo1可以作为单链RNA（ssRNA）的传感器，调节5-HT的产生。粪便ssRNA被鉴定为天然的Piezo1配体，其刺激的5-HT合成可以影响肠道蠕动和骨骼形成。这揭示了肠道微生物群通过核酸信号分子影响宿主生理的新机制 65。
综上所述，肠道菌群并非被动存在，而是通过其代谢产物积极地参与到肠道-脑轴的复杂通信中。这些“化学信使”通过神经、内分泌和免疫系统，直接或间接地调节神经递质平衡、神经炎症和神经可塑性，从而对宿主的情绪、行为和认知功能产生深远影响 515266。深入理解这些机制为靶向肠道菌群以治疗神经精神疾病提供了新的视角和潜在的干预策略 67。
3. 肠道-脑轴与疾病的关联：从消化到神经精神障碍
3.1 功能性胃肠病中的肠道-脑轴失调
功能性胃肠病（Functional Gastrointestinal Disorders, FGIDs）是一类以持续或反复发作的胃肠道症状为特征，但常规检查未发现器质性病变的疾病。其中，肠易激综合征（Irritable Bowel Syndrome, IBS）是最常见的FGIDs之一，其病理生理学被广泛认为是肠道-脑轴功能紊乱的典型体现 686970。IBS患者的临床表现高度异质，主要包括腹痛、腹胀，以及排便习惯的改变（腹泻、便秘或两者交替） 7071。
3.1.1 肠道敏感性增高与动力异常
IBS患者的一个显著特征是内脏敏感性增高（visceral hypersensitivity），即对肠道扩张或其他刺激的感知阈值降低，即使是生理性刺激也能引起不适或疼痛 7072。这种敏感性增高被认为是肠道传入神经末梢敏感化，以及中枢神经系统对传入信号处理异常的结果。例如，一项研究表明，IBS患者在直肠扩张时，大脑前扣带回（anterior cingulate cortex, ACC）、脑岛（insula）和前额叶皮层等痛觉处理中枢的激活程度显著高于健康对照组 7374。ACC与疼痛的情绪成分和认知调控有关，脑岛则参与内脏感觉整合和情绪体验。对不舒服的直肠扩张的预期不确定性与扣带下前扣带皮层（subgenual anterior cingulate cortex, sgACC）的激活有关，这表明焦虑情绪可能加剧对内脏刺激的感知 75。
此外，IBS患者常伴有肠道动力异常，表现为胃肠道蠕动过快或过慢 70。这些动力学改变可能由肠神经系统（ENS）功能障碍、局部神经递质（如5-羟色胺）释放异常或肠道菌群失调引起 76。例如，腹泻型IBS（IBS-D）患者肠道中5-HT及其受体（5-HT3R和5-HT4R）的表达可能增加，导致肠道运动加速和内脏敏感性增高 77。
3.1.2 脑内痛觉处理中枢的异常活动
IBS患者大脑中与疼痛感知和情绪调节相关的区域，如前扣带回、脑岛、杏仁核和前额叶皮层，常表现出功能异常。功能磁共振成像（fMRI）研究显示，在疼痛性直肠扩张期间，IBS患者的这些脑区激活增强 7374。这意味着IBS不仅仅是肠道问题，更是肠道与大脑之间异常通信的结果。例如，抗抑郁药物阿米替林（amitriptyline）能降低IBS患者在应激状态下痛觉相关的前扣带回和顶叶皮层激活，从而缓解症状 73。这提示了针对中枢神经系统的干预在治疗IBS中的潜在作用。
3.1.3 微生物群失调在其中的中介作用
肠道微生物群失调（dysbiosis）在IBS的病理生理学中发挥着关键的中介作用 6869。IBS患者的肠道菌群组成和功能常发生改变，例如，某些共生菌的丰度降低，而一些潜在致病菌或产气菌可能增多 71。这种失调可能导致：
- 肠道屏障功能受损：菌群失调可能引起肠道通透性增加，使得细菌产物（如脂多糖LPS）和代谢物更容易进入血液循环。心理应激可通过激活肠道粘膜免疫并改变肠道通透性来影响IBS症状 78。
- 免疫激活与炎症：心理应激通过神经-内分泌-免疫途径影响肠-脑轴和微生物群-肠-脑轴，从而激活粘膜免疫，引起症状加重或爆发 78。
- 神经递质代谢改变：肠道菌群能够影响多种神经递质（如5-HT、GABA）的合成和代谢，进而影响情绪、痛觉感知和肠道动力。例如，某些细菌可以促进肠嗜铬细胞释放5-HT，从而影响肠道运动和敏感性 6976。
- 短链脂肪酸（SCFAs）改变：菌群失调可能改变SCFAs的产生，而SCFAs对肠道屏障功能和免疫调节至关重要。
3.1.4 双向关联与共病现象
肠易激综合征与多种其他疾病存在双向关联，这进一步突显了肠道-脑轴在疾病发生发展中的核心作用：
- 心理应激与IBS：心理应激是IBS发病和症状加重的重要因素 6978。慢性应激可以通过改变肠道通透性、菌群组成、免疫激活和内脏敏感性来加剧IBS症状 78。反之，IBS症状本身也会引起患者的心理困扰，如焦虑和抑郁，形成恶性循环 7980。
- IBS与精神障碍：IBS患者常伴有较高的焦虑症和抑郁症患病率，被认为是肠-脑轴功能障碍的共同表现 6979。
- IBS与全身性疾病：多项研究表明，IBS与其他全身性疾病之间存在双向关联。例如，2型糖尿病患者发生IBS的风险增加，反之IBS患者发生2型糖尿病的风险也更高 81。哮喘与IBS之间也存在双向关联 82。此外，斑秃 83、过敏性鼻炎 84 和类风湿关节炎 85 也与IBS存在双向关联。这些共病现象进一步支持了肠道-脑轴在全身健康中的关键作用。
综上所述，IBS作为典型的功能性胃肠病，其病理生理学机制复杂，涉及肠道敏感性、动力、肠道菌群以及大脑对内脏信号的异常处理。肠道-脑轴的失调在其中扮演核心角色，并通过神经、免疫和代谢途径介导肠道与大脑之间的异常对话，导致IBS症状的发生和发展，并与其他多种疾病形成复杂的共病关系。对这些机制的深入理解为IBS的诊断和治疗提供了新的靶点和策略。
3.2 神经退行性疾病的肠道起源假说
近年来，“肠道起源假说”为阿尔茨海默病（AD）和帕金森病（PD）等神经退行性疾病的病理机制提供了新的视角。该假说认为，肠道菌群失调在这些疾病的发生发展中扮演着关键角色，通过影响β-淀粉样蛋白（Aβ）和α-突触核蛋白（αSyn）的异常聚集，并通过迷走神经或血液循环向脑内传播，最终引发神经退行性病变 868788。
3.2.1 阿尔茨海默病（AD）的肠道起源
阿尔茨海默病是最常见的痴呆症类型，其特征是脑内Aβ斑块的积累和tau蛋白的过度磷酸化 8990。越来越多的证据表明，肠道菌群失调（Gut dysbiosis）与AD的发生和进展密切相关 86919293。
- 肠道菌群失调与Aβ聚集：AD患者的肠道菌群组成与健康人存在显著差异 9194。例如，在5xFAD小鼠模型中，与Aβ负荷增加相关的一个关键特征是梭菌（Clostridium）丰度增加和拟杆菌（Bacteroides）丰度减少 95。肠道菌群失调会导致肠道通透性增加，使得细菌产物如脂多糖（LPS）等更容易进入血液循环并穿过血脑屏障，诱发神经炎症 899192。一些肠道细菌本身也能分泌淀粉样蛋白，这些细菌淀粉样蛋白可能通过分子模拟（molecular mimicry）机制诱导宿主Aβ蛋白的错误折叠和聚集，进而促进AD病理进展 89。
- 代谢产物的影响：肠道菌群的代谢产物在AD进程中也发挥作用。例如，研究发现厚壁菌门（Firmicutes）与拟杆菌门（Bacteroidetes）的比例改变，以及丁酸盐等短链脂肪酸（SCFAs）水平的异常，可能影响脑内Aβ的沉积和神经炎症 91。最新的研究表明，拟杆菌属卵形杆菌（Bacteroides ovatus）及其代谢产物溶血磷脂酰胆碱（lysophosphatidylcholine, LPC）能显著减少Aβ负荷并改善认知障碍 95。LPC通过抑制ACSL4的表达来抑制铁死亡（ferroptosis），从而缓解AD病理 95。
- 神经炎症与氧化应激：肠道菌群失调引起的系统性炎症和氧化应激可通过肠-脑轴影响AD的病理发生 9192。肠道菌群的变化可能促进Aβ聚集、神经炎症和氧化应激，并导致胰岛素抵抗，这些都与AD的病理生理学有关 91。
3.2.2 帕金森病（PD）的肠道起源
帕金森病是一种以黑质多巴胺能神经元丢失和αSyn蛋白异常聚集形成路易小体为特征的神经退行性疾病 8796。越来越多的证据支持PD可能始于肠道，并沿着迷走神经传播到大脑的假说 979899。
- α-突触核蛋白（αSyn）的肠道聚集：在许多PD患者中，αSyn聚集体（路易小体）不仅存在于中枢神经系统，也常见于肠道神经丛，有时甚至在运动症状出现之前就已经存在 97100。这支持了PD可能从肠道开始的观点。
- 迷走神经在传播中的作用：肠道内的αSyn聚集体被认为可以通过迷走神经的逆行传播途径到达脑干，进而扩散至黑质和其他脑区，引发神经变性 97100101。一项使用αSyn过表达小鼠的研究发现，肠道菌群是运动障碍、小胶质细胞活化和αSyn病理发生所必需的 101。抗生素治疗可以改善小鼠的病理，而微生物再定植则会促进其病理进展，这表明肠道和大脑之间的信号传递是疾病病理的关键 101。令人震惊的是，将PD患者的肠道菌群移植给过表达αSyn的小鼠，会加剧其身体功能障碍，而健康捐赠者的菌群则不会 101。
- 肠道菌群失调与PD：PD患者的肠道菌群通常表现出失调，例如黏蛋白降解菌Akkermansia丰度增加，而短链脂肪酸（SCFA）产生菌减少 97。这种失调会增加肠道通透性，使肠道神经丛暴露于毒素（如LPS和农药），从而促进αSyn的异常聚集 9799。LPS可以通过LPS-TLR4信号通路在肠道和大脑中介导炎症反应，加剧PD的病理进展 99。
- SCFAs与神经炎症：PD患者肠道中SCFA水平较低 102。SCFAs，尤其是丁酸盐，对维持肠道屏障完整性和调节免疫反应至关重要。SCFA减少可能导致肠道屏障功能受损，进而加剧神经炎症 97102。此外，SCFAs能调控αSyn聚集、神经炎症和活性氧/活性氮（ROS/RNS）介导的氧化应激 102。
综上所述，神经退行性疾病的“肠道起源假说”通过大量证据表明，肠道菌群失调和其代谢产物的异常，能够通过迷走神经、血液循环以及免疫途径，影响Aβ和αSyn的聚集与传播，并最终诱发脑内的神经炎症和神经变性。深入理解这些机制为AD和PD的早期诊断、预防以及开发基于肠道菌群的干预策略提供了新的方向 86103104。
3.3 精神心理障碍的肠道机制
肠道-脑轴在精神心理障碍，特别是抑郁症和焦虑症的发生发展中扮演着关键角色。越来越多的研究表明，肠道菌群的组成和功能紊乱，以及其对神经递质代谢和下丘脑-垂体-肾上腺（HPA）轴的影响，是这些精神障碍的重要生物学机制 60105106。
3.3.1 肠道菌群与5-HT代谢的交互作用
5-羟色胺（5-HT，血清素）是一种重要的神经递质，广泛参与情绪、睡眠、食欲和认知功能的调节。肠道是人体内5-HT的主要合成和储存部位，大约95%的5-HT在肠道内的肠嗜铬细胞（ECs）中合成 57。肠道菌群通过多种机制影响5-HT的代谢：
- 促进5-HT合成：某些肠道菌群可以直接或间接刺激ECs合成和释放5-HT。肠道菌群与ECs之间的动态相互作用对宿主生理具有重要影响 57。
- 色氨酸代谢：5-HT由必需氨基酸色氨酸（Tryptophan, Trp）合成。肠道菌群显著影响色氨酸的代谢途径。除了合成5-HT，色氨酸还可以通过犬尿氨酸（Kynurenine）途径代谢 60。在炎症或应激条件下，犬尿氨酸途径的活性增加，导致更多的色氨酸转化为犬尿氨酸及其代谢产物（如喹啉酸），而用于合成5-HT的色氨酸减少 60。这些犬尿氨酸代谢物可能具有神经毒性，并与抑郁症等疾病相关 60。因此，肠道菌群失调可能通过改变色氨酸的代谢平衡，减少5-HT的可用性，从而导致情绪障碍 60107。
- 影响5-HT浓度：肠道菌群能够影响局部肠道5-HT浓度，并通过肠-脑轴将信号传递至中枢神经系统，进而影响中枢神经递质功能 60。
3.3.2 下丘脑-垂体-肾上腺（HPA）轴的调控
HPA轴是人体对压力的主要内分泌应答系统，其过度激活或功能失调与抑郁症和焦虑症的发生密切相关 105108。肠道菌群通过肠-脑轴对HPA轴的活性产生显著影响：
- 菌群-HPA轴的互动：肠道菌群可以通过神经、内分泌和免疫途径影响HPA轴。例如，在无菌小鼠（germ-free mice）中，HPA轴的应激反应异常增强，表明正常的肠道菌群对HPA轴的稳态维持至关重要。
- 应激与菌群失调：慢性应激可以直接导致肠道菌群组成的变化（菌群失调），并增加肠道通透性，进而引发炎症反应，进一步激活HPA轴 106109。这种恶性循环加剧了精神障碍的症状。肠道屏障功能的破坏使得细菌内毒素（如LPS）更容易进入循环系统，激活免疫系统并诱导HPA轴的激活，导致皮质醇水平升高，进而影响大脑功能和情绪 108。
- 抗生素的影响：一些研究表明，抗生素的使用，通过破坏肠道菌群平衡，可能导致HPA轴的改变，甚至诱发抑郁和焦虑样行为 106110。这进一步支持了肠道菌群在调节HPA轴活性中的关键作用。
3.3.3 “心理益生菌”与情绪障碍改善
鉴于肠道菌群在精神心理障碍中的重要作用，通过调节肠道微环境来改善情绪障碍的“心理益生菌”（Psychobiotics）受到了广泛关注 111112113114。心理益生菌是指那些摄入后能对中枢神经系统产生有益影响，从而改善精神心理健康的益生菌。
- 潜在作用机制：心理益生菌可能通过以下机制改善情绪障碍：
- 临床应用前景：多项临床研究正在探索心理益生菌在治疗抑郁症和焦虑症中的潜力。一些研究已显示，多菌株益生菌补充剂可以有效改善抑郁症患者的症状，特别是在作为抗抑郁药物的辅助治疗时 111113117118。例如，一项研究发现，益生菌干预组在抑郁症状（HAMD-17和IDS量表）和焦虑症状（HAMA量表）上均取得了显著改善 118。然而，目前对特定菌株及其作用机制的深入研究仍在进行中，仍需更大规模、更严谨的临床试验来明确其疗效和适用人群 111119。
- 粪菌移植（FMT）：除了益生菌，粪菌移植（Fecal Microbiota Transplantation, FMT）作为一种更直接的菌群干预手段，也显示出改善抑郁和焦虑症状的潜力 107108120。将健康人的粪便菌群移植给患者，旨在重建健康的肠道微生态，从而发挥治疗作用。
综上所述，精神心理障碍与肠道微生物群、5-HT代谢以及HPA轴之间存在复杂的交互作用。肠道菌群的失调可能通过多种途径影响大脑功能，从而导致抑郁和焦虑等症状。心理益生菌作为一种新兴的干预手段，通过调节肠道微环境，为这些精神心理障碍的治疗带来了新的希望 112121。
4. 影响肠道-脑轴的关键因素：从饮食到环境
4.1 饮食模式与肠道-脑轴的可塑性
饮食是塑造肠道菌群组成和功能的最主要环境因素之一，进而对肠道-脑轴的健康和功能产生深远影响。不同的饮食模式，如高纤维饮食和高脂高糖饮食，对肠道菌群和脑功能具有差异化的影响，揭示了饮食干预在维持肠道-脑轴稳态及防治相关疾病中的巨大潜力。
4.1.1 高纤维饮食：促进短链脂肪酸生成，有益脑功能
膳食纤维（Dietary fiber, DF）是碳水化合物的一种，因其在人体小肠中不能被消化吸收而在大肠中被肠道菌群发酵而得名 122。高纤维饮食能够显著促进肠道菌群的健康，尤其是那些能发酵纤维产生短链脂肪酸（SCFAs）的细菌 123。SCFAs，如乙酸、丙酸和丁酸，是肠道菌群-脑轴通信的关键“化学信使”，它们通过多种机制对脑功能产生积极影响 53123124：
- 维持肠道屏障完整性：丁酸是结肠细胞的主要能量来源，有助于维持肠道屏障的完整性，减少有害物质（如脂多糖LPS）进入血液循环和大脑的机会 123。
- 调节神经炎症：SCFAs具有抗炎特性，能减少全身和神经炎症。例如，丁酸被证实能穿过血脑屏障，直接影响脑功能，并可能通过调节神经递质合成或小胶质细胞功能来改善情绪和行为 123。
- 改善认知功能：多项研究表明，富含膳食纤维的饮食有助于改善认知功能。例如，一项针对小鼠的研究发现，高纤维饮食可以通过肠道-脑轴减轻母体肥胖引起的后代认知和社会功能障碍，这与缓解突触损伤和改善小胶质细胞成熟有关 125。益生菌和膳食纤维复合物的联合补充，也被发现可以改善老年小鼠的认知能力，减轻脑部氧化应激和肠道炎症，并增加SCFAs浓度 126。
- 调节神经递质和神经可塑性：SCFAs可以影响多种神经递质的水平，并调节脑源性神经营养因子（BDNF）的表达，BDNF对神经元的生长、分化和突触可塑性至关重要。
- 改善昼夜节律认知波动：果寡糖（Fructo-Oligosaccharides, FOS）作为一种益生元，能通过重塑肠道菌群昼夜动力学，增强肠道屏障完整性，并使SCFA的昼夜模式正常化，从而恢复高脂饮食引起的小鼠认知功能昼夜波动紊乱，改善海马区神经可塑性基因和神经炎症标志物的昼夜节律振荡 127。
4.1.2 高脂高糖饮食：诱发肠道屏障损伤，损害脑功能
与高纤维饮食相反，长期摄入高脂高糖饮食（Western Diet）会导致肠道菌群失调，肠道屏障功能受损，并诱发全身性和神经炎症，进而对脑功能产生负面影响 128129：
- 肠道菌群失调：高脂饮食（HFD）常导致肠道菌群多样性降低，某些有益菌数量减少，而促炎细菌增多 129。这种菌群失调与肥胖相关的认知能力下降密切相关 130。
- 肠道屏障损伤：HFD会导致肠道通透性增加（“肠漏”），使得细菌内毒素LPS等有害物质更容易进入血液循环。LPS激活免疫系统，导致慢性低度炎症，并可能穿过血脑屏障，直接作用于大脑，引发神经炎症 129131。
- 神经炎症与认知障碍：HFD诱导的肠道菌群失调和肠道屏障损伤，是导致神经炎症和认知功能障碍的重要原因。例如，一项研究表明，高脂饮食可以诱发小鼠的抑郁样行为和认知损伤，而这种影响与肠道菌群的改变、肠道屏障功能受损以及脑内神经炎症密切相关 132133。研究也观察到石刁柏提取物能通过调节肠道菌群、修复肠道屏障和减轻神经炎症来改善高脂饮食诱导的认知障碍 127。
- 精神心理障碍：肥胖诱发的抑郁症也与肠道菌群-脑轴有关，高脂饮食可以导致肥胖并引发抑郁样行为。研究发现，淫羊藿苷II（Icariside II）能够通过调节肠道菌群、增加SCFA、缓解肠道屏障损伤和全身性炎症，以及减轻神经炎症和血脑屏障损伤，从而改善高脂饮食诱导的抑郁症 132。此外，远红外线疗法也被发现能通过改善肠道通透性、血脑屏障完整性，并减少炎症反应，来缓解高脂饮食引起的焦虑样行为 131。
- 认知下降与微胶质细胞功能：肥胖相关的认知能力下降与肠道菌群失调有关。研究发现，生酮饮食和隔日禁食等饮食干预能改善肥胖个体的认知表现，其中隔日禁食在改善认知方面效果最显著，这与肠道菌群的改变、炎症减轻以及增强的微胶质细胞吞噬能力有关 130。
4.1.3 饮食干预的潜在价值
综合来看，饮食干预在调节肠道-脑轴功能方面具有巨大的潜力。
- 优化膳食结构：增加膳食纤维摄入，减少高脂高糖食物，可以促进有益菌生长，增加SCFA产生，维护肠道屏障，并减轻全身和神经炎症，从而改善情绪和认知功能。
- 多样化饮食模式：考虑到不同饮食模式对肠道菌群和神经疾病的差异影响，未来的研究可能会进一步探索各种饮食干预策略。例如，地中海饮食和素食饮食因其抗炎特性，在帕金森病等神经炎症相关疾病中显示出潜力 128。
通过调整饮食模式，我们可以积极地塑造肠道菌群，从而对肠道-脑轴产生正向影响，这为预防和治疗多种神经精神及代谢性疾病提供了重要的策略 128。
4.2 压力与应激：肠道-脑轴的“双向应激反应”
压力（Stress）是现代社会中普遍存在的现象，长期或慢性的心理应激不仅影响个体的心理健康，更通过肠道-脑轴（Gut-Brain Axis）对肠道功能产生深远影响，反之，肠道功能紊乱也能通过神经信号反馈增强中枢应激反应，构成一个复杂的“双向应激反应”环路 64134135。
4.2.1 慢性压力对肠道-脑轴的影响
长期的心理应激事件会通过多种途径对肠道和肠道菌群造成负面影响，并增加罹患心理疾病（如焦虑和抑郁）的风险 64。
- HPA轴的激活与肠道通透性增加：下丘脑-垂体-肾上腺（HPA）轴是机体应对应激的主要内分泌系统。当感受到压力时，下丘脑释放促肾上腺皮质激素释放因子（CRF），刺激垂体分泌促肾上腺皮质激素（ACTH），进而促使肾上腺皮质释放皮质醇等糖皮质激素 64。这些应激激素能够直接影响肠道，导致：
- 肠道神经系统（ENS）功能紊乱：应激可以直接影响ENS，导致肠道动力、分泌和感觉功能的异常。CRF能够扰乱胃肠系统，并导致肠道微生物群失调，从而增加功能性胃肠疾病的风险 64。CRF甚至会影响肠道干细胞（ISC）的分化，导致肠嗜铬细胞分泌过量的5-羟色胺（5-HT）64。5-HT的过度释放可能导致肠道蠕动异常和内脏敏感性增高，进一步加剧肠道不适感。
- 免疫反应与炎症：压力诱导的CRF还会增加肠道的氧化损伤，并触发涉及肥大细胞、中性粒细胞和单核细胞的免疫反应 64。这些炎症介质的释放不仅直接损害肠道，其产生的细胞因子（如IL-6、TNF-α）也能通过血液循环或迷走神经进入大脑，激活脑内小胶质细胞，引起神经炎症，进而导致焦虑和抑郁等行为改变 64135。已有研究证实，应激对胃肠道粘膜免疫的激活以及肠道通透性的改变在IBS患者中尤其明显 135。
- 加剧焦虑/抑郁行为：肠道菌群失调和肠道炎症通过多种途径（如神经炎症、神经递质代谢改变）影响中枢神经系统，从而加剧或诱发焦虑和抑郁症状。例如，肠道微生物群可以调节CRF、5-HT、多巴胺和去甲肾上腺素等激素和神经递质的合成 64。
4.2.2 肠道功能紊乱对中枢应激反应的反馈
“双向应激反应”的另一方面体现在肠道功能紊乱（如便秘、肠易激综合征）能够反过来通过神经信号反馈增强中枢应激反应，形成恶性循环。
- 迷走神经介导的信号传递：肠道不适、疼痛或炎症信号可以通过迷走传入神经（Vagal afferent nerves）将信息传递至大脑。这些信号在大脑中被解释为不适或威胁，从而激活HPA轴，增强应激反应 135136。
- 肠道微生物群的直接影响：肠道菌群及其代谢产物可以直接影响宿主的应激反应。研究表明，在应激和抑郁的病理生理学中，肠道微生物群与大脑之间的双向相互作用（即微生物-肠-脑轴）发挥着重要作用 134。某些微生物代谢产物，如短链脂肪酸（SCFAs），能够调节应激反应。例如，一些NOD样受体（NLRs）——一种在肠道和大脑中表达的先天免疫模式识别受体——被发现是肠道-脑信号传导的新型调节因子。Nod1在肠上皮细胞中的缺失会增加应激诱导的焦虑样行为和认知障碍的易感性 137。
- 心理影响：持续的肠道不适和症状（如慢性便秘或腹泻、腹痛）会给患者带来巨大的心理负担，导致焦虑、抑郁、睡眠障碍等，这些心理因素本身就是强大的应激源，从而进一步激活HPA轴，加重应激反应 134138。例如，炎症性肠病（IBD）患者比健康个体更有可能发展出焦虑和抑郁症状，心理应激被认为是诱发IBD恶化和复发的重要因素，这进一步表明肠道炎症与精神心理障碍的“双向应激反应” 138。
综上所述，压力与应激通过HPA轴、肠道菌群、肠道屏障功能和免疫系统对肠道-脑轴产生复杂的负面影响，导致肠道功能紊乱和神经精神障碍。同时，肠道功能紊乱也能反过来加剧中枢应激反应，形成一个相互作用、相互影响的恶性循环。理解这种“双向应激反应”机制对于开发基于肠道-脑轴的综合性干预策略，以应对压力相关疾病至关重要 64。
4.3 药物与微生物干预的双向调节
肠道-脑轴的功能受到多种外部因素的影响，其中药物，特别是抗生素和阿片类药物，以及基于微生物的干预措施，如益生菌和粪菌移植，都能对肠道微生物群和脑功能产生显著的双向调节作用。理解这些作用机制对于优化临床治疗和开发新型干预策略至关重要。
4.3.1 抗生素：破坏菌群平衡，影响肠道-脑轴
抗生素是广泛使用的抗菌药物，但其广谱性常常导致肠道微生物群（gut microbiota）的破坏，进而对肠道-脑轴产生负面影响。
- 菌群失衡（Dysbiosis）：抗生素通过杀死或抑制细菌生长，不仅针对病原菌，也对肠道内的有益菌群造成打击，导致肠道菌群多样性下降，组成失衡。这种失衡可能持续数周甚至数月 139。菌群失调是导致功能性胃肠病的重要因素，抗生素引起的菌群失调是肠道感染后肠易激综合征发生的重要因素 140。
- 肠道屏障损伤：菌群失衡会削弱肠道屏障功能，增加肠道通透性，使得细菌产物（如脂多糖LPS）更容易进入血液循环，引发全身性炎症，甚至影响血脑屏障的完整性，从而诱发神经炎症 140。
- 神经递质代谢改变：肠道菌群在神经递质代谢中发挥关键作用，抗生素介导的菌群失调可能影响5-HT、GABA等神经递质的产生和平衡，进而影响情绪、认知和行为。例如，长期抗生素治疗的小鼠表现出焦虑样行为和学习记忆障碍，且大脑中BDNF（脑源性神经营养因子）水平下降 141。
- 神经精神疾病风险：抗生素对肠道菌群的影响可能增加神经精神疾病的风险。有研究提出，抗生素诱导的菌群改变与阿尔茨海默病（AD）的发生发展有关 93139142。抗生素在AD中的作用是复杂且可能双向的，需要进一步研究 139。
4.3.2 阿片类药物：抑制肠道神经系统胆碱能神经，影响肠道功能
阿片类药物是强效镇痛剂，但其副作用也包括对肠道功能的显著影响。
- 肠道动力抑制：阿片受体广泛分布于胃肠道，尤其是肠道神经系统（ENS）中的胆碱能神经元。阿片类药物通过激活这些受体，抑制乙酰胆碱的释放，从而减缓肠道蠕动，导致阿片类药物引起的便秘（OIC）143。
- 菌群改变：长期使用阿片类药物还会导致肠道菌群的改变，可能加剧肠道功能的紊乱，甚至影响肠道屏障功能 144。这种菌群改变也可能影响疼痛感知，并与阿片类药物耐受性有关 144。
- 疼痛与肠道-脑轴：阿片类药物通过抑制ENS的胆碱能神经，影响肠道动力，同时也会影响肠道-脑轴的疼痛信号传导。肠道菌群失调与慢性疼痛（包括内脏痛、炎症痛和神经性痛）的发生发展密切相关，阿片类药物的使用可能通过影响菌群来进一步调节疼痛感知 144。
4.3.3 益生菌与粪菌移植：修复菌群，改善脑功能
鉴于肠道菌群在肠道-脑轴中的核心作用，通过微生物干预来修复菌群平衡、改善脑功能已成为研究热点。
- 益生菌：益生菌是活的微生物，当摄入足够数量时，能对宿主健康产生益处。它们通过多种机制调节肠道-脑轴：
- 重建菌群平衡：益生菌可以增加肠道有益菌（如双歧杆菌、乳酸杆菌）的丰度，抑制有害菌的生长，恢复菌群多样性 145。
- 调节神经递质：某些益生菌可以直接产生GABA等神经递质，或影响宿主神经递质前体的代谢，如色氨酸向5-HT的转化，从而改善情绪和认知 120146。
- 减少炎症和氧化应激：益生菌可以增强肠道屏障功能，减少LPS等有害物质的易位，降低全身性和神经炎症，并具有抗氧化作用 145。
- 改善认知和情绪：多项研究表明益生菌可以改善认知功能和情绪障碍。例如，一项随机、双盲、安慰剂对照研究发现，补充两歧双歧杆菌BGN4和长双歧杆菌BORI的益生菌12周后，健康老年人的心理灵活性和压力评分显著改善，血脑源性神经营养因子（BDNF）水平增加，并且炎症相关的肠道细菌丰度显著降低 145。益生菌也被证明能有效改善抑郁症和焦虑症症状 146147148。
- 粪菌移植（FMT）：FMT是将健康供体的粪便微生物群转移到患者胃肠道内，以重建受者肠道菌群的干预方法。FMT被认为是治疗难辨梭菌感染（CDI）的有效方法，并在其他疾病中展现出潜力 149。
- 重建完整菌群生态：FMT能够引入更完整、多样化的微生物群落，相较于单一或少数菌株的益生菌，FMT在重建肠道微生态方面可能更具优势 148。
- 治疗神经精神疾病：FMT在治疗抑郁症、帕金森病（PD）等神经精神疾病方面显示出初步的积极效果 120148150。粪菌移植研究表明，帕金森病患者的肠道菌群与健康人群存在差异，这些差异可能与疾病的进展和症状有关 150。FMT也被提议作为阿尔茨海默病（AD）等神经退行性疾病的潜在治疗方法 93142。
- 酒精成瘾：有研究表明，FMT通过增加肠道有益菌（如双歧杆菌和乳杆菌），可以改善酒精性肝病患者的肝功能指标，并对焦虑和抑郁症状产生有益的精神作用 151。
- 前景与挑战：尽管FMT展现出巨大潜力，但其长期疗效、安全性以及标准化的菌群选择仍需进一步深入研究 149。
综上所述，药物（如抗生素和阿片类药物）对肠道菌群的负面影响突显了其对肠道-脑轴的潜在风险。与此同时，以益生菌和粪菌移植为代表的微生物干预措施，通过修复菌群平衡、调节代谢、免疫和神经递质系统，为改善脑功能和治疗多种神经精神疾病提供了新的希望和策略 147152。
5. “第二大脑”概念的科学意义与研究展望
5.1 概念的科学性与局限性
“肠道是人的第二个大脑”这一说法形象地概括了肠道神经系统（ENS）在人体生理功能中的独特地位和重要性。从科学角度来看，这个概念既有其深刻的内涵和科学基础，也存在一定的局限性。
5.1.1 ENS的“类脑”特性与科学内涵
ENS被誉为“第二个大脑”主要基于其在解剖、生理和生化层面的诸多“类脑”特性：
- 自主调控能力：ENS最显著的特征是其高度的自主性。它拥有完整的反射回路，包括感觉神经元、中间神经元和运动神经元，能够独立感知肠道内部环境变化（如机械拉伸、化学刺激），处理信息，并自主调导肠道运动（蠕动、分节运动）、分泌消化液、吸收营养以及调节局部血流，而无需中枢神经系统（CNS）的直接指令 153。这种独立性使其能够应对局部需求，维持肠道稳态。
- 神经元数量与复杂性：ENS包含约2亿至6亿个神经元，数量远超脊髓，仅次于大脑。这些神经元以高度复杂的方式组织成肌间神经丛和黏膜下神经丛，形成庞大的神经网络 153。神经元的多样性，包括兴奋性和抑制性神经元，以及它们之间的复杂连接，使得ENS能够执行精细的调节功能。
- 神经递质合成与利用：ENS能够合成并释放多种神经递质，其中一些与CNS中的神经递质相同。例如，GABA在脑-肠-微生物轴中扮演重要角色，肠道微生物可能通过影响神经递质水平来影响肠道和大脑之间的交流 154。肠道微生物也可能通过影响5-HT等神经递质水平来影响肠道和大脑之间的交流 4。这些神经递质在调节肠道功能、感知、情绪和行为中发挥着关键作用。
- 胶质细胞支持：ENS中存在肠胶质细胞（enteric glial cells），它们在功能上类似于CNS中的星形胶质细胞，为神经元提供支持、营养和保护，参与维持肠道屏障功能，并在肠道损伤和炎症中发挥作用 155。肠胶质细胞在帕金森病等神经退行性疾病的发生发展中也起到重要作用 155。
- 共同的发育起源：ENS的神经元起源于神经嵴细胞，与CNS的神经元在胚胎发育上具有共同的起源，这进一步凸显了两者之间的内在联系。
- 神经可塑性：ENS的神经元具有一定的可塑性，能够适应肠道内环境的变化，并且其结构和功能受到饮食等多种因素的调控 156。
5.1.2 概念的局限性与科学边界
尽管ENS具有诸多“类脑”特性，但将其称为“第二个大脑”更多是一种形象的比喻，而非严格意义上的科学定义。其局限性主要体现在：
- 依赖性：ENS并非完全独立于CNS。它与CNS之间存在着密切的双向通信，即“肠-脑轴” 157158。迷走神经是主要的神经桥梁，将肠道信息上传至大脑，同时也将大脑指令下达至肠道 4159。这意味着ENS的功能在很大程度上受到CNS的调控，特别是在情绪、应激反应和高级认知功能方面。肠道运动的正常恢复需要肠道微生物在断奶期早期发挥关键作用，说明肠道微生物群在ENS发育的敏感期起着决定性作用 160。
- 缺乏高级认知功能：ENS不具备意识、思想、决策、记忆或情感体验等高级认知功能。它主要负责局部反射弧和调节肠道基础生理活动，而心理和行为的复杂性仍然由CNS主导。
- 微生物群的调控：肠道菌群在肠道-脑轴中扮演着核心角色，通过其代谢产物（如短链脂肪酸、神经递质前体）对ENS和CNS产生深远影响 154161。这意味着ENS的功能并非完全由其自身决定，而是受到其所处的微生物环境的强烈影响。因此，肠道微生物在肠道-脑轴中扮演着重要的调控者角色 162。
- 病理过程的复杂性：在许多疾病中，肠道-脑轴的失调是复杂的病理过程，涉及神经、免疫、内分泌和微生物多重因素的协同作用 159。简单地将ENS比作“第二个大脑”可能会忽略其与其他系统之间的复杂交互。例如，糖尿病胃肠道自主神经病变（DGAN）的复杂病理生理学涉及神经损伤与肠道菌群失调的内在联系 163。
总结
“肠道是人的第二个大脑”这一概念强调了ENS的独立性、复杂性和在维持生理功能方面的重要性，并促使人们重新审视肠道在全身健康，特别是神经精神健康中的作用 164165。它成功地引起了公众对肠道健康的关注，并推动了肠道-脑轴研究的飞速发展。然而，我们必须认识到，这个比喻的科学内涵主要聚焦于ENS的自主调节能力和与CNS的结构功能相似性，但其不具备高级认知功能，且其功能受到CNS和肠道微生物群的显著调控。因此，在理解和应用这一概念时，应明确其比喻意义与科学边界，以避免过度解读或产生误解。
5.2 未来研究方向与应用潜力
“肠道是人的第二个大脑”这一概念的提出，极大地拓展了我们对生命科学的理解，并为未来研究指明了方向。深入解析肠道-脑轴的复杂机制，不仅具有重要的理论意义，也蕴含着巨大的临床应用潜力，特别是在神经精神疾病的防治领域。
5.2.1 需深入解析的关键问题
尽管肠道-脑轴研究已取得显著进展，但仍有许多关键科学问题亟待解决：
- ENS与CNS的发育协同机制：
- 发育起源与信号通路：虽然已知ENS和CNS的神经元都来源于神经嵴细胞，但两者在胚胎发育过程中如何协同演进、相互影响的分子和细胞机制尚不完全清楚。特别是，肠道微生物群在ENS和CNS早期发育中的确切作用，以及其在神经回路建立和功能完善中的关键时期和影响方式，仍需深入探讨。
- 早期生命阶段的干预窗口：理解ENS和CNS发育的协同机制，有助于识别关键的干预窗口，从而通过靶向肠道或大脑的早期干预，预防或减轻神经发育障碍的发生。
- 菌群代谢物的脑靶向作用及其分子机制：
- 代谢物的精确鉴定与功能解析：肠道菌群能产生数以千计的代谢物，目前仅少数代谢物被明确其对大脑的作用。未来需要更精确地鉴定这些具有神经活性的代谢物，阐明它们如何穿过肠道屏障和血脑屏障，以及在脑内与哪些受体或信号通路结合，从而影响神经元功能、神经递质平衡和神经炎症。
- 多组学整合研究：结合宏基因组学、代谢组学、蛋白质组学和转录组学等多组学技术，系统性地描绘肠道菌群、宿主代谢与脑功能之间的动态关系。例如，需要深入探究色氨酸、短链脂肪酸以及其他新型神经活性分子（如微生物源的神经肽、类激素物质）如何影响大脑皮层、海马、杏仁核等特定脑区的结构和功能。
- 时间和剂量效应：不同的菌群代谢物，在不同的浓度和作用时间下，对大脑的影响可能存在显著差异。需要精细化研究这些代谢物的时空动态及其剂量-反应关系。
- 肠道-脑轴的性别特异性差异：
- 生理和病理表现：越来越多的证据表明，肠道-脑轴的功能及其在疾病中的作用存在显著的性别差异。例如，许多神经精神疾病（如抑郁症、肠易激综合征）在女性中更为普遍，而另一些疾病（如帕金森病）则在男性中多见。未来研究需要更系统地探索这些性别差异的生物学基础，包括性激素、基因、微生物群组成和免疫反应等因素的影响。
- 个性化干预策略：揭示性别差异有助于开发针对不同性别患者的个性化诊断和治疗策略。
- 肠道-脑轴在健康衰老中的作用：
- 衰老与菌群变化：随着年龄增长，肠道菌群组成和多样性发生变化，肠道屏障功能可能受损，这些变化如何影响老年人的认知功能、情绪和神经系统健康，是亟待解决的问题。
- 长寿与肠道健康：探索长寿人群的肠道菌群特征，以及这些特征如何促进健康衰老和预防神经退行性疾病，可能为抗衰老策略提供新的思路。
5.2.2 基于肠道-脑轴的精准干预策略前景
对肠道-脑轴机制的深入理解，将为多种神经精神疾病的防治提供创新性策略：
- 代谢物靶向药物开发：
- 小分子模拟物或抑制剂：基于对菌群代谢物作用机制的理解，开发能够模拟有益代谢物作用或抑制有害代谢物生成和作用的小分子药物。例如，针对丁酸、丙酸等短链脂肪酸的受体激动剂，或针对犬尿氨酸途径关键酶的抑制剂，可能用于治疗抑郁症、帕金森病等疾病。
- 药物递送系统：开发能够精确靶向肠道或大脑的药物递送系统，提高治疗效果并减少副作用。
- 个性化饮食方案：
- 基于菌群特征的精准营养：通过对个体肠道菌群的分析（如宏基因组测序），结合个体的基因背景和健康状况，设计个性化的饮食方案。例如，针对性地补充益生元（膳食纤维），促进特定有益菌的生长和神经活性代谢物的产生，或调整饮食结构以减少有害菌及其代谢产物。这种“精准营养”策略有望优化肠道-脑轴功能，改善认知、情绪和行为。
- 功能性食品与益生菌/益生元补充：开发含有特定菌株或益生元的食品，作为辅助治疗或健康管理手段。例如，针对阿尔茨海默病患者，可以开发能够通过调节炎症过程、对抗氧化应激和改变肠道菌群来减缓疾病进展的益生菌产品 166。
- 新型微生物疗法：
- 早期诊断与预警生物标志物：
- 菌群指纹与代谢谱：通过分析肠道菌群的特定“指纹”或血清/粪便中的代谢物谱，识别神经精神疾病的早期风险人群，实现疾病的早期诊断和干预。
- 多模态融合：结合肠道菌群、代谢物、神经影像学、遗传学和临床表现等多模态数据，构建更全面的风险评估模型。
总而言之，对“肠道是人的第二个大脑”的深入理解，正推动着神经科学和胃肠病学领域迎来一场革命。未来的研究将聚焦于阐明肠道-脑轴更精细的分子、细胞和系统层面的互作机制，并在此基础上开发出更具靶向性、个性化和高效的诊断与治疗策略，从而有效应对神经精神疾病带来的全球性挑战。
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参考文献
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Jonathan I Lake, Robert O Heuckeroth
Am J Physiol Gastrointest Liver Physiol. 2013 Jul 1;305(1):G1-24. doi: 10.1152/ajpgi.00452.2012. Epub 2013 May 2.
The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system, consisting of two layers of ganglia and fibers encircling the gastrointestinal tract. The ENS is vital for life and is capable of autonomous regulation of motility and secretion. Developmental studies in model organisms and genetic studies of the most common congenital disease of the ENS, Hirschsprung disease, have provided a detailed understanding of ENS development. The ENS originates in the neural crest, mostly from the vagal levels of the neuraxis, which invades, proliferates, and migrates within the intestinal wall until the entire bowel is colonized with enteric neural crest-derived cells (ENCDCs). After initial migration, the ENS develops further by responding to guidance factors and morphogens that pattern the bowel concentrically, differentiating into glia and neuronal subtypes and wiring together to form a functional nervous system. Molecules controlling this process, including glial cell line-derived neurotrophic factor and its receptor RET, endothelin (ET)-3 and its receptor endothelin receptor type B, and transcription factors such as SOX10 and PHOX2B, are required for ENS development in humans. Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting. Recent work also focuses on disease treatment by exploring the natural role of ENS stem cells and investigating potential therapeutic uses. Disease prevention may also be possible by modifying the fetal microenvironment to reduce the penetrance of Hirschsprung disease-causing mutations.
2The enteric nervous system.PubMed
Keith A Sharkey, Gary M Mawe
Physiol Rev. 2023 Apr 1;103(2):1487-1564. doi: 10.1152/physrev.00018.2022. Epub 2022 Dec 15.
Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss ) the intrinsic neural control of gut functions involved in digestion and ) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.
3Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System.PubMed
Erica A Wehrwein, Hakan S Orer, Susan M Barman
Compr Physiol. 2016 Jun 13;6(3):1239-78. doi: 10.1002/cphy.c150037.
Comprised of the sympathetic nervous system, parasympathetic nervous system, and enteric nervous system, the autonomic nervous system (ANS) provides the neural control of all parts of the body except for skeletal muscles. The ANS has the major responsibility to ensure that the physiological integrity of cells, tissues, and organs throughout the entire body is maintained (homeostasis) in the face of perturbations exerted by both the external and internal environments. Many commonly prescribed drugs, over-the-counter drugs, toxins, and toxicants function by altering transmission within the ANS. Autonomic dysfunction is a signature of many neurological diseases or disorders. Despite the physiological relevance of the ANS, most neuroscience textbooks offer very limited coverage of this portion of the nervous system. This review article provides both historical and current information about the anatomy, physiology, and pharmacology of the sympathetic and parasympathetic divisions of the ANS. The ultimate aim is for this article to be a valuable resource for those interested in learning the basics of these two components of the ANS and to appreciate its importance in both health and disease. Other resources should be consulted for a thorough understanding of the third division of the ANS, the enteric nervous system. © 2016 American Physiological Society. Compr Physiol 6:1239-1278, 2016.
4The gut, its microbiome, and the brain: connections and communications.PubMed
Michael D Gershon, Kara Gross Margolis
J Clin Invest. 2021 Sep 15;131(18). doi: 10.1172/JCI143768.
Modern research on gastrointestinal behavior has revealed it to be a highly complex bidirectional process in which the gut sends signals to the brain, via spinal and vagal visceral afferent pathways, and receives sympathetic and parasympathetic inputs. Concomitantly, the enteric nervous system within the bowel, which contains intrinsic primary afferent neurons, interneurons, and motor neurons, also senses the enteric environment and controls the detailed patterns of intestinal motility and secretion. The vast microbiome that is resident within the enteric lumen is yet another contributor, not only to gut behavior, but to the bidirectional signaling process, so that the existence of a microbiota-gut-brain "connectome" has become apparent. The interaction between the microbiota, the bowel, and the brain now appears to be neither a top-down nor a bottom-up process. Instead, it is an ongoing, tripartite conversation, the outline of which is beginning to emerge and is the subject of this Review. We emphasize aspects of the exponentially increasing knowledge of the microbiota-gut-brain "connectome" and focus attention on the roles that serotonin, Toll-like receptors, and macrophages play in signaling as exemplars of potentially generalizable mechanisms.
5Enteric Glia.PubMed
Meenakshi Rao, Brian D Gulbransen
Cold Spring Harb Perspect Biol. 2025 Apr 1;17(4):a041368. doi: 10.1101/cshperspect.a041368.
Enteric glia are a unique type of peripheral neuroglia that accompany neurons in the enteric nervous system (ENS) of the digestive tract. The ENS displays integrative neural circuits that are capable of governing moment-to-moment gut functions independent of input from the central nervous system. Enteric glia are interspersed with neurons throughout these intrinsic gut neural circuits and are thought to fulfill complex roles directed at maintaining homeostasis in the neuronal microenvironment and at neuroeffector junctions in the gut. Changes to glial functions contribute to a wide range of gastrointestinal diseases, but the precise roles of enteric glia in gut physiology and pathophysiology are still under examination. This review summarizes current concepts regarding enteric glial development, diversity, and functions in health and disease.
6Gut Microbiota-brain Axis.PubMed
Hong-Xing Wang, Yu-Ping Wang
Chin Med J (Engl). 2016 Oct 5;129(19):2373-80. doi: 10.4103/0366-6999.190667.
OBJECTIVE: To systematically review the updated information about the gut microbiota-brain axis. DATA SOURCES: All articles about gut microbiota-brain axis published up to July 18, 2016, were identified through a literature search on PubMed, ScienceDirect, and Web of Science, with the keywords of "gut microbiota", "gut-brain axis", and "neuroscience". STUDY SELECTION: All relevant articles on gut microbiota and gut-brain axis were included and carefully reviewed, with no limitation of study design. RESULTS: It is well-recognized that gut microbiota affects the brain's physiological, behavioral, and cognitive functions although its precise mechanism has not yet been fully understood. Gut microbiota-brain axis may include gut microbiota and their metabolic products, enteric nervous system, sympathetic and parasympathetic branches within the autonomic nervous system, neural-immune system, neuroendocrine system, and central nervous system. Moreover, there may be five communication routes between gut microbiota and brain, including the gut-brain's neural network, neuroendocrine-hypothalamic-pituitary-adrenal axis, gut immune system, some neurotransmitters and neural regulators synthesized by gut bacteria, and barrier paths including intestinal mucosal barrier and blood-brain barrier. The microbiome is used to define the composition and functional characteristics of gut microbiota, and metagenomics is an appropriate technique to characterize gut microbiota. CONCLUSIONS: Gut microbiota-brain axis refers to a bidirectional information network between the gut microbiota and the brain, which may provide a new way to protect the brain in the near future.
7The Gut-Brain Axis and the Microbiome: Mechanisms and Clinical Implications.PubMed
Vadim Osadchiy, Clair R Martin, Emeran A Mayer
Clin Gastroenterol Hepatol. 2019 Jan;17(2):322-332. doi: 10.1016/j.cgh.2018.10.002. Epub 2018 Oct 4.
BACKGROUND & AIMS: Based largely on results from preclinical studies, the concept of a brain gut microbiome axis has been established, mediating bidirectional communication between the gut, its microbiome, and the nervous system. Limited data obtained in human beings suggest that alterations in these interactions may play a role in several brain gut disorders. METHODS: We reviewed the preclinical and clinical literature related to the topic of brain gut microbiome interactions. RESULTS: Well-characterized bidirectional communication channels, involving neural, endocrine, and inflammatory mechanisms, exist between the gut and the brain. Communication through these channels may be modulated by variations in the permeability of the intestinal wall and the blood-brain barrier. Brain gut microbiome interactions are programmed during the first 3 years of life, including the prenatal period, but can be modulated by diet, medications, and stress throughout life. Based on correlational studies, alterations in these interactions have been implicated in the regulation of food intake, obesity, and in irritable bowel syndrome, even though causality remains to be established. CONCLUSIONS: Targets within the brain gut microbiome axis have the potential to become targets for novel drug development for brain gut disorders.
8Brain-gut-microbiome interactions in obesity and food addiction.PubMed
Arpana Gupta, Vadim Osadchiy, Emeran A Mayer
Nat Rev Gastroenterol Hepatol. 2020 Nov;17(11):655-672. doi: 10.1038/s41575-020-0341-5. Epub 2020 Aug 27.
Normal eating behaviour is coordinated by the tightly regulated balance between intestinal and extra-intestinal homeostatic and hedonic mechanisms. By contrast, food addiction is a complex, maladaptive eating behaviour that reflects alterations in brain-gut-microbiome (BGM) interactions and a shift of this balance towards hedonic mechanisms. Each component of the BGM axis has been implicated in the development of food addiction, with both brain to gut and gut to brain signalling playing a role. Early-life influences can prime the infant gut microbiome and brain for food addiction, which might be further reinforced by increased antibiotic usage and dietary patterns throughout adulthood. The ubiquitous availability and marketing of inexpensive, highly palatable and calorie-dense food can further shift this balance towards hedonic eating through both central (disruptions in dopaminergic signalling) and intestinal (vagal afferent function, metabolic endotoxaemia, systemic immune activation, changes to gut microbiome and metabolome) mechanisms. In this Review, we propose a systems biology model of BGM interactions, which incorporates published reports on food addiction, and provides novel insights into treatment targets aimed at each level of the BGM axis.
9The science of Hirschsprung disease: What we know and where we are headed.PubMed
Jessica L Mueller, Allan M Goldstein
Semin Pediatr Surg. 2022 Apr;31(2):151157. doi: 10.1016/j.sempedsurg.2022.151157. Epub 2022 Apr 18.
The enteric nervous system (ENS) is a rich network of neurons and glial cells that comprise the gastrointestinal tract's intrinsic nervous system and are responsible for controlling numerous complex functions, including digestion, transit, secretion, barrier function, and maintenance of a healthy microbiome. Development of a functional ENS relies on the coordinated interaction between enteric neural crest-derived cells and their environment as the neural crest-derived cells migrate rostrocaudally along the embryonic gut mesenchyme. Congenital or acquired disruption of ENS development leads to various neurointestinal diseases. Hirschsprung disease is a congenital neurocristopathy, a disease of the neural crest. It is characterized by a variable length of distal colonic aganglionosis due to a failure in enteric neural crest-derived cell proliferation, migration, differentiation, and/or survival. In this review, we will review the science of Hirschsprung disease, targeting an audience of pediatric surgeons. We will discuss the basic biology of normal ENS development, as well as what goes awry in ENS development in Hirschsprung disease. We will review animal models that have been integral to studying this disease, as well as current hot topics and future research, including genetic risk profiling, stem cell therapy, non-invasive diagnostic techniques, single-cell sequencing techniques, and genotype-phenotype correlation.
10SOX10: 20 years of phenotypic plurality and current understanding of its developmental function.PubMed
Veronique Pingault, Lisa Zerad, William Bertani-Torres, et al.
J Med Genet. 2022 Feb;59(2):105-114. doi: 10.1136/jmedgenet-2021-108105. Epub 2021 Oct 19.
SOX10 belongs to a family of 20 SRY (sex-determining region Y)-related high mobility group box-containing (SOX) proteins, most of which contribute to cell type specification and differentiation of various lineages. The first clue that SOX10 is essential for development, especially in the neural crest, came with the discovery that heterozygous mutations occurring within and around SOX10 cause Waardenburg syndrome type 4. Since then, heterozygous mutations have been reported in Waardenburg syndrome type 2 (Waardenburg syndrome type without Hirschsprung disease), PCWH or PCW (peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, with or without Hirschsprung disease), intestinal manifestations beyond Hirschsprung (ie, chronic intestinal pseudo-obstruction), Kallmann syndrome and cancer. All of these diseases are consistent with the regulatory role of SOX10 in various neural crest derivatives (melanocytes, the enteric nervous system, Schwann cells and olfactory ensheathing cells) and extraneural crest tissues (inner ear, oligodendrocytes). The recent evolution of medical practice in constitutional genetics has led to the identification of variants in atypical contexts, such as isolated hearing loss or neurodevelopmental disorders, making them more difficult to classify in the absence of both a typical phenotype and specific expertise. Here, we report novel mutations and review those that have already been published and their functional consequences, along with current understanding of SOX10 function in the affected cell types identified through in vivo and in vitro models. We also discuss research options to increase our understanding of the origin of the observed phenotypic variability and improve the diagnosis and medical care of affected patients.
11The enteric nervous system and gastrointestinal innervation: integrated local and central control.PubMed
John B Furness, Brid P Callaghan, Leni R Rivera, et al.
Adv Exp Med Biol. 2014;817:39-71. doi: 10.1007/978-1-4939-0897-4_3.
The digestive system is innervated through its connections with the central nervous system (CNS) and by the enteric nervous system (ENS) within the wall of the gastrointestinal tract. The ENS works in concert with CNS reflex and command centers and with neural pathways that pass through sympathetic ganglia to control digestive function. There is bidirectional information flow between the ENS and CNS and between the ENS and sympathetic prevertebral ganglia.The ENS in human contains 200-600 million neurons, distributed in many thousands of small ganglia, the great majority of which are found in two plexuses, the myenteric and submucosal plexuses. The myenteric plexus forms a continuous network that extends from the upper esophagus to the internal anal sphincter. Submucosal ganglia and connecting fiber bundles form plexuses in the small and large intestines, but not in the stomach and esophagus. The connections between the ENS and CNS are carried by the vagus and pelvic nerves and sympathetic pathways. Neurons also project from the ENS to prevertebral ganglia, the gallbladder, pancreas and trachea.The relative roles of the ENS and CNS differ considerably along the digestive tract. Movements of the striated muscle esophagus are determined by neural pattern generators in the CNS. Likewise the CNS has a major role in monitoring the state of the stomach and, in turn, controlling its contractile activity and acid secretion, through vago-vagal reflexes. In contrast, the ENS in the small intestine and colon contains full reflex circuits, including sensory neurons, interneurons and several classes of motor neuron, through which muscle activity, transmucosal fluid fluxes, local blood flow and other functions are controlled. The CNS has control of defecation, via the defecation centers in the lumbosacral spinal cord. The importance of the ENS is emphasized by the life-threatening effects of some ENS neuropathies. By contrast, removal of vagal or sympathetic connections with the gastrointestinal tract has minor effects on GI function. Voluntary control of defecation is exerted through pelvic connections, but cutting these connections is not life-threatening and other functions are little affected.
12Basics of autonomic nervous system function.PubMed
Christopher H Gibbons
Handb Clin Neurol. 2019;160:407-418. doi: 10.1016/B978-0-444-64032-1.00027-8.
The autonomic nervous system has widespread innervation to nearly every organ system in the body. In order to understand the basics of autonomic function, knowledge of the neuroanatomy of the autonomic nervous system is necessary. Frequently considered to control the "fight or flight" and "rest and digest" functions, the autonomic nervous system has an intricate network of connections to finely tune the systemic response to nearly any situation. Although traditionally considered two discrete systems (sympathetic and parasympathetic), the enteric nervous system is now considered a third component of the autonomic nervous system. This chapter reviews the background of the neuroanatomical distribution of the autonomic nervous system in order to facilitate understanding the basics of autonomic function.
13Quantitative analysis of enteric neurons containing choline acetyltransferase and nitric oxide synthase immunoreactivities in the submucosal and myenteric plexuses of the porcine colon.PubMed
Maurizio Mazzoni, Filippo Caremoli, Luis Cabanillas, et al.
Cell Tissue Res. 2021 Feb;383(2):645-654. doi: 10.1007/s00441-020-03286-7. Epub 2020 Sep 23.
The enteric nervous system (ENS) controls gastrointestinal functions. In large mammals' intestine, it comprises an inner (ISP) and outer (OSP) submucous plexus and a myenteric plexus (MP). This study quantifies enteric neurons in the ISP, OSP, and MP of the pig ascending (AC) and descending colon (DC) using the HuC/D, choline acetyltransferase (ChAT), and neuronal nitric oxide synthase (nNOS) neuronal markers in whole mount preparations with multiple labeling immunofluorescence. We established that the ISP contains the highest number of HuC/D neurons/mm, which were more abundant in AC vs. DC, followed by OSP and MP with similar density in AC and DC. In the ISP, the density of ChAT immunoreactive (IR) neurons was very similar in AC and DC (31% and 35%), nNOS-IR neurons were less abundant in AC than DC (15% vs. 42%, P < 0.001), and ChAT/nNOS-IR neurons were 5% and 10%, respectively. In the OSP, 39-44% of neurons were ChAT-IR in AC and DC, while 45% and 38% were nNOS-IR and 10-12% were ChAT/nNOS-IR (AC vs. DC P < 0.05). In the MP, ChAT-IR neurons were 44% in AC and 54% in DC (P < 0.05), nNOS-IR neurons were 50% in both, and ChAT/nNOS-IR neurons were 12 and 18%, respectively. The ENS architecture with multilayered submucosal plexuses and the distribution of functionally distinct groups of neurons in the pig colon are similar to humans, supporting the suitability of the pig as a model and providing the platform for investigating the mechanisms underlying human colonic diseases.
14Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility.PubMed
Nick J Spencer, Hongzhen Hu
Nat Rev Gastroenterol Hepatol. 2020 Jun;17(6):338-351. doi: 10.1038/s41575-020-0271-2. Epub 2020 Mar 9.
The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.
15Boundaries and integration between microbiota, the nervous system, and immunity.PubMed
Andrew J Macpherson, Vassilis Pachnis, Marco Prinz
Immunity. 2023 Aug 8;56(8):1712-1726. doi: 10.1016/j.immuni.2023.07.011.
The enteric nervous system is largely autonomous, and the central nervous system is compartmentalized behind the blood-brain barrier. Yet the intestinal microbiota shapes gut function, local and systemic immune responses, and central nervous system functions including cognition and mood. In this review, we address how the gut microbiota can profoundly influence neural and immune networks. Although many of the interactions between these three systems originate in the intestinal mucosa, intestinal function and immunity are modulated by neural pathways that connect the gut and brain. Furthermore, a subset of microbe-derived penetrant molecules enters the brain and regulates central nervous system function. Understanding how these seemingly isolated entities communicate has the potential to open up new avenues for therapies and interventions.
16Distribution and chemical coding of corticotropin-releasing factor-immunoreactive neurons in the guinea pig enteric nervous system.PubMed
Sumei Liu, Na Gao, Hong-Zhen Hu, et al.
J Comp Neurol. 2006 Jan 1;494(1):63-74. doi: 10.1002/cne.20781.
Immunofluorescence was used to study immunoreactivity (IR) for corticotropin-releasing factor (CRF) in the guinea pig enteric nervous system. CRF-IR was expressed in both the myenteric and the submucosal plexuses of all regions of the large and small intestine and the myenteric plexus of the stomach. CRF-IR nerve fibers were present in the myenteric and submucosal plexuses, in the circular muscle coat, and surrounding submucosal arterioles. Most of the CRF-IR fibers persisted in the myenteric and submucosal plexuses after 7 days in organotypic culture. CRF-IR was not coexpressed with tyrosine hydroxylase-IR or calcitonin gene-related peptide-IR fibers. The proportions of CRF-IR cell bodies in the myenteric plexus increased progressively from the stomach (0.6%) to the distal colon (2.8%). Most of the CRF-IR myenteric neurons (95%) had uniaxonal morphology; the remainder had Dogiel type II multipolar morphology. CRF-IR cell bodies in the myenteric plexus of the ileum expressed IR for choline acetyltransferase (56.9%), substance P (55.0%), and nitric oxide synthase (37.9%). CRF-IR never colocalized with IR for calbindin, calretinin, neuropeptide Y, serotonin, or somatostatin in the myenteric plexus. CRF-IR cell bodies were more abundant in the submucosal plexus (29.9-38.0%) than in the myenteric plexus. All CRF-IR neurons in submucosal ganglia expressed vasoactive intestinal peptide-IR and were likely to be secretomotor/vasodilator neurons. CRF-IR neurons did not express IR for the CRF(1) receptor. CRF(1)-IR was expressed in neuronal neighbors of those with CRF-IR. Collective evidence suggests that VIPergic secretomotor neurons might provide synaptic input to neighboring cholinergic neurons.
17Neurochemical characterization and distribution of enteric GABAergic neurons and nerve fibres in the human colon.PubMed
A Krantis, K Nichols, W Staines
J Auton Nerv Syst. 1998 Jan 19;68(1-2):33-42. doi: 10.1016/s0165-1838(97)00113-6.
GABA, somatostatin and enkephalin are neurotransmitters of enteric interneurons and comprise part of the intrinsic neural circuits regulating peristalsis. Within the relaxation phase of reflex peristalsis, nitric oxide (NO) is released by inhibitory motor neurons and perhaps enteric interneurons as well. Previously, we identified by GABA transaminase (GABA-T) immunohistochemistry, a subpopulation of GABAergic interneurons in the human colon which also contain NO synthase activity and hence produce NO. In this study, we have examined further the capacity for cotransmission within the GABAergic innervation in human colon. The expression of two important neuropeptides within GABAergic neurons was determined by combined double-labelled immunocytochemistry using antibodies for GABA-T, enkephalin and somatostatin, together with the demonstration of NO synthase-related NADPH diaphorase staining in cryosectioned colon. Both neuropeptides were found in GABAergic neurons of the colon. The evidence presented herein confirms the colocalization of NO synthase activity and GABA-T immunoreactivity in subpopulations of enteric neurons and further allows the neurochemical classification of GABAergic neurons of the human colon into three subsets: (i) neurons colocalizing somatostatin-like immunoreactivity representing about 40% of the GABAergic neurons, (ii) neurons colocalizing enkephalin-like immunoreactivity, about 9% of the GABAergic neurons and (iii) neurons colocalizing NO synthase activity, about 23% of the GABAergic neurons. This division of GABAergic interneurons into distinct subpopulations of neuropeptide or NO synthase containing cells is consistent with and provides an anatomical correlate for the pharmacology of these transmitters and the pattern of transmitter release during reflex peristalsis.
18The enteric nervous system and the musculature of the colon are altered in patients with spina bifida and spinal cord injury.PubMed
Marjanne den Braber-Ymker, Martin Lammens, Michel J A M van Putten, et al.
Virchows Arch. 2017 Feb;470(2):175-184. doi: 10.1007/s00428-016-2060-4. Epub 2017 Jan 6.
Neurogenic bowel dysfunction occurs in a large percentage of adult patients with spina bifida (SB) and spinal cord injury (SCI), significantly affecting their quality of life. Although bowel motility is autonomously regulated by the enteric nervous system (ENS), disruption of the modulation of the ENS by extrinsic innervation as present in many patients with SB and SCI might lead to motility disorders. In order to gain insight in the pathophysiology, we studied histological changes of the neuromuscular structures in the colon of SB and SCI patients. Archival colon tissue blocks from SB (n = 13) and SCI (n = 34) patients were collected nationwide in The Netherlands and compared with control samples (n = 16). Histological (semiquantitative) evaluation of the ENS, the network of interstitial cells of Cajal (ICC), and the muscularis propria was performed using hematoxylin and eosin, periodic acid Schiff, and elastic von Gieson staining, and immunohistochemistry with antibodies against HuC/D, calretinin, S100, CD117, α-smooth muscle actin, and desmin. Compared to controls, SB and SCI patients showed neuronal loss and decreased nerve fiber density in the myenteric plexus. Lower nerve fiber density was significantly more often found in patients with severe bowel dysfunction. Other major findings were loss of ICCs around the myenteric plexus and fibrosis in the longitudinal muscle layer. Altered histology of the ENS may explain abnormal intestinal motility in SB and SCI patients. Furthermore, loss of myenteric nerve fibers (including enteric glial cells) may play a major role in the development of severe motility complaints.
19Damage to the enteric nervous system in experimental colitis.PubMed
S Sanovic, D P Lamb, M G Blennerhassett
Am J Pathol. 1999 Oct;155(4):1051-7. doi: 10.1016/S0002-9440(10)65207-8.
Inflammation of the intestine causes pain and altered motility, at least in part through effects on the enteric nervous system. While these changes may be reversed with healing, permanent damage may contribute to inflammatory bowel disease (IBD) and post-enteritis irritable bowel syndrome. Since little information exists, we induced colitis in male Sprague-Dawley rats with dinitrobenzene sulfonic acid and used immunocytochemistry to examine the number and distribution of enteric neurons at times up to 35 days later. Inflammation caused significant neuronal loss in the inflamed region by 24 hours, with only 49% of neurons remaining by days 4 to 6 and thereafter, when inflammation had subsided. Eosinophils were found within the myenteric plexus at only at the earliest time points, despite a general infiltration of neutrophils into the muscle wall. While the number of myenteric ganglia remained constant, there was significant decrease in the number of ganglia in the submucosal plexus. Despite reduced neuronal number and hyperplasia of smooth muscle, the density of axons among the smooth muscle cells remained unchanged during and after inflammation. Intracolonic application of the topical steroid budesonide caused a dose-dependent prevention of neuronal loss, suggesting that evaluation of anti-inflammatory therapy in inflammatory bowel disease should include quantitative assessment of neural components.
20Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system.PubMed
Michael J Workman, Maxime M Mahe, Stephen Trisno, et al.
Nat Med. 2017 Jan;23(1):49-59. doi: 10.1038/nm.4233. Epub 2016 Nov 21.
The enteric nervous system (ENS) of the gastrointestinal tract controls many diverse functions, including motility and epithelial permeability. Perturbations in ENS development or function are common, yet there is no human model for studying ENS-intestinal biology and disease. We used a tissue-engineering approach with embryonic and induced pluripotent stem cells (PSCs) to generate human intestinal tissue containing a functional ENS. We recapitulated normal intestinal ENS development by combining human-PSC-derived neural crest cells (NCCs) and developing human intestinal organoids (HIOs). NCCs recombined with HIOs in vitro migrated into the mesenchyme, differentiated into neurons and glial cells and showed neuronal activity, as measured by rhythmic waves of calcium transients. ENS-containing HIOs grown in vivo formed neuroglial structures similar to a myenteric and submucosal plexus, had functional interstitial cells of Cajal and had an electromechanical coupling that regulated waves of propagating contraction. Finally, we used this system to investigate the cellular and molecular basis for Hirschsprung's disease caused by a mutation in the gene PHOX2B. This is, to the best of our knowledge, the first demonstration of human-PSC-derived intestinal tissue with a functional ENS and how this system can be used to study motility disorders of the human gastrointestinal tract.
22Irritable bowel syndrome: a model of the brain-gut interactions.PubMed
Agata Mulak, Bruno Bonaz
Med Sci Monit. 2004 Apr;10(4):RA55-62.
Brain-gut interactions are increasingly recognized as underlying pathomechanisms of functional gastrointestinal disorders. Bi-directional communication between the central nervous system (CNS) and the enteric nervous system (ENS) occurs both in health and disease. Various CNS- and gut-directed stressors stimulate the brain-gut axis. Processes modulating responsiveness to stressors along the brain-gut axis involve neural pathways, the immunological, and endocrinological mechanisms. Disturbances at every level of neural control of the gastrointestinal tract can affect modulation of gastrointestinal motility, secretion, immune functions as well as perception and emotional response to visceral events. ENS function, central processing, and autonomic regulation play an important role in the brain-gut dialogue. Stress and emotions may trigger neuroimmune and neuroendocrine reactions via the brain-gut axis. Various non-site specific neurotransmitters influence gastrointestinal, endocrine and immune function, as well as human behavior and emotional state, depending on their location. The physiology of the digestive tract, the subjective experience of symptom, health behavior, and treatment outcome are strongly affected by psychosocial factors. Recently, a biopsychosocial model of IBS containing physiological, emotional, cognitive and behavioral components has been proposed. Rapid progress in neurogastroenterology, using new brain imaging techniques, should bring better understanding of the brain-gut axis and open new therapeutic perspectives.
23[Brain-Gut-Microbiota Axis].PubMed
Ayoung Lee, Ju Yup Lee, Sung Won Jung, et al.
Korean J Gastroenterol. 2023 Apr 25;81(4):145-153. doi: 10.4166/kjg.2023.028.
Patients frequently report that stress causes or exacerbates gastrointestinal (GI) symptoms, indicating a functional relationship between the brain and the GI tract. The brain and GI tract are closely related embryologically and functionally, interacting in various ways. The concept of the brain-gut axis was originally established in the 19th and early 20th centuries based on physiological observations and experiments conducted in animals and humans. In recent years, with the growing recognition that gut microbiota plays a vital role in human health and disease, this concept has been expanded to the brain-gut-microbiota axis. The brain influences the motility, secretion, and immunity of the GI tract, with consequent effects on the composition and function of the gut microbiota. On the other hand, gut microbiota plays an essential role in the development and function of the brain and enteric nervous system. Although knowledge of the mechanisms through which the gut microbiota influences distant brain function is incomplete, studies have demonstrated communication between these organs through the neuronal, immune, and endocrine systems. The brain-gut-microbiota axis is an essential aspect of the pathophysiology of functional GI disorders such as irritable bowel syndrome, and is also involved in other GI diseases, including inflammatory bowel disease. This review summarizes the evolving concept of the brain-gut-microbiota axis and its implications for GI diseases, providing clinicians with new knowledge to apply in clinical practice.
24Vagal neurocircuitry and its influence on gastric motility.PubMed
R Alberto Travagli, Laura Anselmi
Nat Rev Gastroenterol Hepatol. 2016 Jul;13(7):389-401. doi: 10.1038/nrgastro.2016.76. Epub 2016 May 25.
A large body of research has been dedicated to the effects of gastrointestinal peptides on vagal afferent fibres, yet multiple lines of evidence indicate that gastrointestinal peptides also modulate brainstem vagal neurocircuitry, and that this modulation has a fundamental role in the physiology and pathophysiology of the upper gastrointestinal tract. In fact, brainstem vagovagal neurocircuits comprise highly plastic neurons and synapses connecting afferent vagal fibres, second order neurons of the nucleus tractus solitarius (NTS), and efferent fibres originating in the dorsal motor nucleus of the vagus (DMV). Neuronal communication between the NTS and DMV is regulated by the presence of a variety of inputs, both from within the brainstem itself as well as from higher centres, which utilize an array of neurotransmitters and neuromodulators. Because of the circumventricular nature of these brainstem areas, circulating hormones can also modulate the vagal output to the upper gastrointestinal tract. This Review summarizes the organization and function of vagovagal reflex control of the upper gastrointestinal tract, presents data on the plasticity within these neurocircuits after stress, and discusses the gastrointestinal dysfunctions observed in Parkinson disease as examples of physiological adjustment and maladaptation of these reflexes.
25Role of the gut-brain axis in energy and glucose metabolism.PubMed
Hallie R Wachsmuth, Savanna N Weninger, Frank A Duca
Exp Mol Med. 2022 Apr;54(4):377-392. doi: 10.1038/s12276-021-00677-w. Epub 2022 Apr 26.
The gastrointestinal tract plays a role in the development and treatment of metabolic diseases. During a meal, the gut provides crucial information to the brain regarding incoming nutrients to allow proper maintenance of energy and glucose homeostasis. This gut-brain communication is regulated by various peptides or hormones that are secreted from the gut in response to nutrients; these signaling molecules can enter the circulation and act directly on the brain, or they can act indirectly via paracrine action on local vagal and spinal afferent neurons that innervate the gut. In addition, the enteric nervous system can act as a relay from the gut to the brain. The current review will outline the different gut-brain signaling mechanisms that contribute to metabolic homeostasis, highlighting the recent advances in understanding these complex hormonal and neural pathways. Furthermore, the impact of the gut microbiota on various components of the gut-brain axis that regulates energy and glucose homeostasis will be discussed. A better understanding of the gut-brain axis and its complex relationship with the gut microbiome is crucial for the development of successful pharmacological therapies to combat obesity and diabetes.
26Neuroanatomy of visceral nociception: vagal and splanchnic afferent.PubMed
D Grundy
Gut. 2002 Jul;51 Suppl 1(Suppl 1):i2-5. doi: 10.1136/gut.51.suppl_1.i2.
Afferent fibres convey sensory information from the upper gastrointestinal tract to the central nervous system but the nature of this information is different for vagal and spinal pathways. Vagal afferents convey predominantly physiological information while spinal afferents are able to encode noxious events. Because of the different response profiles following activation of these pathways, it is likely that vagal and splanchnic afferents play different roles in mediating sensation.
27Neuropod Cells: The Emerging Biology of Gut-Brain Sensory Transduction.PubMed
Melanie Maya Kaelberer, Laura E Rupprecht, Winston W Liu, et al.
Annu Rev Neurosci. 2020 Jul 8;43:337-353. doi: 10.1146/annurev-neuro-091619-022657. Epub 2020 Feb 26.
Guided by sight, scent, texture, and taste, animals ingest food. Once ingested, it is up to the gut to make sense of the food's nutritional value. Classic sensory systems rely on neuroepithelial circuits to convert stimuli into signals that guide behavior. However, sensation of the gut milieu was thought to be mediated only by the passive release of hormones until the discovery of synapses in enteroendocrine cells. These are gut sensory epithelial cells, and those that form synapses are referred to as neuropod cells. Neuropod cells provide the foundation for the gut to transduce sensory signals from the intestinal milieu to the brain through fast neurotransmission onto neurons, including those of the vagus nerve. These findings have sparked a new field of exploration in sensory neurobiology-that of gut-brain sensory transduction.
28Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism.PubMed
Diba Borgmann, Elisa Ciglieri, Nasim Biglari, et al.
Cell Metab. 2021 Jul 6;33(7):1466-1482.e7. doi: 10.1016/j.cmet.2021.05.002. Epub 2021 May 26.
Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed intersectional genetic manipulations to probe the feeding and glucoregulatory function of distinct sensory neurons. We reconstruct the gut innervation patterns of numerous molecularly defined vagal and spinal afferents and identify their downstream brain targets. Bidirectional chemogenetic manipulations, coupled with behavioral and circuit mapping analysis, demonstrated that gut-innervating, glucagon-like peptide 1 receptor (GLP1R)-expressing vagal afferents relay anorexigenic signals to parabrachial nucleus neurons that control meal termination. Moreover, GLP1R vagal afferent activation improves glucose tolerance, and their inhibition elevates blood glucose levels independent of food intake. In contrast, gut-innervating, GPR65-expressing vagal afferent stimulation increases hepatic glucose production and activates parabrachial neurons that control normoglycemia, but they are dispensable for feeding regulation. Thus, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits and may provide specific targets for metabolic control.
29Vagal afferent innervation of smooth muscle in the stomach and duodenum of the mouse: morphology and topography.PubMed
E A Fox, R J Phillips, F A Martinson, et al.
J Comp Neurol. 2000 Dec 18;428(3):558-76. doi: 10.1002/1096-9861(20001218)428:3<558::aid-cne11>3.0.co;2-m.
Intraganglionic laminar endings (IGLEs) and intramuscular arrays (IMAs), the two putative mechanoreceptors that the vagus nerve supplies to the gastrointestinal smooth muscle, have been characterized almost exclusively in the rat. To provide normative inventories of these afferents for the mouse, the authors examined the endings in the stomach and small intestine of three strains used as backgrounds for gene manipulations (i.e., C57, 129/SvJ, and WBB6). Animals received nodose ganglion injections of wheat germ agglutinin-horseradish peroxidase or dextran-tetramethylrhodamine conjugated to biotin. The horseradish peroxidase tissue was processed with tetramethylbenzidine and was used to map the distributions and densities of the two endings; the dextran material was counterstained with c-Kit immunohistochemistry to assess interactions between intramuscular arrays and interstitial cells of Cajal. IGLEs and IMAs constituted the vagal innervation of mouse gastric and duodenal smooth muscle. IGLE morphology and distributions, with peak densities in the corpus-antrum, were similar in the three strains of mice and comparable to those observed in rats. IMAs varied in complexity from region to region but tended to be simpler (fewer telodendria) in mice than in rats. IMAs were most concentrated in the forestomach and sphincters in mice, as in rats, but the topographic distributions of the endings varied both between strains of mice (subtly) and between species (more dramatically). IMAs appeared to make appositions with both interstitial cells and smooth muscle fibers. This survey should make it practical to assay the effects of genetic (e.g., knockout) and experimental (e.g., regeneration) manipulations affecting visceral afferents and their target tissues.
30The mast cell degranulator compound 48/80 directly activates neurons.PubMed
Michael Schemann, Eva Maria Kugler, Sabine Buhner, et al.
PLoS One. 2012;7(12):e52104. doi: 10.1371/journal.pone.0052104. Epub 2012 Dec 18.
BACKGROUND: Compound 48/80 is widely used in animal and tissue models as a "selective" mast cell activator. With this study we demonstrate that compound 48/80 also directly activates enteric neurons and visceral afferents. METHODOLOGY/PRINCIPAL FINDINGS: We used in vivo recordings from extrinsic intestinal afferents together with Ca(++) imaging from primary cultures of DRG and nodose neurons. Enteric neuronal activation was examined by Ca(++) and voltage sensitive dye imaging in isolated gut preparations and primary cultures of enteric neurons. Intraluminal application of compound 48/80 evoked marked afferent firing which desensitized on subsequent administration. In egg albumen-sensitized animals, intraluminal antigen evoked a similar pattern of afferent activation which also desensitized on subsequent exposure to antigen. In cross-desensitization experiments prior administration of compound 48/80 failed to influence the mast cell mediated response. Application of 1 and 10 µg/ml compound 48/80 evoked spike discharge and Ca(++) transients in enteric neurons. The same nerve activating effect was observed in primary cultures of DRG and nodose ganglion cells. Enteric neuron cultures were devoid of mast cells confirmed by negative staining for c-kit or toluidine blue. In addition, in cultured enteric neurons the excitatory action of compound 48/80 was preserved in the presence of histamine H(1) and H(2) antagonists. The mast cell stabilizer cromolyn attenuated compound 48/80 and nicotine evoked Ca(++) transients in mast cell-free enteric neuron cultures. CONCLUSIONS/SIGNIFICANCE: The results showed direct excitatory action of compound 48/80 on enteric neurons and visceral afferents. Therefore, functional changes measured in tissue or animal models may involve a mast cell independent effect of compound 48/80 and cromolyn.
31Psychoactive bacteria Lactobacillus rhamnosus (JB-1) elicits rapid frequency facilitation in vagal afferents.PubMed
Azucena Perez-Burgos, Bingxian Wang, Yu-Kang Mao, et al.
Am J Physiol Gastrointest Liver Physiol. 2013 Jan 15;304(2):G211-20. doi: 10.1152/ajpgi.00128.2012. Epub 2012 Nov 8.
Mounting evidence supports the influence of the gut microbiome on the local enteric nervous system and its effects on brain chemistry and relevant behavior. Vagal afferents are involved in some of these effects. We previously showed that ingestion of the probiotic bacterium Lactobacillus rhamnosus (JB-1) caused extensive neurochemical changes in the brain and behavior that were abrogated by prior vagotomy. Because information can be transmitted to the brain via primary afferents encoded as neuronal spike trains, our goal was to record those induced by JB-1 in vagal afferents in the mesenteric nerve bundle and thus determine the nature of the signals sent to the brain. Male Swiss Webster mice jejunal segments were cannulated ex vivo, and serosal and luminal compartments were perfused separately. Bacteria were added intraluminally. We found no evidence for translocation of labeled bacteria across the epithelium during the experiment. We recorded extracellular multi- and single-unit neuronal activity with glass suction pipettes. Within minutes of application, JB-1 increased the constitutive single- and multiunit firing rate of the mesenteric nerve bundle, but Lactobacillus salivarius (a negative control) or media alone were ineffective. JB-1 significantly augmented multiunit discharge responses to an intraluminal distension pressure of 31 hPa. Prior subdiaphragmatic vagotomy abolished all of the JB-1-evoked effects. This detailed exploration of the neuronal spike firing that encodes behavioral signaling to the brain may be useful to identify effective psychoactive bacteria and thereby offer an alternative new perspective in the field of psychiatry and comorbid conditions.
32Integrative neurocircuits that control metabolism and food intake.PubMed
Jens C Brüning, Henning Fenselau
Science. 2023 Sep 29;381(6665):eabl7398. doi: 10.1126/science.abl7398.
Systemic metabolism has to be constantly adjusted to the variance of food intake and even be prepared for anticipated changes in nutrient availability. Therefore, the brain integrates multiple homeostatic signals with numerous cues that predict future deviations in energy supply. Recently, our understanding of the neural pathways underlying these regulatory principles-as well as their convergence in the hypothalamus as the key coordinator of food intake, energy expenditure, and glucose metabolism-have been revealed. These advances have changed our view of brain-dependent control of metabolic physiology. In this Review, we discuss new concepts about how alterations in these pathways contribute to the development of prevalent metabolic diseases such as obesity and type 2 diabetes mellitus and how this emerging knowledge may provide new targets for their treatment.
33Highly selective brain-to-gut communication via genetically defined vagus neurons.PubMed
Jenkang Tao, John N Campbell, Linus T Tsai, et al.
Neuron. 2021 Jul 7;109(13):2106-2115.e4. doi: 10.1016/j.neuron.2021.05.004. Epub 2021 Jun 1.
The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles-whether or not there are dedicated neurons with restricted targets that act as "labeled lines" to perform certain functions, including two opposing ones (gastric contraction versus relaxation). By performing unbiased transcriptional profiling of DMV cholinergic neurons, we discovered seven molecularly distinct subtypes of motor neurons. Then, by using subtype-specific Cre driver mice, we show that two of these subtypes exclusively innervate the glandular domain of the stomach where, remarkably, they contact different enteric neurons releasing functionally opposing neurotransmitters (acetylcholine versus nitric oxide). Thus, the vagus motor nerve communicates via genetically defined labeled lines to control functionally unique enteric neurons within discrete subregions of the gastrointestinal tract. This discovery reveals that the parasympathetic nervous system utilizes a striking division of labor to control autonomic function.
34Neuronal regulation of the gut immune system and neuromodulation for treating inflammatory bowel disease.PubMed
Luis Populin, Martin J Stebbing, John B Furness
FASEB Bioadv. 2021 Aug 27;3(11):953-966. doi: 10.1096/fba.2021-00070. eCollection 2021 Nov.
The gut immune system in the healthy intestine is anti-inflammatory, but can move to a pro-inflammatory state when the gut is challenged by pathogens or in disease. The nervous system influences the level of inflammation through enteric neurons and extrinsic neural connections, particularly vagal and sympathetic innervation of the gastrointestinal tract, each of which exerts anti-inflammatory effects. Within the enteric nervous system (ENS), three neuron types that influence gut immune cells have been identified, intrinsic primary afferent neurons (IPANs), vasoactive intestinal peptide (VIP) neurons that project to the mucosa, and cholinergic neurons that influence macrophages in the external muscle layers. The enteric neuropeptides, calcitonin gene-related peptide (CGRP), tachykinins, and neuromedin U (NMU), which are contained in IPANs, and VIP produced by the mucosa innervating neurons, all influence immune cells, notably innate lymphoid cells (ILCs). ILC2 are stimulated by VIP to release IL-22, which promotes microbial defense and tissue repair. Enteric neurons are innervated by the vagus, and, in the large intestine, by the pelvic nerves. Vagal nerve stimulation reduces gut inflammation, which may be both by stimulation of efferent (motor) pathways to the ENS, and stimulation of afferent pathways that connect to integrating centers in the CNS. Efferent pathways from the CNS have their anti-inflammatory effects through either or both vagal efferent neurons and sympathetic pathways. The final neurons in sympathetic pathways reduce gut inflammation by the action of noradrenaline on β2 adrenergic receptors expressed by immune cells. Activation of neural anti-inflammatory pathways is an attractive option to treat inflammatory bowel disease that is refractory to other treatments. Further investigation of the ways in which enteric reflexes, vagal pathways and sympathetic pathways integrate their effects to modulate the gut immune system and gut inflammation is needed to optimize neuromodulation therapy.
36Vagal pathway activation links chronic stress to decline in intestinal stem cell function.PubMed
Guoying Zhang, Yannan Lian, Qingguo Li, et al.
Cell Stem Cell. 2025 May 1;32(5):778-794.e10. doi: 10.1016/j.stem.2025.02.016. Epub 2025 Mar 21.
Chronic stress adversely affects intestinal health, but the specific neural pathways linking the brain to intestinal tissue are not fully understood. Here, we show that chronic stress-induced activation of the central amygdala-dorsal motor nucleus of the vagus (CeA-DMV) pathway accelerates premature aging and impairs the stemness of intestinal stem cells (ISCs). This pathway influences ISC function independently of the microbiota, the hypothalamic-pituitary-adrenal (HPA) axis, the immune response, and the sympathetic nervous system (SNS). Under chronic stress, DMV-mediated vagal activation prompts cholinergic enteric neurons to release acetylcholine (ACh), which engages ISCs via the M3 muscarinic acetylcholine receptor (CHRM3). This interaction activates the p38 mitogen-activated protein kinase (MAPK) pathway, triggering growth arrest and mitochondrial fragmentation, thereby accelerating an aging-like decline in ISCs. Together, our findings provide insights into an alternative neural mechanism that links stress to intestinal dysfunction. Strategies targeting the DMV-associated vagal pathway represent potential therapeutic approaches for stress-induced intestinal diseases.
37Microbes and the gut-brain axis.PubMed
P Bercik, S M Collins, E F Verdu
Neurogastroenterol Motil. 2012 May;24(5):405-13. doi: 10.1111/j.1365-2982.2012.01906.x. Epub 2012 Mar 8.
BACKGROUND: The 'gut-brain' or 'brain-gut axis', depending on whether we emphasize bottom-up or top-bottom pathways, is a bi-directional communication system, comprised of neural pathways, such as the enteric nervous system (ENS), vagus, sympathetic and spinal nerves, and humoral pathways, which include cytokines, hormones, and neuropeptides as signaling molecules. Recent evidence, mainly arising from animal models, supports a role of microbes as signaling components in the gut-brain axis. AIMS: The purpose of this review is to summarize our current knowledge regarding the role of microbes, including commensals, probiotics and gastrointestinal pathogens, in bottom-up pathways of communication in the gut-brain axis. Although this has clear implications for psychiatric co-morbidity in functional and inflammatory conditions of the gut, the focus of this review will be to discuss the current evidence for a role of bacteria (commensals, probiotics, and pathogens) as key modulators of gut-brain communication. RESULTS & CONCLUSIONS: The strongest evidence for a role of microbes as signaling components in the gut-brain axis currently arises from animal studies and indicate that mechanisms of communication are likely to be multiple. There is need for the concepts generated in animal models to be translated to the human in the future.
38Microbiota Signaling Pathways that Influence Neurologic Disease.PubMed
Laura M Cox, Howard L Weiner
Neurotherapeutics. 2018 Jan;15(1):135-145. doi: 10.1007/s13311-017-0598-8.
Though seemingly distinct and autonomous, emerging evidence suggests there is a bidirectional interaction between the intestinal microbiota and the brain. This crosstalk may play a substantial role in neurologic diseases, including anxiety, depression, autism, multiple sclerosis, Parkinson's disease, and, potentially, Alzheimer's disease. Long hypothesized by Metchnikoff and others well over 100 years ago, investigations into the mind-microbe axis is now seeing a rapid resurgence of research. If specific pathways and mechanisms of interaction are understood, it could have broad therapeutic potential, as the microbiome is environmentally acquired and can be modified to promote health. This review will discuss immune, endocrine, and neural system pathways that interconnect the gut microbiota to central nervous system and discuss how these findings might be applied to neurologic disease.
39The Microbiota-Gut-Immune-Glia (MGIG) Axis in Major Depression.PubMed
Leszek Rudzki, Michael Maes
Mol Neurobiol. 2020 Oct;57(10):4269-4295. doi: 10.1007/s12035-020-01961-y. Epub 2020 Jul 22.
There is robust evidence that major depression (MDD) is accompanied by a low-grade activation of the immune-inflammatory response system, which is involved in the pathophysiology of this disorder. It is also becoming apparent that glia cells are in reciprocal communication with neurons, orchestrate various neuromodulatory, homeostatic, metabolic, and immune mechanisms, and have a crucial role in neuroinflammatory mechanisms in MDD. Those cells mediate the central nervous system (CNS) response to systemic inflammation and psychological stress, but at the same time, they may be an origin of the inflammatory response in the CNS. The sources of activation of the inflammatory response in MDD are immense; however, in recent years, it is becoming increasingly evident that the gastrointestinal tract with gut-associated lymphoid tissue (GALT) and increased intestinal permeability to bacterial LPS and food-derived antigens contribute to activation of low-grade inflammatory response with subsequent psychiatric manifestations. Furthermore, an excessive permeability to gut-derived antigenic material may lead to subsequent autoimmunities which are also known to be comorbid with MDD. In this review, we discuss fascinating interactions between the gastrointestinal tract, increased intestinal permeability, intestinal microbiota, and glia-neuron cross talk, and their roles in the pathogenesis of the inflammatory hypothesis of MDD. To emphasize those crucial intercommunications for the brain functions, we propose the term of microbiota-gut-immune-glia (MGIG) axis.
40Reappraisal of Adipose Tissue Inflammation in Obesity.PubMed
Atilla Engin
Adv Exp Med Biol. 2024;1460:297-327. doi: 10.1007/978-3-031-63657-8_10.
Chronic low-grade inflammation is a central component in the pathogenesis of obesity-related expansion of adipose tissue and complications in other metabolic tissues. Five different signaling pathways are defined as dominant determinants of adipose tissue inflammation: These are increased circulating endotoxin due to dysregulation in the microbiota-gut-brain axis, systemic oxidative stress, macrophage accumulation, and adipocyte death. Finally, the nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasome pathway is noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome and associated metabolic inflammation play an important role in the relationships among fatty acids and obesity. Several highly active molecules, including primarily leptin, resistin, adiponectin, visfatin, and classical cytokines, are abundantly released from adipocytes. The most important cytokines that are released by inflammatory cells infiltrating obese adipose tissue are tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2), and IL-1. All these molecules mentioned above act on immune cells, causing local and then general inflammation. Three metabolic pathways are noteworthy in the development of adipose tissue inflammation: toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, endoplasmic reticulum (ER) stress-derived unfolded protein response (UPR), and inhibitor of nuclear factor kappa-B kinase beta (IKKβ)-nuclear factor kappa B (NF-κB) pathway. In fact, adipose tissue inflammation is an adaptive response that contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. Excessive fatty acid release worsens adipose tissue inflammation and contributes to insulin resistance. However, suppression of adipose inflammation in obesity with anti-inflammatory drugs is not a rational solution and paradoxically promotes insulin resistance, despite beneficial effects on weight gain. Inflammatory pathways in adipocytes are indeed indispensable for maintaining systemic insulin sensitivity. Cannabinoid type 1 receptor (CB1R) is important in obesity-induced pro-inflammatory response; however, blockade of CB1R, contrary to anti-inflammatory drugs, breaks the links between insulin resistance and adipose tissue inflammation. Obesity, however, could be decreased by improving leptin signaling, white adipose tissue browning, gut microbiota interactions, and alleviating inflammation. Furthermore, capsaicin synthesized by chilies is thought to be a new and promising therapeutic option in obesity, as it prevents metabolic endotoxemia and systemic chronic low-grade inflammation caused by high-fat diet.
41The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology.PubMed
Andrina Rutsch, Johan B Kantsjö, Francesca Ronchi
Front Immunol. 2020 Dec 10;11:604179. doi: 10.3389/fimmu.2020.604179. eCollection 2020.
The human microbiota has a fundamental role in host physiology and pathology. Gut microbial alteration, also known as dysbiosis, is a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs. Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiology and inflammation. The nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the vagus nerve, the immune system, and bacterial metabolites and products. During dysbiosis, these pathways are dysregulated and associated with altered permeability of the blood-brain barrier (BBB) and neuroinflammation. However, numerous mechanisms behind the impact of the gut microbiota in neuro-development and -pathogenesis remain poorly understood. There are several immune pathways involved in CNS homeostasis and inflammation. Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer's and Parkinson's diseases, but also anxiety and depressive-like disorders. The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the production of pro-inflammatory cytokines (interleukin-1β and interleukin-18) and to pyroptosis. Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain. However, how this influence is precisely working is yet to be discovered. Herein, we discuss the status of the knowledge and the open questions in the field focusing on the function of intestinal microbial metabolites or products on CNS cells during healthy and inflammatory conditions, such as multiple sclerosis, Alzheimer's and Parkinson's diseases, and also neuropsychiatric disorders. In particular, we focus on the innate inflammasome pathway as immune mechanism that can be involved in several of these conditions, upon exposure to certain microbes.
42Bidirectional gut-brain communication: A role for orexin-A.PubMed
Cristina Mediavilla
Neurochem Int. 2020 Dec;141:104882. doi: 10.1016/j.neuint.2020.104882. Epub 2020 Oct 14.
It is increasingly evident that bidirectional gut-brain signaling provides a communication pathway that uses neural, hormonal, and immunological routes to regulate homeostatic mechanisms such as hunger/satiety as well as emotions and inflammation. Hence, disruption of the gut-brain axis can cause numerous pathophysiologies, including obesity and intestinal inflammatory diseases. One chemical mediator in the gut-brain axis is orexin-A, given that hypothalamic orexin-A affects gastrointestinal motility and secretion, and peripheral orexin in the intestinal mucosa can modulate brain functions, making possible an orexinergic gut-brain network. It has been proposed that orexin-A acts on this axis to regulate nutritional processes, such as short-term intake, gastric acid secretion, and motor activity associated with the cephalic phase of feeding. Orexin-A has also been related to stress systems and stress responses via the hypothalamic-pituitary-adrenal axis. Recent studies on the relationship of orexin with immune system-brain communications in an animal model of colitis suggested an immunomodulatory role for orexin-A in signaling and responding to infection by reducing the production of pro-inflammatory cytokines (e.g., tumor necrosis factor α, interleukin-6, and monocyte chemoattractant protein-1). These studies suggested that orexin administration might be of potential therapeutic value in irritable bowel syndrome or chronic intestinal inflammatory diseases, in which gastrointestinal symptoms frequently coexist with behavioral disorders, including loss of appetite, anxiety, depression, and sleeping disorders. Interventions in the orexinergic system have been proposed as a therapeutic approach to these diseases and for the treatment of chemotherapeutic drug-related hyperalgesia and fatigue in cancer patients.
43[Intestinal-brain axis. Neuronal and immune-inflammatory mechanisms of brain and intestine pathology].PubMed
V M Bondarenko, E V Riabichenko
Zh Mikrobiol Epidemiol Immunobiol. 2013 Mar-Apr(2):112-20.
Mutually directed connections between intestine and brain are implemented by endocrine, neural and immune systems and nonspecific natural immunity. Intestine micro flora as an active participant of intestine-brain axis not only influences intestine functions but also stimulates the development of CNS in perinatal period and interacts with higher nervous centers causing depression and cognitive disorders in pathology. A special role belongs to intestine microglia. Apart from mechanic (protective) and trophic functions for intestine neurons, glia implements neurotransmitter, immunologic, barrier and motoric functions in the intestine. An interconnection between intestine barrier function and hematoencephalic barrier regulation exists. Chronic endotoxinemia as a result of intestine barrier dysfunction forms sustained inflammation state in periventricular zone of the brain with consequent destabilization of hematoencephalic barriers and spread oF inflammation to other parts of the brain resulting in neurodegradation development.
44[Mechanism of stress-induced microglial activation in depression and traditional Chinese medicine regulation].PubMed
Yi-Ze Sun, Hai-Bin Zhao, Zhe-Yi Wang
Zhongguo Zhong Yao Za Zhi. 2023 Aug;48(16):4285-4294. doi: 10.19540/j.cnki.cjcmm.20230215.402.
Depression exists with high prevalence and heavy disease burden. Stress events play a key role in the occurrence of depression, but the pathological mechanism has not been fully clarified by reason of the complexity and heterogeneity. In recent years, neuroinflammation as a pathological mechanism of depression has received extensive attention. The activated microglia is regarded as the marker of neuroinflammation, which is an important link of stress-induced depression. Stress might induce microglia activation through pattern recognition receptors(PRR), intestinal flora, hypothalamic-pituitary-adrenal(HPA) axis, and other pathways. Cross-talk between impaired microglia function and neurobiological factors such as inflammatory cytokines, serotonin metabolism, and neuroplasticity may lead to depression. At present, a large number of studies have proved that traditional Chinese medicine(TCM) plays an anti-depressive role by inhibiting microglia activation, which may be potential treatment strategies for depressive disorder. This paper reviewed the research progress of stress-induced microglia activation in depression and summarized the mechanism of TCM against depression with regard to microglia, hoping to provide experimental evidence and consideration for TCM against depression through microglia.
45Chemotherapy-induced gut microbiome disruption, inflammation, and cognitive decline in female patients with breast cancer.PubMed
L D Otto-Dobos, C V Grant, A A Lahoud, et al.
Brain Behav Immun. 2024 Aug;120:208-220. doi: 10.1016/j.bbi.2024.05.039. Epub 2024 May 31.
Chemotherapy is notorious for causing behavioral side effects (e.g., cognitive decline). Notably, the gut microbiome has recently been reported to communicate with the brain to affect behavior, including cognition. Thus, the aim of this clinical longitudinal observational study was to determine whether chemotherapy-induced disruption of the gut microbial community structure relates to cognitive decline and circulating inflammatory signals. Fecal samples, blood, and cognitive measures were collected from 77 patients with breast cancer before, during, and after chemotherapy. Chemotherapy altered the gut microbiome community structure and increased circulating TNF-α. Both the chemotherapy-induced changes in microbial relative abundance and decreased microbial diversity were related to elevated circulating pro-inflammatory cytokines TNF-α and IL-6. Participants reported subjective cognitive decline during chemotherapy, which was not related to changes in the gut microbiome or inflammatory markers. In contrast, a decrease in overall objective cognition was related to a decrease in microbial diversity, independent of circulating cytokines. Stratification of subjects, via a reliable change index based on 4 objective cognitive tests, identified objective cognitive decline in 35% of the subjects. Based on a differential microbial abundance analysis, those characterized by cognitive decline had unique taxonomic shifts (Faecalibacterium, Bacteroides, Fusicatenibacter, Erysipelotrichaceae UCG-003, and Subdoligranulum) over chemotherapy treatment compared to those without cognitive decline. Taken together, gut microbiome change was associated with cognitive decline during chemotherapy, independent of chemotherapy-induced inflammation. These results suggest that microbiome-related strategies may be useful for predicting and preventing behavioral side effects of chemotherapy.
46The role of the immune system in posttraumatic stress disorder.PubMed
Seyma Katrinli, Nayara C S Oliveira, Jennifer C Felger, et al.
Transl Psychiatry. 2022 Aug 4;12(1):313. doi: 10.1038/s41398-022-02094-7.
Posttraumatic stress disorder (PTSD) develops in a subset of individuals upon exposure to traumatic stress. In addition to well-defined psychological and behavioral symptoms, some individuals with PTSD also exhibit elevated concentrations of inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor-α. Moreover, PTSD is often co-morbid with immune-related conditions, such as cardiometabolic and autoimmune disorders. Numerous factors, including lifetime trauma burden, biological sex, genetic background, metabolic conditions, and gut microbiota, may contribute to inflammation in PTSD. Importantly, inflammation can influence neural circuits and neurotransmitter signaling in regions of the brain relevant to fear, anxiety, and emotion regulation. Given the link between PTSD and the immune system, current studies are underway to evaluate the efficacy of anti-inflammatory treatments in those with PTSD. Understanding the complex interactions between PTSD and the immune system is essential for future discovery of diagnostic and therapeutic tools.
47Costunolide ameliorates intestinal dysfunction and depressive behaviour in mice with stress-induced irritable bowel syndrome colonic mast cell activation and central 5-hydroxytryptamine metabolism.PubMed
Xi Li, Qingqing Liu, Jiaoyan Yu, et al.
Food Funct. 2021 May 11;12(9):4142-4151. doi: 10.1039/d0fo03340e.
Irritable bowel syndrome (IBS) is a common chronic functional bowel disease, associated with a high risk of depression and anxiety. The brain-gut axis plays an important role in the pathophysiological changes involved in IBS; however, an effective treatment for the same is lacking. The natural compound costunolide (COS) has been shown to exert gastroprotective, enteroprotective, and neuroprotective effects, but its therapeutic effects in IBS are unclear. Our study explored the effect of COS on intestinal dysfunction and depressive behaviour in stress-induced IBS mice. Mice were subjected to chronic unpredictable mild stress to trigger IBS, and some were administered COS. Behavioural tests, histochemical assays, western blotting, and measurement of 5-hydroxytryptamine (5-HT) levels in the colon and hippocampus were applied to monitor the physiological and molecular consequences of COS treatment in IBS mice. COS administration relieved intestinal dysfunction and depression-like behaviours in IBS mice. Improvements in low-grade colon inflammation and intestinal mucosal permeability, inhibition of the activation of mast cells, upregulation of colonic Occludin expression, and downregulation of Claudin 2 expression were also observed. COS was also found to upregulate GluN2A, BDNF, p-ERK1/2, and p-CREB expression and 5-HT levels in hippocampal cells but inhibited 5-HT metabolism. Molecular docking showed that COS could form hydrogen bonds with the serotonin transporter (SERT) to affect the reuptake of 5-HT in the intercellular space. In conclusion, COS alleviates intestinal dysfunction and depressive behaviour in stress-induced IBS mice by inhibiting mast cell activation in the colon and regulating 5-HT metabolism in the central nervous system.
48The influence of neuroinflammation in Autism Spectrum Disorder.PubMed
Samantha M Matta, Elisa L Hill-Yardin, Peter J Crack
Brain Behav Immun. 2019 Jul;79:75-90. doi: 10.1016/j.bbi.2019.04.037. Epub 2019 Apr 25.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by deficits in social communication and restricted or repetitive behaviours. The clinical presentation of ASD is highly variable and diagnosis is based on the presence of impaired social communication and repetitive and/or restricted behaviours. Although the precise pathophysiologies underlying ASD are unclear, growing evidence supports a role for dysregulated neuroinflammation. The potential involvement of microglia and astrocytes reactive to inflammatory stimuli in ASD has generated much interest due to their varied roles including in mounting an immune response and regulating synaptic function. Increased numbers of reactive microglial and astrocytes in both ASD postmortem tissue and animal models have been reported. Whether dysregulation of glial subtypes exacerbates alterations in neural connectivity in the brain of autistic patients is not well explored. A role for the gut-brain axis involving microbial-immune-neuronal cross talk is also a growing area of neuroinflammation research. Greater understanding of these interactions under patho/physiological conditions and the identification of consistent immune profile abnormalities can potentially lead to more reliable diagnostic measures and treatments in ASD.
49Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells.PubMed
Corinne Benakis, David Brea, Silvia Caballero, et al.
Nat Med. 2016 May;22(5):516-23. doi: 10.1038/nm.4068. Epub 2016 Mar 28.
Commensal gut bacteria impact the host immune system and can influence disease processes in several organs, including the brain. However, it remains unclear whether the microbiota has an impact on the outcome of acute brain injury. Here we show that antibiotic-induced alterations in the intestinal flora reduce ischemic brain injury in mice, an effect transmissible by fecal transplants. Intestinal dysbiosis alters immune homeostasis in the small intestine, leading to an increase in regulatory T cells and a reduction in interleukin (IL)-17-positive γδ T cells through altered dendritic cell activity. Dysbiosis suppresses trafficking of effector T cells from the gut to the leptomeninges after stroke. Additionally, IL-10 and IL-17 are required for the neuroprotection afforded by intestinal dysbiosis. The findings reveal a previously unrecognized gut-brain axis and an impact of the intestinal flora and meningeal IL-17(+) γδ T cells on ischemic injury.
50The Gut Microbiome Regulates Psychological-Stress-Induced Inflammation.PubMed
Chunliang Xu, Sung Kyun Lee, Dachuan Zhang, et al.
Immunity. 2020 Aug 18;53(2):417-428.e4. doi: 10.1016/j.immuni.2020.06.025. Epub 2020 Jul 30.
Psychological stress has adverse effects on various human diseases, including those of the cardiovascular system. However, the mechanisms by which stress influences disease activity remain unclear. Here, using vaso-occlusive episodes (VOEs) of sickle cell disease as a vascular disease model, we show that stress promotes VOEs by eliciting a glucocorticoid hormonal response that augments gut permeability, leading to microbiota-dependent interleukin-17A (IL-17A) secretion from T helper 17 (Th17) cells of the lamina propria, followed by the expansion of the circulating pool of aged neutrophils that trigger VOEs. We identify segmented filamentous bacteria as the commensal essential for the stress-induced expansion of aged neutrophils that enhance VOEs in mice. Importantly, the inhibition of glucocorticoids synthesis, blockade of IL-17A, or depletion of the Th17 cell-inducing gut microbiota markedly reduces stress-induced VOEs. These results offer potential therapeutic targets to limit the impact of psychological stress on acute vascular occlusion.
51The Microbiota-Gut-Brain Axis.PubMed
John F Cryan, Kenneth J O'Riordan, Caitlin S M Cowan, et al.
Physiol Rev. 2019 Oct 1;99(4):1877-2013. doi: 10.1152/physrev.00018.2018.
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
52Gut Biofactory-Neurocompetent Metabolites within the Gastrointestinal Tract. A Scoping Review.PubMed
Karolina Skonieczna-Żydecka, Karolina Jakubczyk, Dominika Maciejewska-Markiewicz, et al.
Nutrients. 2020 Nov 1;12(11):3369. doi: 10.3390/nu12113369.
The gut microbiota have gained much scientific attention recently. Apart from unravelling the taxonomic data, we should understand how the altered microbiota structure corresponds to functions of this complex ecosystem. The metabolites of intestinal microorganisms, especially bacteria, exert pleiotropic effects on the human organism and contribute to the host systemic balance. These molecules play key roles in regulating immune and metabolic processes. A subset of them affect the gut brain axis signaling and balance the mental wellbeing. Neurotransmitters, short chain fatty acids, tryptophan catabolites, bile acids and phosphatidylcholine, choline, serotonin, and -carnitine metabolites possess high neuroactive potential. A scoping literature search in PubMed/Embase was conducted up until 20 June 2020, using three major search terms "microbiota metabolites" AND "gut brain axis" AND "mental health". This review aimed to enhance our knowledge regarding the gut microbiota functional capacity, and support current and future attempts to create new compounds for future clinical interventions.
53The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication.PubMed
Ygor Parladore Silva, Andressa Bernardi, Rudimar Luiz Frozza
Front Endocrinol (Lausanne). 2020 Jan 31;11:25. doi: 10.3389/fendo.2020.00025. eCollection 2020.
A substantial body of evidence supports that the gut microbiota plays a pivotal role in the regulation of metabolic, endocrine and immune functions. In recent years, there has been growing recognition of the involvement of the gut microbiota in the modulation of multiple neurochemical pathways through the highly interconnected gut-brain axis. Although amazing scientific breakthroughs over the last few years have expanded our knowledge on the communication between microbes and their hosts, the underpinnings of microbiota-gut-brain crosstalk remain to be determined. Short-chain fatty acids (SCFAs), the main metabolites produced in the colon by bacterial fermentation of dietary fibers and resistant starch, are speculated to play a key role in neuro-immunoendocrine regulation. However, the underlying mechanisms through which SCFAs might influence brain physiology and behavior have not been fully elucidated. In this review, we outline the current knowledge about the involvement of SCFAs in microbiota-gut-brain interactions. We also highlight how the development of future treatments for central nervous system (CNS) disorders can take advantage of the intimate and mutual interactions of the gut microbiota with the brain by exploring the role of SCFAs in the regulation of neuro-immunoendocrine function.
54Cannabidiol Lipid Nanoparticles Stabilize Gut-Brain-Bone Axis Integrity and Enhance Neuroplasticity in Stressed Rats: A Comparison with Atomoxetine and Escitalopram.PubMed
Sarawut Lapmanee, Jitpatima Lumsutti, Natthawut Charoenphon, et al.
Int J Mol Sci. 2025 Sep 24;26(19):9318. doi: 10.3390/ijms26199318.
Chronic stress induces mood disturbances, disrupts gut barrier function, and promotes low-grade systemic inflammation. This study assessed the therapeutic effects of atomoxetine (ATX), escitalopram (ESC), cannabidiol (CBD), and CBD-loaded lipid nanoparticles (CBD/LNP) in male rats exposed to repeated restraint stress. Stressed rats exhibited a 2.03-fold increase in interleukin-6 and a 1.89-fold increase in TNF-α, a 1.20-fold decrease in brain-derived neurotrophic factor, a 1.36-fold decrease in osteocalcin, accompanied by alterations in gut metabolites, particularly short-chain fatty acids (SCFAs; from 155.3 to 94.83 μmol/L), polyamines (from 273.6 to 192.4 μmol/L), and bile acids (BAs; from 21.19 to 14.53 μmol/L), compared with the control group. Protein analysis revealed gut barrier disruption and microglial/macrophage activation, accompanied by reduced synaptic plasticity. ATX improved gut permeability and reduced glial activation but did not restore osteocalcin. ESC provided neuroimmune benefits with limited and BA gut restoration and modulated the gut-brain axis and improved anxiety-like behaviors, partly by altering gut microbiota and metabolites. CBD and CBD/LNP treatment restored intestinal barrier function, as indicated by intestinal permeability in the range of 1.15-1.61-fold. These treatments also normalized bile acids (1.0-1.38-fold) and osteocalcin (1.0-1.28-fold) and significantly reduced glial activation (0.63-1.12-fold) as opposed to the non-treated stressed group. All treatments were found to be effective in correcting SCFA and polyamine levels. Histological analysis confirmed that CBD/LNP, ATX, and ESC ameliorated tissue alterations. These findings highlight CBD/LNP as a promising intervention for stress-induced gut-brain-bone axis disruption, supporting its potential as a therapeutic alternative through modulation of microbiota-driven gut-brain communication in stress-associated disorders.
55Tryptophan Metabolism and Gut-Brain Homeostasis.PubMed
William Roth, Kimia Zadeh, Rushi Vekariya, et al.
Int J Mol Sci. 2021 Mar 15;22(6):2973. doi: 10.3390/ijms22062973.
Tryptophan is an essential amino acid critical for protein synthesis in humans that has emerged as a key player in the microbiota-gut-brain axis. It is the only precursor for the neurotransmitter serotonin, which is vital for the processing of emotional regulation, hunger, sleep, and pain, as well as colonic motility and secretory activity in the gut. Tryptophan catabolites from the kynurenine degradation pathway also modulate neural activity and are active in the systemic inflammatory cascade. Additionally, tryptophan and its metabolites support the development of the central and enteric nervous systems. Accordingly, dysregulation of tryptophan metabolites plays a central role in the pathogenesis of many neurologic and psychiatric disorders. Gut microbes influence tryptophan metabolism directly and indirectly, with corresponding changes in behavior and cognition. The gut microbiome has thus garnered much attention as a therapeutic target for both neurologic and psychiatric disorders where tryptophan and its metabolites play a prominent role. In this review, we will touch upon some of these features and their involvement in health and disease.
56Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain.PubMed
Kan Gao, Chun-Long Mu, Aitak Farzi, et al.
Adv Nutr. 2020 May 1;11(3):709-723. doi: 10.1093/advances/nmz127.
The gut-brain axis (GBA) is a bilateral communication network between the gastrointestinal (GI) tract and the central nervous system. The essential amino acid tryptophan contributes to the normal growth and health of both animals and humans and, importantly, exerts modulatory functions at multiple levels of the GBA. Tryptophan is the sole precursor of serotonin, which is a key monoamine neurotransmitter participating in the modulation of central neurotransmission and enteric physiological function. In addition, tryptophan can be metabolized into kynurenine, tryptamine, and indole, thereby modulating neuroendocrine and intestinal immune responses. The gut microbial influence on tryptophan metabolism emerges as an important driving force in modulating tryptophan metabolism. Here, we focus on the potential role of tryptophan metabolism in the modulation of brain function by the gut microbiota. We start by outlining existing knowledge on tryptophan metabolism, including serotonin synthesis and degradation pathways of the host, and summarize recent advances in demonstrating the influence of the gut microbiota on tryptophan metabolism. The latest evidence revealing those mechanisms by which the gut microbiota modulates tryptophan metabolism, with subsequent effects on brain function, is reviewed. Finally, the potential modulation of intestinal tryptophan metabolism as a therapeutic option for brain and GI functional disorders is also discussed.
57The ever-changing roles of serotonin.PubMed
Lauren A Jones, Emily W Sun, Alyce M Martin, et al.
Int J Biochem Cell Biol. 2020 Aug;125:105776. doi: 10.1016/j.biocel.2020.105776. Epub 2020 May 29.
Serotonin (5-HT) has traditional roles as a key neurotransmitter in the central nervous system and as a regulatory hormone controlling a broad range of physiological functions. Perhaps the most classically-defined functions of 5-HT are centrally in the control of mood, sleep and anxiety and peripherally in the modulation of gastrointestinal motility. A more recently appreciated role for 5-HT has emerged, however, as an important metabolic hormone contributing to glucose homeostasis and adiposity, with a causal relationship existing between circulating 5-HT levels and metabolic diseases. Almost all peripheral 5-HT is derived from specialised enteroendocrine cells, called enterochromaffin (EC) cells, located throughout the length of the lining of the gastrointestinal tract. EC cells are important luminal sensory cells that can detect and respond to an array of ingested nutrients, as well as luminal gut microbiota and their associated metabolites. Intriguingly, the interaction between gut microbiota and EC cells is dynamic in nature and has strong implications for host physiology. In this review, we discuss the traditional and modern functions of 5-HT and highlight an emerging pathway by which gut microbiota influences host health. Serotonin, also known as 5-hydroxytryptamine (5-HT), is an important neurotransmitter, growth factor and hormone that mediates a range of physiological functions. In mammals, serotonin is synthesized from the essential amino acid tryptophan by the rate-limiting enzyme tryptophan hydroxylase (TPH), for which there are two isoforms expressed in distinct cell types throughout the body. Tph1 is mainly expressed by specialized gut endocrine cells known as enterochromaffin (EC) cells and by other non-neuronal cell types such as adipocytes (Walther et al., 2003). Tph2 is primarily expressed in neurons of the raphe nuclei of the brain stem and a subset of neurons in the enteric nervous system (ENS) (Yabut et al., 2019). As 5-HT cannot readily cross the blood-brain barrier, the central and peripheral pools of 5-HT are anatomically separated and as such, act in their own distinct manners (Martin et al., 2017c). In this review we discuss the peripheral roles of serotonin, with particular focus on the interaction of gut-derived serotonin with the gut microbiota, and address emerging evidence linking this relationship with host homeostasis.
58The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine.PubMed
Ning Liu, Shiqiang Sun, Pengjie Wang, et al.
Int J Mol Sci. 2021 Jul 25;22(15):7931. doi: 10.3390/ijms22157931.
Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of tryptophan and is reported to modulate the development and neurogenesis of the enteric nervous system, gut motility, secretion, inflammation, sensation, and epithelial development. Approximately 95% of 5-HT in the body is synthesized and secreted by enterochromaffin (EC) cells, the most common type of neuroendocrine cells in the gastrointestinal (GI) tract, through sensing signals from the intestinal lumen and the circulatory system. Gut microbiota, nutrients, and hormones are the main factors that play a vital role in regulating 5-HT secretion by EC cells. Apart from being an important neurotransmitter and a paracrine signaling molecule in the gut, gut-derived 5-HT was also shown to exert other biological functions (in autism and depression) far beyond the gut. Moreover, studies conducted on the regulation of 5-HT in the immune system demonstrated that 5-HT exerts anti-inflammatory and proinflammatory effects on the gut by binding to different receptors under intestinal inflammatory conditions. Understanding the regulatory mechanisms through which 5-HT participates in cell metabolism and physiology can provide potential therapeutic strategies for treating intestinal diseases. Herein, we review recent evidence to recapitulate the mechanisms of synthesis, secretion, regulation, and biofunction of 5-HT to improve the nutrition and health of humans.
59Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.PubMed
Jessica M Yano, Kristie Yu, Gregory P Donaldson, et al.
Cell. 2015 Apr 9;161(2):264-76. doi: 10.1016/j.cell.2015.02.047.
The gastrointestinal (GI) tract contains much of the body's serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here, we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes.
60Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.PubMed
S M O'Mahony, G Clarke, Y E Borre, et al.
Behav Brain Res. 2015 Jan 15;277:32-48. doi: 10.1016/j.bbr.2014.07.027. Epub 2014 Jul 29.
The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders.
61Ruminococcus gnavus plays a pathogenic role in diarrhea-predominant irritable bowel syndrome by increasing serotonin biosynthesis.PubMed
Lixiang Zhai, Chunhua Huang, Ziwan Ning, et al.
Cell Host Microbe. 2023 Jan 11;31(1):33-44.e5. doi: 10.1016/j.chom.2022.11.006. Epub 2022 Dec 9.
Diarrhea-predominant irritable bowel syndrome (IBS-D), a globally prevalent functional gastrointestinal (GI) disorder, is associated with elevated serotonin that increases gut motility. While anecdotal evidence suggests that the gut microbiota contributes to serotonin biosynthesis, mechanistic insights are limited. We determined that the bacterium Ruminococcus gnavus plays a pathogenic role in IBS-D. Monocolonization of germ-free mice with R. gnavus induced IBS-D-like symptoms, including increased GI transit and colonic secretion, by stimulating the production of peripheral serotonin. R. gnavus-mediated catabolism of dietary phenylalanine and tryptophan generated phenethylamine and tryptamine that directly stimulated serotonin biosynthesis in intestinal enterochromaffin cells via a mechanism involving activation of trace amine-associated receptor 1 (TAAR1). This R. gnavus-driven increase in serotonin levels elevated GI transit and colonic secretion but was abrogated upon TAAR1 inhibition. Collectively, our study provides molecular and pathogenetic insights into how gut microbial metabolites derived from dietary essential amino acids affect serotonin-dependent control of gut motility.
62Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice.PubMed
Manfei Zhou, Yichun Fan, Liuting Xu, et al.
Microbiome. 2023 Jun 30;11(1):145. doi: 10.1186/s40168-023-01589-9.
BACKGROUND: Adolescent depression is becoming one of the major public health concerns, because of its increased prevalence and risk of significant functional impairment and suicidality. Clinical depression commonly emerges in adolescence; therefore, the prevention and intervention of depression at this stage is crucial. Recent evidence supports the importance of the gut microbiota (GM) in the modulation of multiple functions associated with depression through the gut-brain axis (GBA). However, the underlying mechanisms remain poorly understood. Therefore, in the current study, we aimed to screen the microbiota out from healthy and depressive adolescents, delineate the association of the targeted microbiota and the adolescent depression, address the salutary effects of the targeted microbiota on anti-depressive behaviors in mice involving the metabolism of the tryptophan (Trp)-derived neurotransmitters along the GBA. RESULTS: Here, we found the gut microbiota from healthy adolescent volunteers, first diagnosis patients of adolescent depression, and sertraline interveners after first diagnosis displayed significant difference, the relative abundance of Faecalibacterium, Roseburia, Collinsella, Blautia, Phascolarctobacterium, Lachnospiraceae-unclassified decreased in adolescent depressive patients, while restored after sertraline treatment. Of note, the Roseburia abundance exhibited a high efficiency in predicting adolescent depression. Intriguingly, transplantation of the fecal microbiota from healthy adolescent volunteers to the chronic restraint stress (CRS)-induced adolescent depressed mice significantly ameliorated mouse depressive behaviors, in which the Roseburia exerted critical roles, since its effective colonization in the mouse colon resulted in remarkably increased 5-HT level and reciprocally decreased kynurenine (Kyn) toxic metabolites quinolinic acid (Quin) and 3-hydroxykynurenine (3-HK) levels in both the mouse brain and colon. The specific roles of the Roseburia were further validated by the target bacteria transplantation mouse model, Roseburia intestinalis (Ri.) was gavaged to mice and importantly, it dramatically ameliorated CRS-induced mouse depressive behaviors, increased 5-HT levels in the brain and colon via promoting tryptophan hydroxylase-2 (TPH2) or -1 (TPH1) expression. Reciprocally, Ri. markedly restrained the limit-step enzyme responsible for kynurenine (indoleamine2,3-dioxygenase 1, IDO1) and quinolinic acid (3-hydroxyanthranilic acid 3,4-dioxygenase, 3HAO) generation, thereby decreased Kyn and Quin levels. Additionally, Ri. administration exerted a pivotal role in the protection of CRS-induced synaptic loss, microglial activation, and astrocyte maintenance. CONCLUSIONS: This study is the first to delineate the beneficial effects of Ri. on adolescent depression by balancing Trp-derived neurotransmitter metabolism and improving synaptogenesis and glial maintenance, which may yield novel insights into the microbial markers and therapeutic strategies of GBA in adolescent depression. Video Abstract.
63Tryptophan metabolites modulate inflammatory bowel disease and colorectal cancer by affecting immune system.PubMed
Moein Ala
Int Rev Immunol. 2022;41(3):326-345. doi: 10.1080/08830185.2021.1954638. Epub 2021 Jul 22.
Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.
64Understanding the Connection between Gut Homeostasis and Psychological Stress.PubMed
Hongyun Zhang, Ziying Wang, Guangqiang Wang, et al.
J Nutr. 2023 Apr;153(4):924-939. doi: 10.1016/j.tjnut.2023.01.026. Epub 2023 Jan 31.
Long-term exposure to adverse life events that provoke acute or chronic psychological stress (hereinafter "stress") can negatively affect physical health and even increase susceptibility to psychological illnesses, such as anxiety and depression. As a part of the hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor (CRF) released from the hypothalamus is primarily responsible for the stress response. Typically, CRF disrupts the gastrointestinal system and leads to gut microbiota dysbiosis, thereby increasing risk of functional gastrointestinal diseases, such as irritable bowel syndrome. Furthermore, CRF increases oxidative damage to the colon and triggers immune responses involving mast cells, neutrophils, and monocytes. CRF even affects the differentiation of intestinal stem cells (ISCs), causing enterochromaffin cells to secrete excessive amounts of 5-hydroxytryptamine (5-HT). Therefore, stress is often accompanied by damage to the intestinal epithelial barrier function, followed by increased intestinal permeability and bacterial translocation. There are multi-network interactions between the gut microbiota and stress, and gut microbiota may relieve the effects of stress on the body. Dietary intake of probiotics can provide energy for ISCs through glycolysis, thereby alleviating the disruption to homeostasis caused by stress, and it significantly bolsters the intestinal barrier, alleviates intestinal inflammation, and maintains endocrine homeostasis. Gut microbiota also directly affect the synthesis of hormones and neurotransmitters, such as CRF, 5-HT, dopamine, and norepinephrine. Moreover, the Mediterranean diet enhances the stress resistance to some extent by regulating the intestinal flora. This article reviews recent research on how stress damages the gut and microbiota, how the gut microbiota can improve gut health by modulating injury due to stress, and how the diet relieves stress injury by interfering with intestinal microflora. This review gives insight into the potential role of the gut and its microbiota in relieving the effects of stress via the gut-brain axis.
65RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis.PubMed
Erika Sugisawa, Yasunori Takayama, Naoki Takemura, et al.
Cell. 2020 Aug 6;182(3):609-624.e21. doi: 10.1016/j.cell.2020.06.022. Epub 2020 Jul 7.
Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders.
66The Microbiota-Gut-Brain Axis in Psychiatric Disorders.PubMed
Aleksandra Góralczyk-Bińkowska, Dagmara Szmajda-Krygier, Elżbieta Kozłowska
Int J Mol Sci. 2022 Sep 24;23(19):11245. doi: 10.3390/ijms231911245.
Modulating the gut microbiome and its influence on human health is the subject of intense research. The gut microbiota could be associated not only with gastroenterological diseases but also with psychiatric disorders. The importance of factors such as stress, mode of delivery, the role of probiotics, circadian clock system, diet, and occupational and environmental exposure in the relationship between the gut microbiota and brain function through bidirectional communication, described as "the microbiome-gut-brain axis", is especially underlined. In this review, we discuss the link between the intestinal microbiome and the brain and host response involving different pathways between the intestinal microbiota and the nervous system (e.g., neurotransmitters, endocrine system, immunological mechanisms, or bacterial metabolites). We review the microbiota alterations and their results in the development of psychiatric disorders, including major depressive disorder (MDD), schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD).
67Prebiotic and Probiotic Modulation of the Microbiota-Gut-Brain Axis in Depression.PubMed
Daniel E Radford-Smith, Daniel C Anthony
Nutrients. 2023 Apr 13;15(8):1880. doi: 10.3390/nu15081880.
Emerging evidence demonstrates that alterations to the gut microbiota can affect mood, suggesting that the microbiota-gut-brain (MGB) axis contributes to the pathogenesis of depression. Many of these pathways overlap with the way in which the gut microbiota are thought to contribute to metabolic disease progression and obesity. In rodents, prebiotics and probiotics have been shown to modulate the composition and function of the gut microbiota. Together with germ-free rodent models, probiotics have provided compelling evidence for a causal relationship between microbes, microbial metabolites, and altered neurochemical signalling and inflammatory pathways in the brain. In humans, probiotic supplementation has demonstrated modest antidepressant effects in individuals with depressive symptoms, though more studies in clinically relevant populations are needed. This review critically discusses the role of the MGB axis in depression pathophysiology, integrating preclinical and clinical evidence, as well as the putative routes of communication between the microbiota-gut interface and the brain. A critical overview of the current approaches to investigating microbiome changes in depression is provided. To effectively translate preclinical breakthroughs in MGB axis research into novel therapies, rigorous placebo-controlled trials alongside a mechanistic and biochemical understanding of prebiotic and probiotic action are required from future research.
68Gut bless you: The microbiota-gut-brain axis in irritable bowel syndrome.PubMed
Eline Margrete Randulff Hillestad, Aina van der Meeren, Bharat Halandur Nagaraja, et al.
World J Gastroenterol. 2022 Jan 28;28(4):412-431. doi: 10.3748/wjg.v28.i4.412.
Irritable bowel syndrome (IBS) is a common clinical label for medically unexplained gastrointestinal symptoms, recently described as a disturbance of the microbiota-gut-brain axis. Despite decades of research, the pathophysiology of this highly heterogeneous disorder remains elusive. However, a dramatic change in the understanding of the underlying pathophysiological mechanisms surfaced when the importance of gut microbiota protruded the scientific picture. Are we getting any closer to understanding IBS' etiology, or are we drowning in unspecific, conflicting data because we possess limited tools to unravel the cluster of secrets our gut microbiota is concealing? In this comprehensive review we are discussing some of the major important features of IBS and their interaction with gut microbiota, clinical microbiota-altering treatment such as the low FODMAP diet and fecal microbiota transplantation, neuroimaging and methods in microbiota analyses, and current and future challenges with big data analysis in IBS.
69The Microbiota-Gut-Brain Axis: From Motility to Mood.PubMed
Kara G Margolis, John F Cryan, Emeran A Mayer
Gastroenterology. 2021 Apr;160(5):1486-1501. doi: 10.1053/j.gastro.2020.10.066. Epub 2021 Jan 22.
The gut-brain axis plays an important role in maintaining homeostasis. Many intrinsic and extrinsic factors influence signaling along this axis, modulating the function of both the enteric and central nervous systems. More recently the role of the microbiome as an important factor in modulating gut-brain signaling has emerged and the concept of a microbiota-gut-brain axis has been established. In this review, we highlight the role of this axis in modulating enteric and central nervous system function and how this may impact disorders such as irritable bowel syndrome and disorders of mood and affect. We examine the overlapping biological constructs that underpin these disorders with a special emphasis on the neurotransmitter serotonin, which plays a key role in both the gastrointestinal tract and in the brain. Overall, it is clear that although animal studies have shown much promise, more progress is necessary before these findings can be translated for diagnostic and therapeutic benefit in patient populations.
70Irritable bowel syndrome: a clinical review.PubMed
William D Chey, Jacob Kurlander, Shanti Eswaran
JAMA. 2015 Mar 3;313(9):949-58. doi: 10.1001/jama.2015.0954.
IMPORTANCE: Irritable bowel syndrome (IBS) affects 7% to 21% of the general population. It is a chronic condition that can substantially reduce quality of life and work productivity. OBJECTIVES: To summarize the existing evidence on epidemiology, pathophysiology, and diagnosis of IBS and to provide practical treatment recommendations for generalists and specialists according to the best available evidence. EVIDENCE REVIEW: A search of Ovid (MEDLINE) and Cochrane Database of Systematic Reviews was performed for literature from 2000 to December 2014 for the terms pathophysiology, etiology, pathogenesis, diagnosis, irritable bowel syndrome, and IBS. The range was expanded from 1946 to December 2014 for IBS, irritable bowel syndrome, diet, treatment, and therapy. FINDINGS: The database search yielded 1303 articles, of which 139 were selected for inclusion. IBS is not a single disease but rather a symptom cluster resulting from diverse pathologies. Factors important to the development of IBS include alterations in the gut microbiome, intestinal permeability, gut immune function, motility, visceral sensation, brain-gut interactions, and psychosocial status. The diagnosis of IBS relies on symptom-based criteria, exclusion of concerning features (symptom onset after age 50 years, unexplained weight loss, family history of selected organic gastrointestinal diseases, evidence of gastrointestinal blood loss, and unexplained iron-deficiency anemia), and the performance of selected tests (complete blood cell count, C-reactive protein or fecal calprotectin, serologic testing for celiac disease, and age-appropriate colorectal cancer screening) to exclude organic diseases that can mimic IBS. Determining the predominant symptom (IBS with diarrhea, IBS with constipation, or mixed IBS) plays an important role in selection of diagnostic tests and treatments. Various dietary, lifestyle, medical, and behavioral interventions have proven effective in randomized clinical trials. CONCLUSIONS AND RELEVANCE: The diagnosis of IBS relies on the identification of characteristic symptoms and the exclusion of other organic diseases. Management of patients with IBS is optimized by an individualized, holistic approach that embraces dietary, lifestyle, medical, and behavioral interventions.
71Diarrhea Predominant-Irritable Bowel Syndrome (IBS-D): Effects of Different Nutritional Patterns on Intestinal Dysbiosis and Symptoms.PubMed
Annamaria Altomare, Claudia Di Rosa, Elena Imperia, et al.
Nutrients. 2021 Apr 29;13(5):1506. doi: 10.3390/nu13051506.
Irritable Bowel Syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by abdominal pain associated with defecation or a change in bowel habits. Gut microbiota, which acts as a real organ with well-defined functions, is in a mutualistic relationship with the host, harvesting additional energy and nutrients from the diet and protecting the host from pathogens; specific alterations in its composition seem to play a crucial role in IBS pathophysiology. It is well known that diet can significantly modulate the intestinal microbiota profile but it is less known how different nutritional approach effective in IBS patients, such as the low-FODMAP diet, could be responsible of intestinal microbiota changes, thus influencing the presence of gastrointestinal (GI) symptoms. The aim of this review was to explore the effects of different nutritional protocols (e.g., traditional nutritional advice, low-FODMAP diet, gluten-free diet, etc.) on IBS-D symptoms and on intestinal microbiota variations in both IBS-D patients and healthy subjects. To date, an ideal nutritional protocol does not exist for IBS-D patients but it seems crucial to consider the effect of the different nutritional approaches on the intestinal microbiota composition to better define an efficient strategy to manage this functional disorder.
72[Intestinal sensitivity disorders and irritable bowel syndrome].PubMed
N Mei
Gastroenterol Clin Biol. 1990;14(5 ( Pt 2)):29C-32C.
Long neglected in the past, the study of visceral sensitivity (interoception) has progressed in recent years because of advances in neurobiological techniques. Dealing with the structure or the function of single neurons, these techniques have profoundly increased our knowledge about the sensitive mechanisms in the digestive tract. According to recent data, the visceral sensitivity organs are richer and more complex than imagined previously. Microphysiological techniques have shown that intestinal sensitive terminations are capable of transmitting information concerning visceral activity and physicochemical modifications of intestinal contents directly to the central nervous system. This means that visceral sensitivity intervenes under physiological as well as pathological conditions. This notion is new and of great interest. As progress was being made concerning the morphologic and electrophysiologic aspects and contemporaneous studies were establishing the richness of visceral, and particularly, intestinal, sensitive receptors, basic science research in humans and animals have emphasized the diversity of the implication of the extrinsic nervous system in pain, regulation of digestive motility, homeostasis and alimentary behaviour. Our present knowledge on the nervous and neurohumoral mechanisms has shed new light on the determinisms in digestive tract pathology. This is especially true in the irritable bowel syndrome which can be considered as an extrinsic nervous system derangement. Due to abnormal sensitivity by modification of the threshold values of sensitivity to distension, and/or to stimulation by substances such as cholecystokinin, for example, motor disorders occur. Other factors, such as stress, can be responsible for revelation or exacerbation of neurohumoral disorders.
73Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome.PubMed
V Morgan, D Pickens, S Gautam, et al.
Gut. 2005 May;54(5):601-7. doi: 10.1136/gut.2004.047423.
BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is a disorder of intestinal hypersensitivity and altered motility, exacerbated by stress. Functional magnetic resonance imaging (fMRI) during painful rectal distension in IBS has demonstrated greater activation of the anterior cingulate cortex (ACC), an area relevant to pain and emotions. Tricyclic antidepressants are effective for IBS. The aim of this study was to determine if low dose amitriptyline reduces ACC activation during painful rectal distension in IBS to confer clinical benefits. Secondary aims were to identify other brain regions altered by amitriptyline, and to determine if reductions in cerebral activation are greater during mental stress. METHODS: Nineteen women with painful IBS were randomised to amitriptyline 50 mg or placebo for one month and then crossed over to the alternate treatment after washout. Cerebral activation during rectal distension was compared between placebo and amitriptyline groups by fMRI. Distensions were performed alternately during auditory stress and relaxing music. RESULTS: Rectal pain induced significant activation of the perigenual ACC, right insula, and right prefrontal cortex. Amitriptyline was associated with reduced pain related cerebral activations in the perigenual ACC and the left posterior parietal cortex, but only during stress. CONCLUSIONS: The tricyclic antidepressant amitriptyline reduces brain activation during pain in the perigenual (limbic) anterior cingulated cortex and parietal association cortex. These reductions are only seen during stress. Amitriptyline is likely to work in the central nervous system rather than peripherally to blunt pain and other symptoms exacerbated by stress in IBS.
74Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis.PubMed
Emeran A Mayer, Steven Berman, Brandall Suyenobu, et al.
Pain. 2005 Jun;115(3):398-409. doi: 10.1016/j.pain.2005.03.023.
Patients with mild chronic inflammation of the rectum or ileum have reduced perceptual responses to rectosigmoid distension compared to patients with irritable bowel syndrome (IBS). The current study sought to identify differences in regional cerebral blood flow (rCBF) during rectal distension, which might correspond to these perceptual differences. In 8 male ulcerative colitis (UC) patients with quiescent disease, 7 male IBS patients and 7 healthy male controls, rCBF was assessed using 15O-water positron emission tomography at baseline and during actual and anticipated but undelivered rectal distensions. No group differences were seen in anterior insula and dorsal anterior cingulate cortex (dACC), two regions consistently activated by painful intestinal stimuli. However, IBS patients showed greater activation of the amygdala, rostroventral ACC, and dorsomedial frontal cortical regions. In contrast, no significant differences were observed between UC and controls. When these two non-IBS groups were combined, functional connectivity analyses showed that right lateral frontal cortex (RLFC) activation positively correlated with activation of the dorsal pons/periaqueductal gray, a key region involved in endogenous pain inhibition. According to the connectivity analysis, this effect was mediated by inhibition of medial frontal cortex by the RLFC. Chronic colonic inflammation is not necessarily associated with increased visceral afferent input to the brain during rectal distension. In the sample studied, the primary difference between functional and quiescent inflammatory disease of the colon was in terms of greater activation of limbic/paralimbic circuits in IBS, and inhibition of these circuits in UC and controls by the RLFC.
75Uncertainty in anticipation of uncomfortable rectal distension is modulated by the autonomic nervous system--a fMRI study in healthy volunteers.PubMed
Amandine Rubio, Lukas Van Oudenhove, Sonia Pellissier, et al.
Neuroimage. 2015 Feb 15;107:10-22. doi: 10.1016/j.neuroimage.2014.11.043. Epub 2014 Dec 3.
The human brain responds both before and during the application of aversive stimuli. Anticipation allows the organism to prepare its nociceptive system to respond adequately to the subsequent stimulus. The context in which an uncomfortable stimulus is experienced may also influence neural processing. Uncertainty of occurrence, timing and intensity of an aversive event may lead to increased anticipatory anxiety, fear, physiological arousal and sensory perception. We aimed to identify, in healthy volunteers, the effects of uncertainty in the anticipation of uncomfortable rectal distension, and the impact of the autonomic nervous system (ANS) activity and anxiety-related psychological variables on neural mechanisms of anticipation of rectal distension using fMRI. Barostat-controlled uncomfortable rectal distensions were preceded by cued uncertain or certain anticipation in 15 healthy volunteers in a fMRI protocol at 3T. Electrocardiographic data were concurrently registered by MR scanner. The low frequency (LF)-component of the heart rate variability (HRV) time-series was extracted and inserted as a regressor in the fMRI model ('LF-HRV model'). The impact of ANS activity was analyzed by comparing the fMRI signal in the 'standard model' and in the 'LF-HRV model' across the different anticipation and distension conditions. The scores of the psychological questionnaires and the rating of perceived anticipatory anxiety were included as covariates in the fMRI data analysis. Our experiments led to the following key findings: 1) the subgenual anterior cingulate cortex (sgACC) is the only activation site that relates to uncertainty in healthy volunteers and is directly correlated to individual questionnaire score for pain-related anxiety; 2) uncertain anticipation of rectal distension involved several relevant brain regions, namely activation of sgACC and medial prefrontal cortex and deactivation of amygdala, insula, thalamus, secondary somatosensory cortex, supplementary motor area and cerebellum; 3) most of the brain activity during anticipation, but not distension, is associated with activity of the central autonomic network. This approach could be applied to study the ANS impact on brain activity in various pathological conditions, namely in patients with chronic digestive conditions characterized by visceral discomfort and ANS imbalance such as irritable bowel syndrome or inflammatory bowel diseases.
76Neurotransmitter and Intestinal Interactions: Focus on the Microbiota-Gut-Brain Axis in Irritable Bowel Syndrome.PubMed
Minjia Chen, Guangcong Ruan, Lu Chen, et al.
Front Endocrinol (Lausanne). 2022 Feb 16;13:817100. doi: 10.3389/fendo.2022.817100. eCollection 2022.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder of unknown etiology. IBS is caused by a disruption in the gut-brain axis. Given the importance of the gut microbiota in maintaining local and systemic homeostasis of immunity, endocrine, and other physiological processes, the microbiota-gut-brain axis has been proposed as a key regulator in IBS. Neurotransmitters have been shown to affect blood flow regulation, intestinal motility, nutrient absorption, the gastrointestinal immune system, and the microbiota in recent studies. It has the potential role to play a function in the pathophysiology of the gastrointestinal and neurological systems. Transmitters and their receptors, including 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, and histamine, play an important role in IBS, especially in visceral sensitivity and gastrointestinal motility. Studies in this field have shed light on revealing the mechanism by which neurotransmitters act in the pathogenesis of IBS and discovering new therapeutic strategies based on traditional pharmacological approaches that target the nervous system or novel therapies that target the microbiota.
77Comparison of electroacupuncture and moxibustion on brain-gut function in patients with diarrhea-predominant irritable bowel syndrome: A randomized controlled trial.PubMed
Ji-meng Zhao, Jin-hua Lu, Xiao-jun Yin, et al.
Chin J Integr Med. 2015 Nov;21(11):855-65. doi: 10.1007/s11655-015-2049-x. Epub 2015 Apr 6.
OBJECTIVE: To compare the effects of electroacupuncture (EA) and moxibustion therapies on patients with diarrhea-predominant irritable bowel syndrome (D-IBS). METHODS: A total of 60 D-IBS patients were randomly allocated to the EA group (30 cases) and moxibustion group (30 cases). Before and after treatment, the gastrointestinal symptoms and psychological symptoms were scored by Visual Analogue Scale, Bristol Stool Form Scale, Hamilton Anxiety Rating Scale (HAMA), and Hamilton Depression Rating Scale (HAMD); the expressions of 5-hydroxytryptamine (5-HT), 5-HT3 receptor (5-HT3R), and 5-HT4 receptor (5-HT4R) in the sigmoid mucosal tissue were measured by immunohistochemical staining. Additionally, the effects on the functional brain areas of the anterior cingulate cortex (ACC), insular cortex (IC) and prefrontal cortex (PFC) were observed by functional magnetic resonance imaging. RESULTS: Compared with before treatment, both EA and moxibustion groups reported significant improvements in abdominal pain and abdominal bloating after treatment (P<0.01 or P<0.05). The moxibustion group reported greater improvements in defecation emergency, defecation frequency, and stool feature than the EA group (P<0.01). Both HAMA and HAMD scores were significantly decreased in the moxibustion group than in the EA group (P<0.01). Both groups demonstrated significantly reduced expressions of 5-HT, 5-HT3R and 5-HT4R in the colonic mucosa after treatment (P<0.01), with a greater reduction of 5-HT in the moxibustion group (P<0.05). Finally, decreased activated voxel values were observed in the left IC, right IC and PFC brain regions of patients in the moxibustion group under stimulation with 150 mL colorectal distension after treatment (P<0.05 or P<0.01), while in the EA group only PFC area demonstrated a reduction (P<0.05). CONCLUSION: Moxibustion can significantly improve the symptoms of D-IBS, suggesting that moxibustion may be a more effective therapy than EA for D-IBS patients.
78Impact of psychological stress on irritable bowel syndrome.PubMed
Hong-Yan Qin, Chung-Wah Cheng, Xu-Dong Tang, et al.
World J Gastroenterol. 2014 Oct 21;20(39):14126-31. doi: 10.3748/wjg.v20.i39.14126.
Psychological stress is an important factor for the development of irritable bowel syndrome (IBS). More and more clinical and experimental evidence showed that IBS is a combination of irritable bowel and irritable brain. In the present review we discuss the potential role of psychological stress in the pathogenesis of IBS and provide comprehensive approaches in clinical treatment. Evidence from clinical and experimental studies showed that psychological stresses have marked impact on intestinal sensitivity, motility, secretion and permeability, and the underlying mechanism has a close correlation with mucosal immune activation, alterations in central nervous system, peripheral neurons and gastrointestinal microbiota. Stress-induced alterations in neuro-endocrine-immune pathways acts on the gut-brain axis and microbiota-gut-brain axis, and cause symptom flare-ups or exaggeration in IBS. IBS is a stress-sensitive disorder, therefore, the treatment of IBS should focus on managing stress and stress-induced responses. Now, non-pharmacological approaches and pharmacological strategies that target on stress-related alterations, such as antidepressants, antipsychotics, miscellaneous agents, 5-HT synthesis inhibitors, selective 5-HT reuptake inhibitors, and specific 5-HT receptor antagonists or agonists have shown a critical role in IBS management. A integrative approach for IBS management is a necessary.
79The gut-brain axis in irritable bowel syndrome and inflammatory bowel disease.PubMed
Angela Ancona, Claudia Petito, Irene Iavarone, et al.
Dig Liver Dis. 2021 Mar;53(3):298-305. doi: 10.1016/j.dld.2020.11.026. Epub 2020 Dec 7.
Research increasingly demonstrates the bidirectional communication between gut microbiota and the brain, enhancing the role of gut microbiota modulation in the treatment of central nervous system (CNS) disorders. The first five years of life are extremely important as it affects the development of gut microbiota, immune system and, consequently, the onset of psychometric alterations, particularly in genetically predisposed individuals. In this review, we focus on the link between specific microbial genera, gastrointestinal (GI) disorders, anxiety and depression and on the effects of different therapeutic strategies for mood disorders on gut microbiota.
80The influence of the brain-gut axis in inflammatory bowel disease and possible implications for treatment.PubMed
David J Gracie, P John Hamlin, Alexander C Ford
Lancet Gastroenterol Hepatol. 2019 Aug;4(8):632-642. doi: 10.1016/S2468-1253(19)30089-5. Epub 2019 May 20.
Brain-gut interactions affect psychological wellbeing and symptom reporting in functional gastrointestinal disorders; the presence of anxiety or depression is associated with the development of new-onset gastrointestinal symptoms, and the presence of gastrointestinal symptoms is associated with the development of psychological disorders de novo. In inflammatory bowel diseases (IBD), the reporting of irritable bowel syndrome (IBS)-type symptoms by patients with quiescent disease is common, and is associated with psychological disorders, impaired quality of life, and increased health-care use. In IBD, data from observational studies suggest that psychological disorders might be associated with relapse of disease activity, and that inflammatory activity is associated with the development of new psychological disorders, as has been described for functional gastrointestinal disorders such as IBS and functional dyspepsia. The brain-gut axis provides the physiological link between the CNS and gastrointestinal tract that might facilitate these relationships. In IBS, treatments targeting disordered brain-gut axis activity, including psychological therapies and antidepressants, might lead to improved symptoms and quality of life. However, in IBD, the benefit of these treatments is less certain because of a scarcity of interventional studies. Despite the scarcity of trials, observational data suggest that the effect of disordered brain-gut axis activity in IBD is substantial, and scope remains for further well designed trials of psychological therapies and antidepressants, particularly in the subset of patients who have coexistent psychological disorders, or in those who report IBS-type symptoms. Integrating these treatments into a biopsychosocial model of care has the potential to improve both psychological wellbeing and quality of life in some patients with IBD, reducing health-care use and altering the natural history of disease.
81Bidirectional association between type 2 diabetes and irritable bowel syndrome: A large-scale prospective cohort study.PubMed
Yesheng Zhou, Si Liu, Qian Zhang, et al.
Diabetes Obes Metab. 2024 Nov;26(11):5107-5115. doi: 10.1111/dom.15852. Epub 2024 Aug 20.
AIM: To examine the bidirectional association between type 2 diabetes (T2D) and irritable bowel syndrome (IBS) in a large prospective population cohort. METHODS: Participants free of IBS at baseline in the UK Biobank were included in the analysis of T2D and incident IBS (cohort 1), with 11 140 T2D patients and 413 979 non-T2D patients. Similarly, those free of T2D at baseline were included in the analysis of IBS and incident T2D (cohort 2), with 21 944 IBS patients and 413 979 non-IBS patients. Diagnoses of T2D and IBS were based on International Classification of Disease-10 codes. The Cox proportional hazards model was used to estimate adjusted hazard ratios (HRs). RESULTS: In cohort 1, 8984 IBS cases were identified during a median 14.5-year follow-up. Compared with non-T2D, T2D patients had a 39.0% increased risk of incident IBS (HR = 1.39, 95% confidence interval [CI]: 1.23-1.56, P < .001), with a higher IBS risk in those with higher fasting blood glucose levels (HR = 1.43, 95% CI: 1.19-1.72, P < .001) or longer T2D duration (HR = 1.47, 95% CI: 1.23-1.74, P < .001). In cohort 2, 29 563 incident T2D cases were identified. IBS patients had an 18.0% higher risk of developing T2D versus non-IBS patients (HR = 1.18, 95% CI: 1.12-1.24, P < .001). A similar excess T2D risk was observed in IBS patients with a duration of either less than 10 years, or of 10 years or longer. Further sensitivity analysis and subgroup analysis indicated consistent findings. CONCLUSIONS: T2D and IBS exhibit a bidirectional association, with an increased risk of co-morbidity. Awareness of this association may improve the prevention and management of both diseases.
82Bidirectional Association between Asthma and Irritable Bowel Syndrome: Two Population-Based Retrospective Cohort Studies.PubMed
Te-Chun Shen, Cheng-Li Lin, Chang-Ching Wei, et al.
PLoS One. 2016 Apr 19;11(4):e0153911. doi: 10.1371/journal.pone.0153911. eCollection 2016.
BACKGROUND: There is a demonstrated association between asthma and irritable bowel syndrome (IBS). In this study, we examined the bidirectional association between asthma and IBS using a nationwide database. METHODS: We conducted two retrospective cohort studies using data obtained from the National Health Insurance of Taiwan. Study 1 included 29,648 asthma patients newly diagnosed between 2000 and 2010. Study 2 included 29,875 IBS patient newly diagnosed between 2000 and 2010. For each study, four subjects without asthma and IBS were selected, respectively, frequency-matched by sex, age, and the diagnosis date. All four cohorts were followed up until the end of 2011 to estimate incident IBS for Study 1 and incident asthma for study 2. Adjusted hazard ratios (aHRs) were estimated using the Cox proportional hazards model after controlling for sex, age and comorbidities. RESULTS: The incidence of IBS was 1.89 times higher in the asthma cohort than in the comparison cohort (8.26 vs. 4.36 per 1,000 person-years), with an aHR of 1.57 [95% confidence interval (CI) = 1.47-1.68]. The aHRs remained significant in all subgroups measured by sex, age and the presence of comorbidities. In contrast, the incidence of asthma was 1.76 times higher in the IBS cohort than the comparison cohort (7.09 vs. 4.03 per 1,000 person-years), with an aHR of 1.54 (95% CI = 1.44-1.64). Similarly, aHRs remained significant in all subgroups measured by sex, age and the presence of comorbidities. CONCLUSION: The present study suggests a bidirectional association between asthma and IBS. Atopy could be a shared pathophysiology underlying this association, deserving a further investigation.
83Bidirectional association between alopecia areata and irritable bowel syndrome: A nationwide population-based cohort study.PubMed
Ying-Xiu Dai, Ying-Hsuan Tai, Yun-Ting Chang, et al.
Australas J Dermatol. 2022 May;63(2):e127-e132. doi: 10.1111/ajd.13809. Epub 2022 Feb 23.
BACKGROUND: Alopecia areata (AA) and irritable bowel syndrome (IBS) are two distinct diseases that share a similar pathophysiology; however, the relationship between these two diseases is unknown. This study aimed to investigate the bidirectional relationship between AA and IBS. METHODS: Participants were recruited from the National Health Insurance Research Database in Taiwan. We included 5446 patients with AA and 21 784 matched controls to assess the risk of IBS, and 56 429 patients with IBS and 225 716 matched controls to assess the risk of AA. The Cox proportional-hazards regression model was used to calculate the adjusted hazard ratio (aHR). RESULTS: After adjustment for potential confounders, patients with AA had an aHR of 5.20 [95% confidence interval (CI) 3.97-6.82] for IBS in comparison with the controls. Furthermore, compared with the controls, IBS patients had an aHR of 5.38 (95% CI 3.95-7.34) for AA. CONCLUSION: AA is bidirectionally associated with IBS. Further investigation is needed to elucidate the shared pathogenesis underlying these two diseases.
84Is there a bidirectional relationship between allergic rhinitis and irritable bowel syndrome? A meta-analysis.PubMed
Yifen Huang, Lun Cai, Jie Liu, et al.
J Glob Health. 2025 Jun 13;15:04155. doi: 10.7189/jogh.15.04155.
BACKGROUND: Some studies suggest a link between allergic rhinitis (AR) and irritable bowel syndrome (IBS), but evidence is insufficient. This meta-analysis aimed to explore the relationship between AR and IBS. METHODS: We searched the relevant literature in six electronic databases. We included a total of nine articles, seven of which took AR as the research object, two of which took IBS as the research object. We performed a meta-analysis using random effects and estimated the resultant odds ratio (OR). RESULTS: A total of 10 627 patients with AR were included in seven studies, including 956 patients diagnosed with AR in the IBS population and 9671 patients diagnosed with AR in the non-IBS population. By heterogeneity test, X = 10.12, F-statistic (F) = 6, P = 0.12, I = 41%, OR = 2.88, and Z-score (Z) = 21.97 (P < 0.00001), the results were statistically significant. Patients with AR have an increased risk of developing IBS compared to patients without AR. A total of 1099 patients with IBS were included in two studies, including 384 patients with IBS in AR patients and 715 patients with IBS in the healthy population. After the heterogeneity test, X = 0.11, F = 1, P = 0.74, I = 0%, OR = 2.15, and Z = 11.81 (P < 0.00001), the results were statistically significant. Patients with IBS have an increased risk of developing AR compared to patients without IBS. CONCLUSIONS: The bidirectional association between AR and IBS provides a basis for exploring potential new mechanisms between the two. REGISTRATION: No. INPLASY202440057.
85Bidirectional Association of Rheumatoid Arthritis and Irritable Bowel Syndrome: A Large-Scale Prospective Cohort Study.PubMed
Yijun Chen, Yesheng Zhou, Si Liu, et al.
Mayo Clin Proc. 2025 Aug 2. doi: 10.1016/j.mayocp.2025.04.031.
OBJECTIVE: To investigate the bidirectional prospective association between rheumatoid arthritis (RA) and irritable bowel syndrome (IBS) in a large-scale, long-term population-based cohort. PATIENTS AND METHODS: Participants without any cancer at baseline were included between 2006 and 2010. Overall, 5455 prevalent RA cases and 419,670 non-RA participants in cohort 1 were included to examine the risk of incident IBS, and 22,126 prevalent IBS cases and 419,670 non-IBS participants in cohort 2 were included to assess the risk of incident RA. A multivariable Cox proportional hazards model was employed to estimate adjusted hazard ratio. RESULTS: Overall, 8984 new IBS cases were identified in cohort 1 during a total of 5,980,083 person-years of follow-up. After adjustment for multiple confounders, RA patients exhibited a 1.30-fold increased risk (95% CI, 1.12 to 1.51) for development of IBS, with an even 1.4-fold higher risk in those with RA duration of 10 years or more. By contrast, a total of 5777 incident RA cases were identified during a median follow-up of 14.3 years in cohort 2. Patients with IBS demonstrated a 1.53-fold increased risk (95% CI, 1.39 to 1.68) for development of RA. Sensitivity and subgroup analyses yielded similar results. CONCLUSION: The findings indicate that RA is associated with an increased risk for development of IBS, and conversely, IBS is associated with an increased risk for development of RA. Further research is necessary to confirm these findings and to elucidate the underlying biologic mechanisms.
86Gut microbiome-targeted therapies for Alzheimer's disease.PubMed
Tao Zhang, Guangqi Gao, Lai-Yu Kwok, et al.
Gut Microbes. 2023 Dec;15(2):2271613. doi: 10.1080/19490976.2023.2271613. Epub 2023 Nov 7.
The advent of high-throughput 'omics' technologies has improved our knowledge of gut microbiome in human health and disease, including Alzheimer's disease (AD), a neurodegenerative disorder. Frequent bidirectional communications and mutual regulation exist between the gastrointestinal tract and the central nervous system through the gut-brain axis. A large body of research has reported a close association between the gut microbiota and AD development, and restoring a healthy gut microbiota may curb or even improve AD symptoms and progression. Thus, modulation of the gut microbiota has become a novel paradigm for clinical management of AD, and emerging effort has focused on developing potential novel strategies for preventing and/or treating the disease. In this review, we provide an overview of the connection and causal relationship between gut dysbiosis and AD, the mechanisms of gut microbiota in driving AD progression, and the successes and challenges of implementing available gut microbiome-targeted therapies (including probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation) in preventive and/or therapeutic preclinical and clinical intervention studies of AD. Finally, we discuss the future directions in this field.
87Gut microbiome and Parkinson's disease: Perspective on pathogenesis and treatment.PubMed
Safa Salim, Fatima Ahmad, Ayesha Banu, et al.
J Adv Res. 2023 Aug;50:83-105. doi: 10.1016/j.jare.2022.10.013. Epub 2022 Nov 1.
BACKGROUND: Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain. AIM: of Review: In this review, we summarize how alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved inneuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further exploredin humans through clinical trials. Key Scientific Concepts of Review: Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.
88The Brain-Gut-Bone Axis in Neurodegenerative Diseases: Insights, Challenges, and Future Prospects.PubMed
Rong Li, Zong Miao, Yu'e Liu, et al.
Adv Sci (Weinh). 2024 Oct;11(38):e2307971. doi: 10.1002/advs.202307971. Epub 2024 Aug 9.
Neurodegenerative diseases are global health challenges characterized by the progressive degeneration of nerve cells, leading to cognitive and motor impairments. The brain-gut-bone axis, a complex network that modulates multiple physiological systems, has gained increasing attention owing to its profound effects on the occurrence and development of neurodegenerative diseases. No comprehensive review has been conducted to clarify the triangular relationship involving the brain-gut-bone axis and its potential for innovative therapies for neurodegenerative disorders. In light of this, a new perspective is aimed to propose on the interplay between the brain, gut, and bone systems, highlighting the potential of their dynamic communication in neurodegenerative diseases, as they modulate multiple physiological systems, including the nervous, immune, endocrine, and metabolic systems. Therapeutic strategies for maintaining the balance of the axis, including brain health regulation, intestinal microbiota regulation, and improving skeletal health, are also explored. The intricate physiological interactions within the brain-gut-bone axis pose a challenge in the development of effective treatments that can comprehensively target this system. Furthermore, the safety of these treatments requires further evaluation. This review offers a novel insights and strategies for the prevention and treatment of neurodegenerative diseases, which have important implications for clinical practice and patient well-being.
89Role of gut-brain axis, gut microbial composition, and probiotic intervention in Alzheimer's disease.PubMed
Periyanaina Kesika, Natarajan Suganthy, Bhagavathi Sundaram Sivamaruthi, et al.
Life Sci. 2021 Jan 1;264:118627. doi: 10.1016/j.lfs.2020.118627. Epub 2020 Oct 22.
Gut microbiota represents a diverse and dynamic population of microorganisms harboring the gastrointestinal tract, which influences the host health and disease. Gut microbiota communicates with the brain and vice versa through complex bidirectional communication systems - the gut-brain axis, which integrates the peripheral intestinal function with emotional and cognitive brain centers via neuro-immuno-endocrine mediators. Aging alters the gut microbial population, which not only leads to gastrointestinal disturbances but also causes central nervous system (CNS) disorders such as dementia. Alzheimer's disease (AD) is the most common form of dementia affecting the older person, characterized by beta-amyloid (Aβ) plaques and neurofibrillary tangles leading to the cognitive deficit and memory impairment. Multiple experimental and clinical studies revealed the role of gut microbiota in host cognition, and its dysbiosis associated with aging leads to neurodegeneration. Gut microbial dysbiosis leads to the secretion of amyloid and lipopolysaccharides (LPS), which disturbs the gastrointestinal permeability and blood-brain barrier. Thereby modulates the inflammatory signaling pathway promoting neuroinflammation, neuronal injury, and ultimately leading to neuronal death in AD. A recent study revealed the antimicrobial property of Aβ peptide as an innate immune response against pathogenic microbes. Another study showed that bacterial amyloid shares molecular mimicry with Aβ peptide, which elicits misfolding and aggregation of Aβ peptide, it's seeding, and propagation through the gut-brain axis followed by microglial cell activation. As aging together with poor diet and gut-derived inflammatory response due to dysbiosis contributes to the pathogenesis of AD, modification of gut microbial composition by uptake of probiotic-rich food can act as a preventive/therapeutic option for AD. The objective of the present review is to summarize the recent findings on the role of gut microbiota in the development of AD. Understanding the relationship between gut microbiota and CNS will help identify novel therapeutic strategies, especially probiotic-based supplementation, for the treatment of AD.
90The Role of Diet and Gut Microbiota in Alzheimer's Disease.PubMed
D M Sithara Dissanayaka, Vijay Jayasena, Stephanie R Rainey-Smith, et al.
Nutrients. 2024 Jan 31;16(3):412. doi: 10.3390/nu16030412.
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau tangles. Currently, Alzheimer's disease (AD) impacts 50 million individuals, with projections anticipating an increase to 152 million by the year 2050. Despite the increasing global prevalence of AD, its underlying pathology remains poorly understood, posing challenges for early diagnosis and treatment. Recent research suggests a link between gut dysbiosis and the aggregation of Aβ, the development of tau proteins, and the occurrence of neuroinflammation and oxidative stress are associated with AD. However, investigations into the gut-brain axis (GBA) in the context of AD progression and pathology have yielded inconsistent findings. This review aims to enhance our understanding of microbial diversity at the species level and the role of these species in AD pathology. Additionally, this review addresses the influence of confounding elements, including diet, probiotics, and prebiotics, on AD throughout different stages (preclinical, mild cognitive impairment (MCI), and AD) of its progression.
91Gut Microbiota and Dysbiosis in Alzheimer's Disease: Implications for Pathogenesis and Treatment.PubMed
Shan Liu, Jiguo Gao, Mingqin Zhu, et al.
Mol Neurobiol. 2020 Dec;57(12):5026-5043. doi: 10.1007/s12035-020-02073-3. Epub 2020 Aug 23.
Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term "microbiota-gut-brain axis" from "gut-brain axis" underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer's disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.
92The Gut Microbiota and Alzheimer's Disease.PubMed
Chunmei Jiang, Guangning Li, Pengru Huang, et al.
J Alzheimers Dis. 2017;58(1):1-15. doi: 10.3233/JAD-161141.
The gut microbiota comprises a complex community of microorganism species that resides in our gastrointestinal ecosystem and whose alterations influence not only various gut disorders but also central nervous system disorders such as Alzheimer's disease (AD). AD, the most common form of dementia, is a neurodegenerative disorder associated with impaired cognition and cerebral accumulation of amyloid-β peptides (Aβ). Most notably, the microbiota-gut-brain axis is a bidirectional communication system that is not fully understood, but includes neural, immune, endocrine, and metabolic pathways. Studies in germ-free animals and in animals exposed to pathogenic microbial infections, antibiotics, probiotics, or fecal microbiota transplantation suggest a role for the gut microbiota in host cognition or AD-related pathogenesis. The increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may mediate or affect AD pathogenesis and other neurodegenerative disorders, especially those associated with aging. In addition, bacteria populating the gut microbiota can secrete large amounts of amyloids and lipopolysaccharides, which might contribute to the modulation of signaling pathways and the production of proinflammatory cytokines associated with the pathogenesis of AD. Moreover, imbalances in the gut microbiota can induce inflammation that is associated with the pathogenesis of obesity, type 2 diabetes mellitus, and AD. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of the gut microbiota in the development of AD. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for AD.
93Alzheimer's disease and gut microbiota.PubMed
Xu Hu, Tao Wang, Feng Jin
Sci China Life Sci. 2016 Oct;59(10):1006-1023. doi: 10.1007/s11427-016-5083-9. Epub 2016 Aug 26.
Alzheimer's disease (AD) is a most common neurodegenerative disorder, which associates with impaired cognition. Gut microbiota can modulate host brain function and behavior via microbiota-gut-brain axis, including cognitive behavior. Germ-free animals, antibiotics, probiotics intervention and diet can induce alterations of gut microbiota and gut physiology and also host cognitive behavior, increasing or decreasing risks of AD. The increased permeability of intestine and blood-brain barrier induced by gut microbiota disturbance will increase the incidence of neurodegeneration disorders. Gut microbial metabolites and their effects on host neurochemical changes may increase or decrease the risk of AD. Pathogenic microbes infection will also increase the risk of AD, and meanwhile, the onset of AD support the "hygiene hypothesis". All the results suggest that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention will probably become a new treatment for AD.
94Gut microbiome composition may be an indicator of preclinical Alzheimer's disease.PubMed
Aura L Ferreiro, JooHee Choi, Jian Ryou, et al.
Sci Transl Med. 2023 Jun 14;15(700):eabo2984. doi: 10.1126/scitranslmed.abo2984.
Alzheimer's disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.
95Microbiota-derived lysophosphatidylcholine alleviates Alzheimer's disease pathology via suppressing ferroptosis.PubMed
Xu Zha, Xicheng Liu, Mengping Wei, et al.
Cell Metab. 2025 Jan 7;37(1):169-186.e9. doi: 10.1016/j.cmet.2024.10.006. Epub 2024 Nov 6.
Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of Bacteroides and LPC. This study thus identifies a B.ovatus-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.
96Gut microbiota and Parkinson's disease.PubMed
Lin Wang, Ying Cui, Bingyu Han, et al.
Chin Med J (Engl). 2025 Feb 5;138(3):289-297. doi: 10.1097/CM9.0000000000003318. Epub 2024 Nov 6.
Emerging evidence suggests that dysbiosis of the gut microbiota is associated with the pathogenesis of Parkinson's disease (PD), a prevalent neurodegenerative disorder. The microbiota-gut-brain axis plays a crucial role in the development and progression of PD, and numerous studies have demonstrated the potential therapeutic benefits of modulations in the intestinal microbiota. This review provides insights into the characterization of the gut microbiota in patients with PD and highlights associations with clinical symptoms and underlying mechanisms. The discussion underscores the increased influence of the gut microbiota in the pathogenesis of PD. While the relationship is not fully elucidated, existing research demonstrates a strong correlation between changes in the composition of gut microbiota and disease development, and further investigation is warranted to explain the specific underlying mechanisms.
97Parkinson's Disease and Gut Microbiota.PubMed
Masaaki Hirayama, Kinji Ohno
Ann Nutr Metab. 2021;77 Suppl 2:28-35. doi: 10.1159/000518147. Epub 2021 Sep 9.
BACKGROUND: Parkinson's disease (PD) is caused by abnormal aggregation of α-synuclein fibrils, called the Lewy bodies, in the central nervous system. Accumulating knowledge points to the notion that α-synuclein fibrils start from the dorsal vagal nucleus and ascend to the locus ceruleus and the substantia nigra (SN). Even in healthy elderly subjects without motor or cognitive impairment, α-synuclein fibrils are frequently observed in the brain and sometimes in the intestinal neural plexus. Enteroendocrine cells have a direct synapse to the vagal afferents, and the vagal nucleus has synaptic pathways to the SN and the striatum. Intestinal bacteria are likely to be involved in the formation of intestinal α-synuclein fibrils. SUMMARY: A nonparametric meta-analysis of intestinal microbiota in PD in 5 countries, as well as scrutinization of the other reports from the other countries, indicates that mucin-degrading Akkermansia is increased in PD and that short-chain fatty acid (SCFA)-producing bacteria are decreased in PD. Both dysbiosis should increase the intestinal permeability, which subsequently facilitates exposure of the intestinal neural plexus to toxins like lipopolysaccharide and pesticide, which should lead to abnormal aggregation of α-synuclein fibrils. Decreased SCFA also downregulates regulatory T cells and fails to suppress neuronal inflammation. Key Messages: Therapeutic intervention may be able to be established against these mechanisms. Additional biochemical, cellular, and animal studies are required to further dissect the direct association between intestinal microbiota and PD.
98Microbiota-Brain-Gut Axis and Neurodegenerative Diseases.PubMed
Eamonn M M Quigley
Curr Neurol Neurosci Rep. 2017 Oct 17;17(12):94. doi: 10.1007/s11910-017-0802-6.
PURPOSE OF REVIEW: The purposes of this review were as follows: first, to provide an overview of the gut microbiota and its interactions with the gut and the central nervous system (the microbiota-gut-brain axis) in health, second, to review the relevance of this axis to the pathogenesis of neurodegenerative diseases, such as Parkinson's disease, and, finally, to assess the potential for microbiota-targeted therapies. RECENT FINDINGS: Work on animal models has established the microbiota-gut-brain axis as a real phenomenon; to date, the evidence for its operation in man has been limited and has been confronted by considerable logistical challenges. Animal and translational models have incriminated a disturbed gut microbiota in a number of CNS disorders, including Parkinson's disease; data from human studies is scanty. While a theoretical basis can be developed for the use of microbiota-directed therapies in neurodegenerative disorders, support is yet to come from high-quality clinical trials. In theory, a role for the microbiota-gut-brain axis is highly plausible; clinical confirmation is awaited.
99Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis.PubMed
Zhe Zhao, Jingwen Ning, Xiu-Qi Bao, et al.
Microbiome. 2021 Nov 17;9(1):226. doi: 10.1186/s40168-021-01107-9.
BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently, it has been increasingly evident that gut microbiota affects the communication between the gut and the brain in PD pathogenesis, known as the microbiota-gut-brain axis. As an approach to re-establishing a normal microbiota community, fecal microbiota transplantation (FMT) has exerted beneficial effects on PD in recent studies. Here, in this study, we established a chronic rotenone-induced PD mouse model to evaluate the protective effects of FMT treatment on PD and to explore the underlying mechanisms, which also proves the involvement of gut microbiota dysbiosis in PD pathogenesis via the microbiota-gut-brain axis. RESULTS: We demonstrated that gut microbiota dysbiosis induced by rotenone administration caused gastrointestinal function impairment and poor behavioral performances in the PD mice. Moreover, 16S RNA sequencing identified the increase of bacterial genera Akkermansia and Desulfovibrio in fecal samples of rotenone-induced mice. By contrast, FMT treatment remarkably restored the gut microbial community, thus ameliorating the gastrointestinal dysfunctions and the motor deficits of the PD mice. Further experiments revealed that FMT administration alleviated intestinal inflammation and barrier destruction, thus reducing the levels of systemic inflammation. Subsequently, FMT treatment attenuated blood-brain barrier (BBB) impairment and suppressed neuroinflammation in the substantia nigra (SN), which further decreased the damage of dopaminergic neurons. Additional mechanistic investigation discovered that FMT treatment reduced lipopolysaccharide (LPS) levels in the colon, the serum, and the SN, thereafter suppressing the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products both in the SN and the colon. CONCLUSIONS: Our current study demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, we prove that rotenone-induced microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axis. Video abstract.
100Brain-gut-microbiota axis in Parkinson's disease.PubMed
Agata Mulak, Bruno Bonaz
World J Gastroenterol. 2015 Oct 7;21(37):10609-20. doi: 10.3748/wjg.v21.i37.10609.
Parkinson's disease (PD) is characterized by alpha-synucleinopathy that affects all levels of the brain-gut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological, neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding. Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gut-microbiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.
101Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease.PubMed
Timothy R Sampson, Justine W Debelius, Taren Thron, et al.
Cell. 2016 Dec 1;167(6):1469-1480.e12. doi: 10.1016/j.cell.2016.11.018.
The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.
102Gut microbiome, short-chain fatty acids, alpha-synuclein, neuroinflammation, and ROS/RNS: Relevance to Parkinson's disease and therapeutic implications.PubMed
Balaraman Kalyanaraman, Gang Cheng, Micael Hardy
Redox Biol. 2024 May;71:103092. doi: 10.1016/j.redox.2024.103092. Epub 2024 Feb 16.
In this review, we explore how short-chain fatty acids (SCFAs) produced by the gut microbiome affect Parkinson's disease (PD) through their modulatory interactions with alpha-synuclein, neuroinflammation, and oxidative stress mediated by reactive oxygen and nitrogen species (ROS/RNS). In particular, SCFAs-such as acetate, propionate, and butyrate-are involved in gut-brain communication and can modulate alpha-synuclein aggregation, a hallmark of PD. The gut microbiome of patients with PD has lower levels of SCFAs than healthy individuals. Probiotics may be a potential strategy to restore SCFAs and alleviate PD symptoms, but the underlying mechanisms are not fully understood. Also in this review, we discuss how alpha-synuclein, present in the guts and brains of patients with PD, may induce neuroinflammation and oxidative stress via ROS/RNS. Alpha-synuclein is considered an early biomarker for PD and may link the gut-brain axis to the disease pathogenesis. Therefore, elucidating the role of SCFAs in the gut microbiome and their impact on alpha-synuclein-induced neuroinflammation in microglia and on ROS/RNS is crucial in PD pathogenesis and treatment.
103Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases.PubMed
Jian Sheng Loh, Wen Qi Mak, Li Kar Stella Tan, et al.
Signal Transduct Target Ther. 2024 Feb 16;9(1):37. doi: 10.1038/s41392-024-01743-1.
The human gastrointestinal tract is populated with a diverse microbial community. The vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect of human biology, including health maintenance, development, aging, and disease. The advent of new sequencing technologies and culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations to shed light on microbiome-host interactions. Evidence has unveiled the bidirectional communication between the gut microbiome and the central nervous system, referred to as the "microbiota-gut-brain axis". The microbiota-gut-brain axis represents an important regulator of glial functions, making it an actionable target to ameliorate the development and progression of neurodegenerative diseases. In this review, we discuss the mechanisms of the microbiota-gut-brain axis in neurodegenerative diseases. As the gut microbiome provides essential cues to microglia, astrocytes, and oligodendrocytes, we examine the communications between gut microbiota and these glial cells during healthy states and neurodegenerative diseases. Subsequently, we discuss the mechanisms of the microbiota-gut-brain axis in neurodegenerative diseases using a metabolite-centric approach, while also examining the role of gut microbiota-related neurotransmitters and gut hormones. Next, we examine the potential of targeting the intestinal barrier, blood-brain barrier, meninges, and peripheral immune system to counteract glial dysfunction in neurodegeneration. Finally, we conclude by assessing the pre-clinical and clinical evidence of probiotics, prebiotics, and fecal microbiota transplantation in neurodegenerative diseases. A thorough comprehension of the microbiota-gut-brain axis will foster the development of effective therapeutic interventions for the management of neurodegenerative diseases.
104Neurodegenerative and Neurodevelopmental Diseases and the Gut-Brain Axis: The Potential of Therapeutic Targeting of the Microbiome.PubMed
Brian Bicknell, Ann Liebert, Thomas Borody, et al.
Int J Mol Sci. 2023 May 31;24(11):9577. doi: 10.3390/ijms24119577.
The human gut microbiome contains the largest number of bacteria in the body and has the potential to greatly influence metabolism, not only locally but also systemically. There is an established link between a healthy, balanced, and diverse microbiome and overall health. When the gut microbiome becomes unbalanced (dysbiosis) through dietary changes, medication use, lifestyle choices, environmental factors, and ageing, this has a profound effect on our health and is linked to many diseases, including lifestyle diseases, metabolic diseases, inflammatory diseases, and neurological diseases. While this link in humans is largely an association of dysbiosis with disease, in animal models, a causative link can be demonstrated. The link between the gut and the brain is particularly important in maintaining brain health, with a strong association between dysbiosis in the gut and neurodegenerative and neurodevelopmental diseases. This link suggests not only that the gut microbiota composition can be used to make an early diagnosis of neurodegenerative and neurodevelopmental diseases but also that modifying the gut microbiome to influence the microbiome-gut-brain axis might present a therapeutic target for diseases that have proved intractable, with the aim of altering the trajectory of neurodegenerative and neurodevelopmental diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, and attention-deficit hyperactivity disorder, among others. There is also a microbiome-gut-brain link to other potentially reversible neurological diseases, such as migraine, post-operative cognitive dysfunction, and long COVID, which might be considered models of therapy for neurodegenerative disease. The role of traditional methods in altering the microbiome, as well as newer, more novel treatments such as faecal microbiome transplants and photobiomodulation, are discussed.
105Depression and obesity: evidence of shared biological mechanisms.PubMed
Yuri Milaneschi, W Kyle Simmons, Elisabeth F C van Rossum, et al.
Mol Psychiatry. 2019 Jan;24(1):18-33. doi: 10.1038/s41380-018-0017-5. Epub 2018 Feb 16.
Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.
106The Role of the Microbiome-Brain-Gut Axis in the Pathogenesis of Depressive Disorder.PubMed
Ewelina Młynarska, Joanna Gadzinowska, Julita Tokarek, et al.
Nutrients. 2022 May 4;14(9):1921. doi: 10.3390/nu14091921.
The role of gut microbiota and its association with the central nervous system via the microbiome-brain-gut axis has been widely discussed in the literature. The aim of this review is to investigate the impact of gut microbiota on the development of depression and underlying molecular mechanisms. There are two possible pathways in which this interaction might occur. The first one suggests that depressive disorder could lead to dysbiosis and one of the causes may be the influence on the hypothalamic-pituitary-adrenal (HPA) axis. The second one considers if changes in the composition of gut microbiota might cause depressive disorder. The mechanisms that could be responsible for this interaction include the secretion of neurotransmitters, gut peptides and the activation of the immune system. However, current knowledge on this topic does not allow for us to state an unambiguous conclusion, and future studies that take into consideration more precise stress-measurement methods are needed to further explore direct mechanisms of the interaction between gut microbiota and mental health.
107Role of Brain-Gut-Microbiota Axis in Depression: Emerging Therapeutic Avenues.PubMed
Shvetank Bhatt, Jovita Kanoujia, S Mohana Lakshmi, et al.
CNS Neurol Disord Drug Targets. 2023;22(2):276-288. doi: 10.2174/1871527321666220329140804.
The human gut microbiota plays a significant role in the pathophysiology of central nervous system-related diseases. Recent studies suggest correlations between the altered gut microbiota and major depressive disorder (MDD). It is proposed that normalization of the gut microbiota alleviates MDD. The imbalance of brain-gut-microbiota axis also results in dysregulation of the hypothalamicpituitary- adrenal (HPA) axis. This imbalance has a crucial role in the pathogenesis of depression. Treatment strategies with certain antibiotics lead to the depletion of useful microbes and thereby induce depression like effects in subjects. Microbiota is also involved in the synthesis of various neurotransmitters (NTs) like 5-hydroxy tryptamine (5-HT; serotonin), norepinephrine (NE) and dopamine (DA). In addition to NTs, the gut microbiota also has an influence on brain derived neurotrophic factor (BDNF) levels. Recent research findings have exhibited that transfer of stress prone microbiota in mice is also responsible for depression and anxiety-like behaviour in animals. The use of probiotics, prebiotics, synbiotics and proper diet have shown beneficial effects in the regulation of depression pathogenesis. Moreover, transplantation of fecal microbiota from depressed individuals to normal subjects also induces depression-like symptoms. With the precedence of limited therapeutic benefits from monoamine targeting drugs, the regulation of brain-gut microbiota is emerging as a new treatment modality for MDDs. In this review, we elaborate on the significance of brain-gut-microbiota axis in the progression of MDD, particularly focusing on the modulation of the gut microbiota as a mode of treating MDD.
108Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation.PubMed
Anastasia I Petra, Smaro Panagiotidou, Erifili Hatziagelaki, et al.
Clin Ther. 2015 May 1;37(5):984-95. doi: 10.1016/j.clinthera.2015.04.002.
PURPOSE: Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. This article reviews the bidirectional relationship between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis, and discusses how it contributes to the pathogenesis of certain disorders that may involve brain inflammation. METHODS: Articles were identified with a search of Medline (starting in 1980) by using the key words anxiety, attention-deficit hypersensitivity disorder (ADHD), autism, cytokines, depression, gut, hypothalamic-pituitary-adrenal (HPA) axis, inflammation, immune system, microbiota, nervous system, neurologic, neurotransmitters, neuroimmune conditions, psychiatric, and stress. FINDINGS: Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, and essential metabolites all convey information to the central nervous system about the intestinal state. Conversely, the hypothalamic-pituitary-adrenal axis, the central nervous system regulatory areas of satiety, and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions seem to influence the pathogenesis of a number of disorders in which inflammation is implicated, such as mood disorder, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity. IMPLICATIONS: Recognition of the relationship between the MGB axis and the neuroimmune systems provides a novel approach for better understanding and management of these disorders. Appropriate preventive measures early in life or corrective measures such as use of psychobiotics, fecal microbiota transplantation, and flavonoids are discussed.
109Brain-gut interactions in inflammatory bowel disease.PubMed
Bruno L Bonaz, Charles N Bernstein
Gastroenterology. 2013 Jan;144(1):36-49. doi: 10.1053/j.gastro.2012.10.003. Epub 2012 Oct 12.
Psycho-neuro-endocrine-immune modulation through the brain-gut axis likely has a key role in the pathogenesis of inflammatory bowel disease (IBD). The brain-gut axis involves interactions among the neural components, including (1) the autonomic nervous system, (2) the central nervous system, (3) the stress system (hypothalamic-pituitary-adrenal axis), (4) the (gastrointestinal) corticotropin-releasing factor system, and (5) the intestinal response (including the intestinal barrier, the luminal microbiota, and the intestinal immune response). Animal models suggest that the cholinergic anti-inflammatory pathway through an anti-tumor necrosis factor effect of the efferent vagus nerve could be a therapeutic target in IBD through a pharmacologic, nutritional, or neurostimulation approach. In addition, the psychophysiological vulnerability of patients with IBD, secondary to the potential presence of any mood disorders, distress, increased perceived stress, or maladaptive coping strategies, underscores the psychological needs of patients with IBD. Clinicians need to address these issues with patients because there is emerging evidence that stress or other negative psychological attributes may have an effect on the disease course. Future research may include exploration of markers of brain-gut interactions, including serum/salivary cortisol (as a marker of the hypothalamic-pituitary-adrenal axis), heart rate variability (as a marker of the sympathovagal balance), or brain imaging studies. The widespread use and potential impact of complementary and alternative medicine and the positive response to placebo (in clinical trials) is further evidence that exploring other psycho-interventions may be important therapeutic adjuncts to the conventional therapeutic approach in IBD.
110Antibiotics and mental health: The good, the bad and the ugly.PubMed
Katherine Dinan, Timothy Dinan
J Intern Med. 2022 Dec;292(6):858-869. doi: 10.1111/joim.13543. Epub 2022 Jul 12.
Antibiotics are recognised as, on occasion, producing psychiatric side effects, most notably depression and anxiety. Apart from antimicrobial activity, antibiotics have multiple off-target effects. The brain-gut-microbiota axis has multiple sites for off-target activity, which may produce either positive or negative antibiotic effects. Here we review how antibiotics impact mental health by acting through the brain-gut-microbiota axis. Microbes in the gut influence brain function by acting through the vagus nerve or by altering the production of short-chain fatty acids or the amino acid tryptophan, the building block of serotonin. Not all antimicrobial actions of antibiotics have a negative impact. The first antidepressant discovered was actually an antibiotic: isoniazid is an antibacterial drug developed for treating tuberculosis. Minocycline, which enters the brain and mediates its effects through microglia, shows antidepressant activity. Some antibiotics bring about a significant decrease in gut microbial diversity, and this is viewed as a risk factor for depression. Other risk factors induced by antibiotics include altered gut barrier function, activation of the hypothalamic-pituitary-adrenal axis, reducing levels of brain-derived neurotrophic factor or oxytocin and alteration of vagal tone. Although most patients taking antibiotics do not suffer from an iatrogenic psychiatric disorder, some do. As clinicians, we need to keep this in mind. The development of new antibiotics is primarily focused on antibiotic resistance, but efforts should be made to reduce off-target brain-gut-microbiota effects resulting in mental health problems.
111From probiotics to psychobiotics - the gut-brain axis in psychiatric disorders.PubMed
A Zagórska, M Marcinkowska, M Jamrozik, et al.
Benef Microbes. 2020 Dec 2;11(8):717-732. doi: 10.3920/BM2020.0063. Epub 2020 Nov 16.
This review aims to present a comprehensive state-of-the-art analysis of the bidirectional crosstalk between gut microbiota and the central nervous system (CNS). The literature concerning the potential effects of gut microbiota on psychiatric disorders through neural pathways comprising the 'gut-brain axis' were gathered. In addition, the influence of probiotics and prebiotics and dairy-rich diets combined with the intake of probiotics and prebiotics on gut microbiota and the subsequent relationship with brain function was reviewed. However, a meta-analysis on the effectiveness of probiotic supplementation in psychiatric disorders is lacking. Therefore, a systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases from January 1969 to December 2019 was conducted. It led to the identification of a total of 844 research articles. Of these, a total of 23 studies met the meta-analysis criteria. Statistical analysis revealed that there was no significant difference in the symptoms of schizophrenia, stress, and anxiety between probiotic and placebo groups, post-intervention. Probiotic administration reduced depressive symptoms among patients with depression in a statistically significant manner (standardised mean difference (SMD) = -0.87; 95% confidence interval (95% confidence interval): -1.66, -0.99; =0.03). Further evidence from larger and more rigorous studies with longer duration of probiotic administration, as well as well-defined populations, homogenous probiotic intervention and outcome measures, are needed to clarify the potential therapeutic effects of probiotics on psychiatric symptoms. Based on the current literature, it seems that not all probiotic-/prebiotic-/dairy-rich diet-based treatments exhibited a psychobiotic effect on the CNS. Among the parameters determining the success of the given treatment, the most significant were probiotic composition (multi-strain formulation), the quantity of ingested psychobiotics and the duration of the study.
112Exploring the gut-brain Axis: Potential therapeutic impact of Psychobiotics on mental health.PubMed
Ana-Maria Cocean, Dan Cristian Vodnar
Prog Neuropsychopharmacol Biol Psychiatry. 2024 Aug 30;134:111073. doi: 10.1016/j.pnpbp.2024.111073. Epub 2024 Jun 22.
One of the most challenging and controversial issues in microbiome research is related to gut microbial metabolism and neuropsychological disorders. Psychobiotics affect human behavior and central nervous system processes via the gut-brain axis, involving neuronal, immune, and metabolic pathways. They have therapeutic potential in the treatment of several neurodegenerative and neurodevelopmental disorders such as depression, anxiety, autism, attention deficit hyperactivity disorder, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, anorexia nervosa, and multiple sclerosis. However, the mechanisms underlying the interaction between psychobiotics and the abovementioned diseases need further exploration. This review focuses on the relationship between gut microbiota and its impact on neurological and neurodegenerative disorders, examining the potential of psychobiotics as a preventive and therapeutic approach, summarising recent research on the gut-brain axis and the potential beneficial effects of psychobiotics, highlighting the need for further research and investigation in this area.
113The Role of Probiotics and Their Metabolites in the Treatment of Depression.PubMed
Monika Elżbieta Jach, Anna Serefko, Aleksandra Szopa, et al.
Molecules. 2023 Apr 4;28(7):3213. doi: 10.3390/molecules28073213.
Depression is a common and complex mental and emotional disorder that causes disability, morbidity, and quite often mortality around the world. Depression is closely related to several physical and metabolic conditions causing metabolic depression. Studies have indicated that there is a relationship between the intestinal microbiota and the brain, known as the gut-brain axis. While this microbiota-gut-brain connection is disturbed, dysfunctions of the brain, immune system, endocrine system, and gastrointestinal tract occur. Numerous studies show that intestinal dysbiosis characterized by abnormal microbiota and dysfunction of the microbiota-gut-brain axis could be a direct cause of mental and emotional disorders. Traditional treatment of depression includes psychotherapy and pharmacotherapy, and it mainly targets the brain. However, restoration of the intestinal microbiota and functions of the gut-brain axis via using probiotics, their metabolites, prebiotics, and healthy diet may alleviate depressive symptoms. Administration of probiotics labeled as psychobiotics and their metabolites as metabiotics, especially as an adjuvant to antidepressants, improves mental disorders. It is a new approach to the prevention, management, and treatment of mental and emotional illnesses, particularly major depressive disorder and metabolic depression. For the effectiveness of antidepressant therapy, psychobiotics should be administered at a dose higher than 1 billion CFU/day for at least 8 weeks.
114Psychobiotics: the Influence of Gut Microbiota on the Gut-Brain Axis in Neurological Disorders.PubMed
Parvin Oroojzadeh, Saber Yari Bostanabad, Hajie Lotfi
J Mol Neurosci. 2022 Sep;72(9):1952-1964. doi: 10.1007/s12031-022-02053-3. Epub 2022 Jul 18.
Nervous system disorders are one of the common problems that affect many people around the world every year. Regarding the beneficial effects of the probiotics on the gut and the gut-brain axis, their application along with current medications has been the subject of intense interest. Psychobiotics are a probiotic strain capable to affect the gut-brain axis. The effective role of Psychobiotics in several neurological disorders is documented. Consumption of the Psychobiotics containing nutrients has positive effects on the improvement of microbiota as well as alleviation of some symptoms of central nervous system (CNS) disorders. In the present study, the effects of probiotic strains on some CNS disorders in terms of controlling the disease symptoms were reviewed. Finding suggests that Psychobiotics can efficiently alleviate the symptoms of several CNS disorders such as autism spectrum disorders, Parkinson's disease, multiple sclerosis, insomnia, depression, diabetic neuropathy, and anorexia nervosa. It can be concluded that functional foods containing psychotropic strains can help to improve mental health.
115Gut microbiota modulates neurotransmitter and gut-brain signaling.PubMed
Shiyan Qu, Zijin Yu, Yaxuan Zhou, et al.
Microbiol Res. 2024 Oct;287:127858. doi: 10.1016/j.micres.2024.127858. Epub 2024 Jul 26.
Neurotransmitters, including 5-hydroxytryptamine (5-HT), dopamine (DA), gamma-aminobutyric acid (GABA), and glutamate, are essential transductors in the Gut-Brain Axis (GBA), playing critical roles both peripherally and centrally. Accumulating evidence suggests that the gut microbiota modulates intestinal neurotransmitter metabolism and gut-to-brain signaling, shedding light on the crucial role of the gut microbiota in brain function and the pathogenesis of various neuropsychiatric diseases, such as major depression disorder (MDD), anxiety, addiction and Parkinson's disease (PD). Despite the exciting findings, the mechanisms underlying the modulation of neurotransmitter metabolism and function by the gut microbiota are still being elucidated. In this review, we aim to provide a comprehensive overview of the existing knowledge about the role of the gut microbiota in neurotransmitter metabolism and function in animal and clinical experiments. Moreover, we will discuss the potential mechanisms through which gut microbiota-derived neurotransmitters contribute to the pathogenesis of neuropsychiatric diseases, thus highlighting a novel therapeutic target for these conditions.
1165-HT attenuates chronic stress-induced cognitive impairment in mice through intestinal flora disruption.PubMed
Junxing Ma, Ran Wang, Yaoxing Chen, et al.
J Neuroinflammation. 2023 Feb 3;20(1):23. doi: 10.1186/s12974-023-02693-1.
BACKGROUND: The microbiota-gut-brain axis plays an important role in the development of depression. The aim of this study was to investigate the effects of 5-HT on cognitive function, learning and memory induced by chronic unforeseeable mild stress stimulation (CUMS) in female mice. CUMS mice and TPH2 KO mice were used in the study. Lactococcus lactis E001-B-8 fungus powder was orally administered to mice with CUMS. METHODS: We used the open field test, Morris water maze, tail suspension test and sucrose preference test to examine learning-related behaviours. In addition, AB-PAS staining, immunofluorescence, ELISA, qPCR, Western blotting and microbial sequencing were employed to address our hypotheses. RESULTS: The effect of CUMS was more obvious in female mice than in male mice. Compared with female CUMS mice, extracellular serotonin levels in TPH2 KO CUMS mice were significantly reduced, and cognitive dysfunction was aggravated. Increased hippocampal autophagy levels, decreased neurotransmitter levels, reduced oxidative stress damage, increased neuroinflammatory responses and disrupted gut flora were observed. Moreover, L. lactis E001-B-8 significantly improved the cognitive behaviour of mice. CONCLUSIONS: These results strongly suggest that L. lactis E001-B-8 but not FLX can alleviate rodent depressive and anxiety-like behaviours in response to CUMS, which is associated with the improvement of 5-HT metabolism and modulation of the gut microbiome composition.
117The Power of Psychobiotics in Depression: A Modern Approach through the Microbiota-Gut-Brain Axis: A Literature Review.PubMed
Angela Dziedzic, Karina Maciak, Katarzyna Bliźniewska-Kowalska, et al.
Nutrients. 2024 Apr 4;16(7):1054. doi: 10.3390/nu16071054.
The microbiota-gut-brain (MGB) axis is a complex communication network linking the gut, microbiota, and brain, influencing various aspects of health and disease. Dysbiosis, a disturbance in the gut microbiome equilibrium, can significantly impact the MGB axis, leading to alterations in microbial composition and function. Emerging evidence highlights the connection between microbiota alterations and neurological and psychiatric disorders, including depression. This review explores the potential of psychobiotics in managing depressive disorders, emphasizing their role in restoring microbial balance and influencing the MGB axis. Psychobiotics exhibit positive effects on the intestinal barrier, immune response, cortisol levels, and the hypothalamic-pituitary-adrenal (HPA) axis. Studies suggest that probiotics may serve as an adjunct therapy for depression, especially in treatment-resistant cases. This review discusses key findings from studies on psychobiotics interventions, emphasizing their impact on the gut-brain axis and mental health. The increasing acceptance of the expanded concept of the MGB axis underscores the importance of microorganisms in mental well-being. As our understanding of the microbiome's role in health and disease grows, probiotics emerge as promising agents for addressing mental health issues, providing new avenues for therapeutic interventions in depressive disorders.
118Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients With Depression: A Randomized Clinical Trial.PubMed
Viktoriya L Nikolova, Anthony J Cleare, Allan H Young, et al.
JAMA Psychiatry. 2023 Aug 1;80(8):842-847. doi: 10.1001/jamapsychiatry.2023.1817.
IMPORTANCE: The microbiota-gut-brain axis is a promising target for novel treatments for mood disorders, such as probiotics. However, few clinical trials have been conducted, and further safety and efficacy data are needed to support this treatment approach. OBJECTIVE: To provide acceptability and tolerability data and estimates of intervention effect size for probiotics as adjunctive treatment for patients with major depressive disorder (MDD). DESIGN, SETTING, AND PARTICIPANTS: In this single-center, double-blind, placebo-controlled pilot randomized clinical trial, adults aged 18 to 55 years with MDD taking antidepressant medication but having an incomplete response were studied. A random sample was recruited from primary and secondary care services and general advertising in London, United Kingdom. Data were collected between September 2019 and May 2022 and analyzed between July and September 2022. INTERVENTION: Multistrain probiotic (8 billion colony-forming units per day) or placebo daily for 8 weeks added to ongoing antidepressant medication. MAIN OUTCOMES AND MEASURES: The pilot outcomes of the trial were retention, acceptability, tolerability, and estimates of putative treatment effect on clinical symptoms (depression: Hamilton Depression Rating Scale [HAMD-17] and Inventory of Depressive Symptomatology [IDS] scores; anxiety: Hamilton Anxiety Rating Scale [HAMA] and General Anxiety Disorder [GAD-7] scores) to be used as indicators for a definitive trial. RESULTS: Of 50 included participants, 49 received the intervention and were included in intent-to-treat analyses; of these, 39 (80%) were female, and the mean (SD) age was 31.7 (9.8) years. A total of 24 were randomized to probiotic and 25 to placebo. Attrition was 8% (1 in the probiotic group and 3 in the placebo group), adherence was 97.2%, and there were no serious adverse reactions. For the probiotic group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 11.00 (5.13) and 8.83 (4.28), respectively; IDS, 30.17 (11.98) and 25.04 (11.68); HAMA, 11.71 (5.86) and 8.17 (4.68); and GAD-7, 7.78 (4.12) and 7.63 (4.77). For the placebo group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 14.04 (3.70) and 11.09 (3.22), respectively; IDS, 33.82 (9.26) and 29.64 (9.31); HAMA, 14.70 (5.47) and 10.95 (4.48); and GAD-7, 10.91 (5.32) and 9.48 (5.18). Standardized effect sizes (SES) from linear mixed models demonstrated that the probiotic group attained greater improvements in depressive symptoms according to HAMD-17 scores (week 4: SES, 0.70; 95% CI, 0.01-0.98) and IDS Self Report scores (week 8: SES, 0.64; 95% CI, 0.03-0.87) as well as greater improvements in anxiety symptoms according to HAMA scores (week 4: SES, 0.67; 95% CI, 0-0.95; week 8: SES, 0.79; 95% CI, 0.06-1.05), but not GAD-7 scores (week 4: SES, 0.57; 95% CI, -0.01 to 0.82; week 8: SES, 0.32; 95% CI, -0.19 to 0.65), compared with the placebo group. CONCLUSIONS AND RELEVANCE: The acceptability, tolerability, and estimated effect sizes on key clinical outcomes are promising and encourage further investigation of probiotics as add-on treatment for people with MDD in a definitive efficacy trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03893162.
119The Gut-Brain Axis and the Microbiome in Anxiety Disorders, Post-Traumatic Stress Disorder and Obsessive-Compulsive Disorder.PubMed
Marnie MacKay, Bohan H Yang, Serdar M Dursun, et al.
Curr Neuropharmacol. 2024;22(5):866-883. doi: 10.2174/1570159X21666230222092029.
A large body of research supports the role of stress in several psychiatric disorders in which anxiety is a prominent symptom. Other research has indicated that the gut microbiome-immune system- brain axis is involved in a large number of disorders and that this axis is affected by various stressors. The focus of the current review is on the following stress-related disorders: generalized anxiety disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder and obsessivecompulsive disorder. Descriptions of systems interacting in the gut-brain axis, microbiome-derived molecules and of pro- and prebiotics are given. Preclinical and clinical studies on the relationship of the gut microbiome to the psychiatric disorders mentioned above are reviewed. Many studies support the role of the gut microbiome in the production of symptoms in these disorders and suggest the potential for pro- and prebiotics for their treatment, but there are also contradictory findings and concerns about the limitations of some of the research that has been done. Matters to be considered in future research include longer-term studies with factors such as sex of the subjects, drug use, comorbidity, ethnicity/ race, environmental effects, diet, and exercise taken into account; appropriate compositions of pro- and prebiotics; the translatability of studies on animal models to clinical situations; and the effects on the gut microbiome of drugs currently used to treat these disorders. Despite these challenges, this is a very active area of research that holds promise for more effective, precision treatment of these stressrelated disorders in the future.
120Human Gut Microbiota for Diagnosis and Treatment of Depression.PubMed
Olga V Averina, Elena U Poluektova, Yana A Zorkina, et al.
Int J Mol Sci. 2024 May 26;25(11):5782. doi: 10.3390/ijms25115782.
Nowadays, depressive disorder is spreading rapidly all over the world. Therefore, attention to the studies of the pathogenesis of the disease in order to find novel ways of early diagnosis and treatment is increasing among the scientific and medical communities. Special attention is drawn to a biomarker and therapeutic strategy through the microbiota-gut-brain axis. It is known that the symbiotic interactions between the gut microbes and the host can affect mental health. The review analyzes the mechanisms and ways of action of the gut microbiota on the pathophysiology of depression. The possibility of using knowledge about the taxonomic composition and metabolic profile of the microbiota of patients with depression to select gene compositions (metagenomic signature) as biomarkers of the disease is evaluated. The use of in silico technologies (machine learning) for the diagnosis of depression based on the biomarkers of the gut microbiota is given. Alternative approaches to the treatment of depression are being considered by balancing the microbial composition through dietary modifications and the use of additives, namely probiotics, postbiotics (including vesicles) and prebiotics as psychobiotics, and fecal transplantation. The bacterium is under consideration as a promising new-generation probiotic and auxiliary diagnostic biomarker of depression. The analysis conducted in this review may be useful for clinical practice and pharmacology.
121Remodeling of microbiota gut-brain axis using psychobiotics in depression.PubMed
Mani Surya Kumar Palepu, Manoj P Dandekar
Eur J Pharmacol. 2022 Sep 15;931:175171. doi: 10.1016/j.ejphar.2022.175171. Epub 2022 Aug 1.
Depression is a multifaceted psychiatric disorder mainly orchestrated by dysfunction of neuroendocrine, neurochemical, immune, and metabolic systems. The interconnection of gut microbiota perturbation with the central nervous system disorders has been well documented in recent times. Indeed, alteration of commensal intestinal microflora is noted in several psychiatric disorders such as anxiety and depression, which are presumed to be routed through the enteric nervous system, autonomic nervous system, endocrine, and immune system. This review summarises the new mechanisms underlying the crosstalk between gut microbiota and brain involved in the management of depression. Depression-induced changes in the commensal intestinal microbiota are majorly linked with the disruption of gut integrity, hyperinflammation, and modulation of short-chain fatty acids, neurotransmitters, kynurenine metabolites, endocannabinoids, brain-derived neurotropic factors, hypothalamic-pituitary-adrenal axis, and gut peptides. The restoration of gut microbiota with prebiotics, probiotics, postbiotics, synbiotics, and fermented foods (psychobiotics) has gained a considerable attention for the management of depression. Recent evidence also propose the role of gut microbiota in the process of treatment-resistant depression. Thus, remodeling of the microbiota-gut-brain axis using psychobiotics appears to be a promising therapeutic approach for the reversal of psychiatric disorders, and it is imperative to decipher the underlying mechanisms for gut-brain crosstalk.
122Dietary fiber: Still alive.PubMed
Jara Pérez-Jiménez
Food Chem. 2024 May 1;439:138076. doi: 10.1016/j.foodchem.2023.138076. Epub 2023 Nov 28.
Dietary fiber (DF) was established as a key dietary constituent some decades ago, as were some of its mechanisms of action and health effects. Although there is consolidated evidence on many features regarding DF, at the same time there are still many aspects to be explored in the field, e.g., deeper explorations of the contribution of phenolic compounds linked to cell walls to the biological activities of DF, or of the relevance of the gut-brain axis. At the same time, increasing DF intake should be seen as a major public health problem since worldwide intakes are quite far from recommendations. The awareness of this fact by public bodies should lead, among others, to the assessment of effective strategies for promoting DF intake among general population or specific groups; and to consider potential regulatory modifications in order to clarify several aspects potentially misleading for consumers.
123The role of short-chain fatty acids in microbiota-gut-brain communication.PubMed
Boushra Dalile, Lukas Van Oudenhove, Bram Vervliet, et al.
Nat Rev Gastroenterol Hepatol. 2019 Aug;16(8):461-478. doi: 10.1038/s41575-019-0157-3.
Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract, are speculated to have a key role in microbiota-gut-brain crosstalk. However, the pathways through which SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, research directly exploring the role of SCFAs as potential mediators of the effects of microbiota-targeted interventions on affective and cognitive functioning is sparse, especially in humans. This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota-gut-brain interactions. The effects of SCFAs on cellular systems and their interaction with gut-brain signalling pathways including immune, endocrine, neural and humoral routes are described. The effects of microbiota-targeted interventions such as prebiotics, probiotics and diet on psychological functioning and the putative mediating role of SCFA signalling will also be discussed, as well as the relationship between SCFAs and psychobiological processes. Finally, future directions to facilitate direct investigation of the effect of SCFAs on psychological functioning are outlined.
124Short chain fatty acids: Microbial metabolites for gut-brain axis signalling.PubMed
Kenneth J O'Riordan, Michael K Collins, Gerard M Moloney, et al.
Mol Cell Endocrinol. 2022 Apr 15;546:111572. doi: 10.1016/j.mce.2022.111572. Epub 2022 Jan 20.
The role of the intestinal microbiota as a regulator of gut-brain axis signalling has risen to prominence in recent years. Understanding the relationship between the gut microbiota, the metabolites it produces, and the brain will be critical for the subsequent development of new therapeutic approaches, including the identification of novel psychobiotics. A key focus in this regard have been the short-chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fibre, which include butyrate, acetate, and propionate. Ongoing research is focused on the entry of SCFAs into systemic circulation from the gut lumen, their migration to cerebral circulation and across the blood brain barrier, and their potential to exert acute and chronic effects on brain structure and function. This review aims to discuss our current mechanistic understanding of the direct and indirect influence that SCFAs have on brain function, behaviour and physiology, which will inform future microbiota-targeted interventions for brain disorders.
125High-fiber diet mitigates maternal obesity-induced cognitive and social dysfunction in the offspring via gut-brain axis.PubMed
Xiaoning Liu, Xiang Li, Bing Xia, et al.
Cell Metab. 2021 May 4;33(5):923-938.e6. doi: 10.1016/j.cmet.2021.02.002. Epub 2021 Mar 1.
Maternal obesity has been reported to be related to neurodevelopmental disorders in the offspring. However, the underlying mechanisms and effective interventions remain unclear. This cross-sectional study with 778 children aged 7-14 years in China indicated that maternal obesity is strongly associated with children's lower cognition and sociality. Moreover, it has been demonstrated that maternal obesity in mice disrupted the behavior and gut microbiome in offspring, both of which were restored by a high-fiber diet in either dams or offspring via alleviating synaptic impairments and microglial maturation defects. Co-housing and feces microbiota transplantation experiments revealed a causal relationship between microbiota and behavioral changes. Moreover, treatment with the microbiota-derived short-chain fatty acids also alleviated the behavioral deficits in the offspring of obese dams. Together, our study indicated that the microbiota-metabolites-brain axis may underlie maternal obesity-induced cognitive and social dysfunctions and that high dietary fiber intake could be a promising intervention.
126Centenarian-Sourced Combined with Dietary Fiber Complex Ameliorates Brain and Gut Function in Aged Mice.PubMed
Minhong Ren, He Li, Zhen Fu, et al.
Nutrients. 2022 Jan 13;14(2):324. doi: 10.3390/nu14020324.
Dietary intervention could modulate age-related neurological disorders via the gut-brain axis. The potential roles of a probiotic and the dietary fiber complex (DFC) on brain and gut function in aged mice were investigated in this study. LTL1361 and DFC were orally administrated for 12 weeks, and the learning and memory ability, as well as the oxidative parameters, inflammatory markers, gut barrier function and microbial metabolite short-chain fatty acids (SCFAs), were investigated. LTL1361 and DFC supplementation ameliorated cognitive ability, attenuated oxidative stress in brain and inflammation in serum and colon, ameliorated gut barrier function, and increased the SCFA concentrations and gene expression of SCFA receptors. The protective effect was more significantly enhanced in aged mice treated with the combination of LTL1361 and DFC than treated with LTL1361 or DFC alone. These results could be associated with the protected morphology of pyramidal nerve cells in hippocampus of mice brain and the downregulation of apoptosis marker caspase-3 in brain and upregulation of tight junction proteins in small intestine and colon. The results indicated that LTL1361 and DFC alleviated age-related cognitive impairment, as well as protected brain and gut function. LTL1361 and DFC might be used as novel and promising antiaging agents in human.
127Fructo-Oligosaccharides Restore High-Fat Diet-Disrupted Diurnal Fluctuations in Cognitive Function in Mice via the Gut-Brain Axis.PubMed
Zhenting Zhao, Yuqi Zhao, Shengquan Dai, et al.
J Agric Food Chem. 2025 Nov 26;73(47):30331-30344. doi: 10.1021/acs.jafc.5c10321. Epub 2025 Nov 7.
Diurnal fluctuations in cognitive function serve as a crucial regulatory foundation for maintaining neuroprotective mechanisms and metabolic homeostasis in the brain. High-fat diet (HFD) disrupts these fluctuations, yet nutritional strategies to mitigate this effect remain poorly explored. Here, the current research demonstrated that prebiotic fructo-oligosaccharides (FOS) ameliorated diurnal cognitive deficits (assessed by Barnes maze and novel object recognition tests) and restored hippocampal diurnal oscillations of neuroplasticity genes (, , ) and neuroinflammatory markers (TNFα, IL-6, IL-1β) in HFD-induced obese mice. Furthermore, FOS reshaped gut microbiota diurnal dynamics, enhanced intestinal barrier integrity (reflected in diurnal expression), and normalized the shifted diurnal patterns of microbial metabolites, particularly short-chain fatty acids (SCFAs). Consequently, FOS reinstated diurnal cognitive plasticity accompanied by normalization of SCFAs and gut-brain axis activity, highlighting a microbiota-targeted dietary approach for diurnal disruption in metabolic disorders.
128Modulation of Gut Microbiota Through Dietary Intervention in Neuroinflammation and Alzheimer's and Parkinson's Diseases.PubMed
Şerife Ayten, Saniye Bilici
Curr Nutr Rep. 2024 Jun;13(2):82-96. doi: 10.1007/s13668-024-00539-7. Epub 2024 Apr 23.
PURPOSE OF REVIEW: The gut microbiota plays a crucial role in the pathogenesis of neuroinflammation and Alzheimer's and Parkinson's diseases. One of the main modulators of the gut microbiota is the diet, which directly influences host homeostasis and biological processes. Some dietary patterns can affect neurodegenerative diseases' progression through gut microbiota composition, gut permeability, and the synthesis and secretion of microbial-derived neurotrophic factors and neurotransmitters. This comprehensive review critically assesses existing studies investigating the impact of dietary interventions on the modulation of the microbiota in relation to neurodegenerative diseases and neuroinflammation. RECENT FINDINGS: There are limited studies on the effects of specific diets, such as the ketogenic diet, Mediterranean diet, vegetarian diet, and Western diet, on the progression of neuroinflammation and Alzheimer's and Parkinson's diseases through the gut-brain axis. The ketogenic diet displays promising potential in ameliorating the clinical trajectory of mild cognitive impairment and Alzheimer's disease. However, conflicting outcomes were observed among various studies, highlighting the need to consider diverse types of ketogenic diets and their respective effects on clinical outcomes and gut microbiota composition. Vegetarian and Mediterranean diets, known for their anti-inflammatory properties, can be effective against Parkinson's disease, which is related to inflammation in the gut environment. On the other hand, the westernization of dietary patterns was associated with reduced gut microbial diversity and metabolites, which ultimately contributed to the development of neuroinflammation and cognitive impairment. Various studies examining the impact of dietary interventions on the gut-brain axis with regard to neuroinflammation and Alzheimer's and Parkinson's diseases are thoroughly reviewed in this article. A strong mechanistic explanation is required to fully understand the complex interactions between various dietary patterns, gut microbiota, and microbial metabolites and the effects these interactions have on cognitive function and the progression of these diseases.
129Bugs, guts and brains, and the regulation of food intake and body weight.PubMed
M K Hamilton, H E Raybould
Int J Obes Suppl. 2016 Dec;6(Suppl 1):S8-S14. doi: 10.1038/ijosup.2016.3. Epub 2016 Nov 16.
The microbiota-gut-brain axis is currently being explored in many types of rodent models, including models of behavioral, neurodegenerative and metabolic disorders. Our laboratory is interested in determining the mechanisms and consequences of activation of vagal afferent neurons that lead to activation of parasympathetic reflexes and changes in feeding behavior in the context of obesity. Obesity is associated with microbial dysbiosis, decreased intestinal barrier function, gut inflammation, metabolic endotoxemia, chronic low-grade systemic inflammation and desensitization of vagal afferent nerves. This review will present the evidence that altered gut microbiota together with decreased gut barrier function allows the passage of bacterial components or metabolites in obese individuals, leading to the disruption of vagal afferent signaling and consequently resulting in an increase in body weight. We first review the most recent descriptions of gut microbial dysbiosis due to a high fat diet and describe changes in the gut barrier and the evidence of increased intestinal permeability in obesity. We then will review the evidence to show how manipulating the gut microbiota via pre and probiotics can restore gut barrier function and prevent weight gain. Lastly, we present possible mechanisms by which the microbe-gut-brain axis may have a role in obesity. The studies mentioned in this review have provided new targets to treat and prevent obesity and have highlighted how the microbiota-gut-brain axis is involved.
130Microbiota fasting-related changes ameliorate cognitive decline in obesity and boost ex vivo microglial function through the gut-brain axis.PubMed
Virginia Mela, Violeta Heras, Monika Iesmantaite, et al.
Gut. 2025 Oct 8;74(11):1828-1846. doi: 10.1136/gutjnl-2025-335353.
BACKGROUND: Obesity-related cognitive decline is linked to gut microbiota dysbiosis, with emerging evidence suggesting that dietary interventions may ameliorate cognitive impairment via gut-brain axis modulation. The role of microglial cells in this process remains underexplored. OBJECTIVE: To investigate how diet-induced changes in gut microbiota influence cognitive function in individuals with obesity and their microglial activity, and to determine the impact of specific dietary interventions. DESIGN: This study included 96 participants with obesity who were randomised into three dietary intervention groups: Mediterranean diet (Med), alternate-day fasting (ADF) and ketogenic diet (Keto). Cognitive performance and microbiota composition were assessed pre-intervention and post-intervention. The effects of microbiota-related changes on microglial function were further evaluated in mice models through faecal transplantation and in vitro model with microbiota exosome treatment. RESULTS: Both the Keto and ADF groups demonstrated significant weight loss, but cognitive performance improved most notably in the ADF group, in association with reduced inflammation. Diet-related microbiota composition was correlated with the cognitive outcomes in the human study. Mice models confirmed that the cognitive benefits of ADF were microbiota-dependent and linked to enhanced microglial phagocytic capacity and reduced inflammation, accompanied by changes in microglia morphology. CONCLUSION: Fasting-induced modifications in gut microbiota contribute to cognitive improvement in individuals with obesity, with microglial cells playing a crucial mediatory role. Among the interventions, ADF most effectively enhanced microglial function and cognitive performance, suggesting its potential as a therapeutic strategy for obesity-related cognitive decline. Further studies are required to fully elucidate the underlying mechanisms. TRIAL REGISTRATION NUMBER: NCT04453150.
131Far-Infrared Therapy Based on Graphene Ameliorates High-Fat Diet-Induced Anxiety-Like Behavior in Obese Mice via Alleviating Intestinal Barrier Damage and Neuroinflammation.PubMed
Jin-Shui Zhang, Shuo Li, Xin Cheng, et al.
Neurochem Res. 2024 Jul;49(7):1735-1750. doi: 10.1007/s11064-024-04133-9. Epub 2024 Mar 26.
The consumption of a high-fat diet (HFD) has been implicated in the etiology of obesity and various neuropsychiatric disturbances, including anxiety and depression. Compelling evidence suggests that far-infrared ray (FIR) possesses beneficial effects on emotional disorders. However, the efficacy of FIR therapy in addressing HFD-induced anxiety and the underlying mechanisms remain to be elucidated. Here, we postulate that FIR emitted from a graphene-based therapeutic device may mitigate HFD-induced anxiety behaviors. The graphene-FIR modify the gut microbiota in HFD-mice, particularly by an enriched abundance of beneficial bacteria Clostridiaceae and Erysipelotrichaceae, coupled with a diminution of harmful bacteria Lachnospiraceae, Anaerovoracaceae, Holdemania and Marvinbryantia. Graphene-FIR also improved intestinal barrier function, as evidenced by the augmented expression of the tight junction protein occludin and G protein-coupled receptor 43 (GPR43). In serum level, we observed the decreased free fatty acids (FFA), lipopolysaccharides (LPS), diamine oxidase (DAO) and D-lactate, and increased the glucagon-like peptide-2 (GLP-2) levels in graphene-FIR mice. Simultaneously, inflammatory cytokines IL-6, IL-1β, and TNF-α manifested a decrease subsequent to graphene-FIR treatment in both peripheral and central system. Notably, graphene-FIR inhibited over expression of astrocytes and microglia. We further noticed that the elevated the BDNF and decreased TLR4 and NF-κB expression in graphene-FIR group. Overall, our study reveals that graphene-FIR rescued HFD-induced anxiety via improving the intestine permeability and the integrity of blood-brain barrier, and reduced inflammatory response by down regulating TLR4/NF-κB inflammatory pathway.
132Icariside II Ameliorates Depression Induced by High-Fat Diet via the Microbiota-Gut-Brain Axis in Mice.PubMed
Yun-Mei Luo, Lan Dong, Ye-Li Li, et al.
Phytother Res. 2025 Nov;39(11):5159-5173. doi: 10.1002/ptr.70103. Epub 2025 Sep 25.
Obesity can lead to depression via the microbiota-gut-brain axis. Icariside II (ICS II), a flavonoid compound derived from the traditional Chinese medicine Herbal Epimedium, exerts excellent neuroprotective effects. However, the pharmacological effects and underlying mechanisms of ICS II in obesity-induced depression remain unexplored. The present study aims to investigate whether ICS II can mitigate depression induced by a high-fat diet (HFD) in mice through modulating the microbiota-gut-brain axis. Metabolic parameters were reflected through changes in body weight and blood lipids, while depressive phenotypes were evaluated through behavioral tests and neurotransmitter analysis. The microbiota composition was analyzed by 16S ribosomal RNA gene sequencing, and short chain fatty acids (SCFAs) were detected by liquid chromatography-tandem mass spectrometry. The gut barrier and brain blood barrier (BBB) functions were observed by pathological methods. Fecal microbiota transplantation was used to demonstrate the causality of microbiota-mediated effects. The results showed that ICS II alleviated obesity status and depressive-like behaviors. ICS II reshaped gut microbiota and increased SCFAs. Meanwhile, ICS II relieved gut barrier impairment and systemic inflammation. In the brain, ICS II alleviated neuroinflammation and BBB injury. Intriguingly, fecal microbiota from ICS II-treated HFD mice improved depressive-like behaviors, intestinal barrier dysfunction, and BBB damage compared with those receiving microbiota from HFD mice. Our findings reveal for the first time that ICS II improves the obesity-related metabolic dysregulation and alleviates HFD-induced depression via the microbiota-gut-brain axis. Overall, this study indicates that ICS II is a potential candidate compound for treating obesity-related mental diseases.
133Green Tea Ameliorates Depression-Like Behavior and Cognitive Impairment Induced by High-Fat Diet and Chronic Mild Stress.PubMed
Minghao Fan, Yudi Jiang, Chao Cai, et al.
Phytother Res. 2025 Apr 17. doi: 10.1002/ptr.8499.
Depression often develops in young individuals and is linked to complications like cognitive impairment. Conventional antidepressants show limited efficacy in restoring cognitive function and may cause adverse effects. Green tea, a safe and health-promoting beverage, offers various health benefits. This study investigated the effects of long-term green tea consumption on stress-induced depression-like behavior and mild cognitive impairment in animal models. We established a rodent model of mild depression and studied the effects of green tea on depression-like behavior and cognitive impairment through comprehensive evaluation, including behavioral assessments, neurotransmitter quantification, gene and protein expression analysis, blood metabolite profiling, and gut microbiota characterization. Results demonstrated significant improvements in mood, long-term memory, and sterol and glycerophospholipid metabolism. Green tea repaired the intestinal barrier and upregulated genes vital for tight junctions and mucin production. It also enhanced gut microbiota composition, reducing the Firmicutes-to-Bacteroidetes ratio and promoting beneficial bacteria such as NK4A136, Muribaculum, and Gordonibacter. These microbiota changes improved liver lipid metabolism and alleviated depressive symptoms. Green tea effectively mitigates depression-like behavior and cognitive deficits by modulating the gut-liver-brain axis.
134The microbiota-gut-brain axis in stress and depression.PubMed
Hwei-Ee Tan
Front Neurosci. 2023 Apr 14;17:1151478. doi: 10.3389/fnins.2023.1151478. eCollection 2023.
Humans and animals are evolved to have instinctive physiological responses to threats. The perception of threat by the brain triggers a multitude of changes across the brain and body. A large body of research have demonstrated that our hardwired survival instinct, the stress response, can become maladaptive and promote major depressive disorders and other neuropsychiatric impairments. However, gaps in our understanding of how chronic stress contributes to depression and mental disorders suggest that we also need to consider factors beyond the biology of the host. The unravelling of the structure and function of microorganisms that humans and animals are host to have driven a paradigm shift in understanding the individual as a collective network composed of the host plus microbes. Well over 90% of bacteria in the body reside in the large intestines, and these microbes in the lower gut function almost like an organ in the body in the way it interacts with the host. Importantly, bidirectional interactions between the gut microbiota and the brain (i.e., the two-way microbiota-gut-brain axis) have been implicated in the pathophysiology of mental disorders including depression. Here, in summarizing the emerging literature, we envisage that further research particularly on the efferent brain-gut-microbiota axis will uncover transformative links in the biology of stress and depression.
135Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome.PubMed
Rachel D Moloney, Anthony C Johnson, Siobhain M O'Mahony, et al.
CNS Neurosci Ther. 2016 Feb;22(2):102-17. doi: 10.1111/cns.12490. Epub 2015 Dec 10.
Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut-brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.
136The microbiota-gut-brain axis in hippocampus-dependent learning and memory: current state and future challenges.PubMed
Eloise J Kuijer, Laura Steenbergen
Neurosci Biobehav Rev. 2023 Sep;152:105296. doi: 10.1016/j.neubiorev.2023.105296. Epub 2023 Jun 26.
A fundamental shift in neuroscience suggests bidirectional interaction of gut microbiota with the healthy and dysfunctional brain. This microbiota-gut-brain axis has mainly been investigated in stress-related psychopathology (e.g. depression, anxiety). The hippocampus, a key structure in both the healthy brain and psychopathologies, is implicated by work in rodents that suggests gut microbiota substantially impact hippocampal-dependent learning and memory. However, understanding microbiota-hippocampus mechanisms in health and disease, and translation to humans, is hampered by the absence of a coherent evaluative approach. We review the current knowledge regarding four main gut microbiota-hippocampus routes in rodents: through the vagus nerve; via the hypothalamus-pituitary-adrenal-axis; by metabolism of neuroactive substances; and through modulation of host inflammation. Next, we suggest an approach including testing (biomarkers of) the four routes as a function of the influence of gut microbiota (composition) on hippocampal-dependent (dys)functioning. We argue that such an approach is necessary to proceed from the current state of preclinical research to beneficial application in humans to optimise microbiota-based strategies to treat and enhance hippocampal-dependent memory (dys)functions.
137Nod-like receptors are critical for gut-brain axis signalling in mice.PubMed
Matteo M Pusceddu, Mariana Barboza, Ciara E Keogh, et al.
J Physiol. 2019 Dec;597(24):5777-5797. doi: 10.1113/JP278640. Epub 2019 Nov 27.
KEY POINTS: •Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. •Nod-like receptors regulate central and peripheral serotonergic biology. •Nod-like receptors are important for maintenance of gastrointestinal physiology. •Intestinal epithelial cell expression of Nod1 receptors regulate behaviour. ABSTRACT: Gut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre Nod1 ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.
138Psychological stress in inflammatory bowel disease: Psychoneuroimmunological insights into bidirectional gut-brain communications.PubMed
Li Ge, Shuman Liu, Sha Li, et al.
Front Immunol. 2022 Oct 6;13:1016578. doi: 10.3389/fimmu.2022.1016578. eCollection 2022.
Inflammatory bowel disease (IBD), mainly including ulcerative colitis (UC) and Crohn's disease (CD), is an autoimmune gastrointestinal disease characterized by chronic inflammation and frequent recurrence. Accumulating evidence has confirmed that chronic psychological stress is considered to trigger IBD deterioration and relapse. Moreover, studies have demonstrated that patients with IBD have a higher risk of developing symptoms of anxiety and depression than healthy individuals. However, the underlying mechanism of the link between psychological stress and IBD remains poorly understood. This review used a psychoneuroimmunology perspective to assess possible neuro-visceral integration, immune modulation, and crucial intestinal microbiome changes in IBD. Furthermore, the bidirectionality of the brain-gut axis was emphasized in the context, indicating that IBD pathophysiology increases the inflammatory response in the central nervous system and further contributes to anxiety- and depression-like behavioral comorbidities. This information will help accurately characterize the link between psychological stress and IBD disease activity. Additionally, the clinical application of functional brain imaging, microbiota-targeted treatment, psychotherapy and antidepressants should be considered during the treatment and diagnosis of IBD with behavioral comorbidities. This review elucidates the significance of more high-quality research combined with large clinical sample sizes and multiple diagnostic methods and psychotherapy, which may help to achieve personalized therapeutic strategies for IBD patients based on stress relief.
139Antibiotics, gut microbiota, and Alzheimer's disease.PubMed
Francesco Angelucci, Katerina Cechova, Jana Amlerova, et al.
J Neuroinflammation. 2019 May 22;16(1):108. doi: 10.1186/s12974-019-1494-4.
Alzheimer's disease (AD) is a neurodegenerative disease whose various pathophysiological aspects are still being investigated. Recently, it has been hypothesized that AD may be associated with a dysbiosis of microbes in the intestine. In fact, the intestinal flora is able to influence the activity of the brain and cause its dysfunctions.Given the growing interest in this topic, the purpose of this review is to analyze the role of antibiotics in relation to the gut microbiota and AD. In the first part of the review, we briefly review the role of gut microbiota in the brain and the various theories supporting the hypothesis that dysbiosis can be associated with AD pathophysiology. In the second part, we analyze the possible role of antibiotics in these events. Antibiotics are normally used to remove or prevent bacterial colonization in the human body, without targeting specific types of bacteria. As a result, broad-spectrum antibiotics can greatly affect the composition of the gut microbiota, reduce its biodiversity, and delay colonization for a long period after administration. Thus, the action of antibiotics in AD could be wide and even opposite, depending on the type of antibiotic and on the specific role of the microbiome in AD pathogenesis.Alteration of the gut microbiota can induce changes in brain activity, which raise the possibility of therapeutic manipulation of the microbiome in AD and other neurological disorders. This field of research is currently undergoing great development, but therapeutic applications are still far away. Whether a therapeutic manipulation of gut microbiota in AD could be achieved using antibiotics is still not known. The future of antibiotics in AD depends on the research progresses in the role of gut bacteria. We must first understand how and when gut bacteria act to promote AD. Once the role of gut microbiota in AD is well established, one can think to induce modifications of the gut microbiota with the use of pre-, pro-, or antibiotics to produce therapeutic effects.
140Gut-Brain-Microbiota Axis: Antibiotics and Functional Gastrointestinal Disorders.PubMed
Tarkan Karakan, Ceren Ozkul, Esra Küpeli Akkol, et al.
Nutrients. 2021 Jan 27;13(2):389. doi: 10.3390/nu13020389.
Gut microbiota composition and function are major areas of research for functional gastrointestinal disorders. There is a connection between gastrointestinal tract and central nervous system and this is mediated by neurotransmitters, inflammatory cytokines, the vagus nerve and the hypothalamic-pituitary-adrenal axis. Functional gastrointestinal disorders are prevalent diseases affecting more than one third of the population. The etiology of these disorders is not clarified. Visceral hyperalgesia is the main hypothesis for explaining clinical symptoms, however gut-brain axis disorder is a new terminology for functional disorders. In this review, microbiota-gut-brain axis connection pathways and related disorders are discussed. Antibiotics are widely used in developed countries and recent evidence indicates antibiotic-induced dysbiosis as an important factor for functional disorders. Antibiotics exert negative effects on gut microbiota composition and functions. Antibiotic-induced dysbiosis is a major factor for occurrence of post-infectious irritable bowel syndrome. Cognitive and mood disorders are also frequent in functional gastrointestinal disorders. Animal and human trials show strong evidence for the causal relationship between gut microbiota and brain functions. Therapeutic implications of these newly defined pathogenic pathways are also discussed.
141Gut/brain axis and the microbiota.PubMed
Emeran A Mayer, Kirsten Tillisch, Arpana Gupta
J Clin Invest. 2015 Mar 2;125(3):926-38. doi: 10.1172/JCI76304. Epub 2015 Feb 17.
Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.
142The Microbiota-Gut-Brain Axis and Alzheimer's Disease: Neuroinflammation Is to Blame?PubMed
Ashwinipriyadarshini Megur, Daiva Baltriukienė, Virginija Bukelskienė, et al.
Nutrients. 2020 Dec 24;13(1):37. doi: 10.3390/nu13010037.
For years, it has been reported that Alzheimer's disease (AD) is the most common cause of dementia. Various external and internal factors may contribute to the early onset of AD. This review highlights a contribution of the disturbances in the microbiota-gut-brain (MGB) axis to the development of AD. Alteration in the gut microbiota composition is determined by increase in the permeability of the gut barrier and immune cell activation, leading to impairment in the blood-brain barrier function that promotes neuroinflammation, neuronal loss, neural injury, and ultimately AD. Numerous studies have shown that the gut microbiota plays a crucial role in brain function and changes in the behavior of individuals and the formation of bacterial amyloids. Lipopolysaccharides and bacterial amyloids synthesized by the gut microbiota can trigger the immune cells residing in the brain and can activate the immune response leading to neuroinflammation. Growing experimental and clinical data indicate the prominent role of gut dysbiosis and microbiota-host interactions in AD. Modulation of the gut microbiota with antibiotics or probiotic supplementation may create new preventive and therapeutic options in AD. Accumulating evidences affirm that research on MGB involvement in AD is necessary for new treatment targets and therapies for AD.
143Opioids, Opioid AntagonistsPubMed
The opioids are a large class of medications related in structure to the natural plant alkaloids found in opium that are derived from the resin of the opium poppy, Papaver somniferum. The natural alkaloids are also referred to as opiates and include morphine and codeine. Synthetic derivatives include heroin, fentanyl, hydromorphone, methadone, buprenorphine and others. The opioids are highly potent and effective analgesics, but most have a high potential for dependency and abuse. Opioids act by engagement of specific cell surface receptors; the opiate receptors, which are designated µ [mu], κ [kappa] and δ [delta]. These receptors are found predominantly in the central nervous system, brain and spinal column, but are also present on vascular, cardiac, lung, gut and even peripheral blood mononuclear cells. Engagement of the opiate receptors generates a series of intracellular signals, including inhibition of adenylate cyclase, decreased opening of calcium channels, increased potassium currents and activation of protein kinase C (PKC). The major effect of these pathways is reduction in cell excitability and neurotransmission. The natural ligands for the opiate receptors are the so-called endogenous opioid peptides such as the enkephalins, endorphins and endomorphins. The opioids have a variety of clinical effects, but are predominantly known and used for their profound pain relieving effects. Other effects that are often linked to opiate analgesia include euphoria, changes in mood, drowsiness and mental clouding. However, the distinctive feature of the analgesia induced by the opioids is the lack of loss of consciousness. The pain is often described as less intense, but still present although better tolerated. Thus, the opioids do not decrease or treat the cause of the painful stimulus, but rather decrease its perception. Other effects of opioids include respiratory depression, decreased gastrointestinal motility, sedation, nausea, vomiting, constipation and intestinal bloating. Opioids also have direct cardiovascular effects, decreasing blood pressure, causing vasodilation and decreasing cardiac work. Most opioids have similar effects and side effects, although pharmacokinetic differences, tissue distribution, and receptor type specificity probably account for the variation in effects of the various synthetic and semisynthetic derivatives of morphine. Morphine is considered the prototype opiate, against which other agents are measured for their analgesic effects as well as adverse side effects. The opioids can be categorized into subclasses on the basis of their chemical structure as opium alkaloids (opiates: codeine, morphine), semisynthetic derivatives of the natural alkaloids (hydrocodone, hydromorphone, oxycodone, buprenorphine), and various classes of synthetic opioids such as the anililopiperidines (fentanyl, alfentanil, sufentanil, remifentanil), diphenylpropylamine derivatives (propoxyphene, dextropropoxyphene, methadone, diphenoxylate, loperamide), and others (pentazocine, butorphanol, nalbuphine, levorphanol, tramadol), and, the opioid antagonists (nalmefene, naloxone and naltrexone). They can also be informally classified based upon their major use such as anesthesia (fentanyl, alfentanil, remifentanil, sufentanil), severe pain (morphine, hydromorphone, levorphanol, meperidine), moderate-to-severe acute or chronic pain (transdermal or transbuccal fentanyl, codeine, oxycodone, hydrocodone, levorphanol, methadone), diarrhea (loperamide, diphenoxylate), and cough (codeine, hydrocodone). Finally, opioids can be categorized on the basis of their action as full agonists, partial agonists or mixed agonists/antagonists, and antagonists of opiate receptors. Opioid receptor antagonists are used to reverse the effects of opioids and are invaluable in the management of opioid overdose (naloxone, naltrexone, nalmefene). Specialized opioid antagonists can be used to reverse unwanted opioid effects, such as constipation in patients with chronic pain on long-term opioids. These agents (naldemedine, naloxegol) are generally modified so as not to cross the blood brain and reverse the central nervous system effects of opiates. Opioids are rare causes of drug induced liver disease and are not mentioned in large case series of clinically apparent liver injury caused by medications. In physiological, pain relieving doses, opioids have not been implicated in causing clinically apparent liver injury, acute liver failure, chronic hepatitis or vanishing bile duct syndrome. However, overdoses of the more potent opioids have been linked to cases of acute liver injury, usually with a precipitous onset and pattern of acute toxicity with marked elevations in serum aminotransferase levels and early onset of signs of hepatic failure. This syndrome has been best characterized after buprenorphine overdose or abuse, but likely occurs with others. It is possible that the implicated opioids are not directly toxic to the liver, but cause ischemic liver injury due to respiratory failure, cardiovascular collapse, shock and anoxia that can occur with severe opioid overdose. The clinical syndrome resembles acute hepatic necrosis and liver failure, but is rapidly reversible and rarely the primary cause of death from overdose. A special form of liver injury linked to opioid use occurs with their fixed drug combinations with acetaminophen. These combinations are commonly used for moderate to moderately severe pain and can lead to abuse. If taken too frequently, acetaminophen doses may reach toxic levels, particularly with overuse for several days in the face of malnutrition, alcohol abuse or intercurrent illness. These other stresses can lower hepatic glutathione levels and predispose to acetaminophen hepatotoxicity. This constellation of events is referred to as inadvertent or unintended acetaminophen overdose or more colloquially as a “therapeutic misadventure”. Because of their potential for hepatotoxicity, opioid combinations in which the dose of acetaminophen is greater than 325 mg per tablet or capsule were discontinued. References to the safety and hepatotoxic potential of the various opiate agonists are given together at the end of this overview section. References to the opioids and the opiate antagonists used to treat substance abuse are given separately with each agent (buprenorphine, methadone, nalmefene, naloxone, naltrexone). The opioids are discussed individually or as groups of agents and links to each are given below. Full and partial agonists: • Alfentanil • Buprenorphine • Butorphanol • Codeine • Diphenoxylate • Fentanyl • Heroin • Hydrocodone • Hydromorphone • Levorphanol • Loperamide • Meperidine • Methadone • Morphine • Oliceridine • Opium • Oxycodone • Oxymorphone • Pentazocine • Remifentanil • Sufentanil • Tramadol Opiate antagonists: • Naldemedine • Nalmefene • Naloxegol • Naloxone • Naltrexone
144Gut microbiota, immunity and pain.PubMed
Matteo Santoni, Francesca Miccini, Nicola Battelli
Immunol Lett. 2021 Jan;229:44-47. doi: 10.1016/j.imlet.2020.11.010. Epub 2020 Nov 25.
The interplay between microbiota and nervous system has been associated with a variety of diseases, including stress, anxiety, depression and cognition. The growing body of evidences on the essential role of gut microbiota in modulating acute and chronic pain has opened a new frontier for pain management. Gut microbiota is involved in the development of visceral, inflammatory and neuropathic pain. Bacterial alterations due to chronic opioid administration have been directly related to the development of drug tolerance, which can be potentially restored by the use of probiotics and antibiotics. In this review we describe the mechanisms underlying the brain/gut axis and the relationship between gut microbiota, immunity and pain.
145Probiotic Supplementation Improves Cognitive Function and Mood with Changes in Gut Microbiota in Community-Dwelling Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.PubMed
Chong-Su Kim, Lina Cha, Minju Sim, et al.
J Gerontol A Biol Sci Med Sci. 2021 Jan 1;76(1):32-40. doi: 10.1093/gerona/glaa090.
Probiotics have been proposed to ameliorate cognitive impairment and depressive disorder via the gut-brain axis in patients and experimental animal models. However, the beneficial role of probiotics in brain functions of healthy older adults remains unclear. Therefore, a randomized, double-blind, and placebo-controlled multicenter trial was conducted to determine the effects of probiotics on cognition and mood in community-dwelling older adults. Sixty-three healthy elders (≥65 years) consumed either placebo or probiotics containing Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI for 12 weeks. The gut microbiota was analyzed using 16S rRNA sequencing and bioinformatics. Brain functions were measured using the Consortium to Establish a Registry for Alzheimer's disease, Satisfaction with life scale, stress questionnaire, Geriatric depression scale, and Positive affect and negative affect schedule. Blood brain-derived neurotrophic factor (BDNF) was determined using enzyme-linked immunosorbent assay. Relative abundance of inflammation-causing gut bacteria was significantly reduced at Week 12 in the probiotics group (p < .05). The probiotics group showed greater improvement in mental flexibility test and stress score than the placebo group (p < .05). Contrary to placebo, probiotics significantly increased serum BDNF level (p < .05). Notably, the gut microbes significantly shifted by probiotics (Eubacterium and Clostridiales) showed significant negative correlation with serum BDNF level only in the probiotics group (RS = -0.37, RS = -0.39, p < .05). In conclusion, probiotics promote mental flexibility and alleviate stress in healthy older adults, along with causing changes in gut microbiota. These results provide evidence supporting health-promoting properties of probiotics as a part of healthy diet in the older adults.
146The Microbiome-Gut-Brain Axis in Health and Disease.PubMed
Timothy G Dinan, John F Cryan
Gastroenterol Clin North Am. 2017 Mar;46(1):77-89. doi: 10.1016/j.gtc.2016.09.007. Epub 2017 Jan 4.
Gut microbes are capable of producing most neurotransmitters found in the human brain. Evidence is accumulating to support the view that gut microbes influence central neurochemistry and behavior. Irritable bowel syndrome is regarded as the prototypic disorder of the brain-gut-microbiota axis that can be responsive to probiotic therapy. Translational studies indicate that certain bacteria may have an impact on stress responses and cognitive functioning. Manipulating the gut microbiota with psychobiotics, prebiotics, or even antibiotics offers a novel approach to altering brain function and treating gut-brain axis disorders, such as depression and autism.
147The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders.PubMed
Katarzyna Socała, Urszula Doboszewska, Aleksandra Szopa, et al.
Pharmacol Res. 2021 Oct;172:105840. doi: 10.1016/j.phrs.2021.105840. Epub 2021 Aug 24.
Emerging evidence indicates that the gut microbiota play a crucial role in the bidirectional communication between the gut and the brain suggesting that the gut microbes may shape neural development, modulate neurotransmission and affect behavior, and thereby contribute to the pathogenesis and/or progression of many neurodevelopmental, neuropsychiatric, and neurological conditions. This review summarizes recent data on the role of microbiota-gut-brain axis in the pathophysiology of neuropsychiatric and neurological disorders including depression, anxiety, schizophrenia, autism spectrum disorders, Parkinson's disease, migraine, and epilepsy. Also, the involvement of microbiota in gut disorders co-existing with neuropsychiatric conditions is highlighted. We discuss data from both in vivo preclinical experiments and clinical reports including: (1) studies in germ-free animals, (2) studies exploring the gut microbiota composition in animal models of diseases or in humans, (3) studies evaluating the effects of probiotic, prebiotic or antibiotic treatment as well as (4) the effects of fecal microbiota transplantation.
148Gut microbes in neurocognitive and mental health disorders.PubMed
Tyler Halverson, Kannayiram Alagiakrishnan
Ann Med. 2020 Dec;52(8):423-443. doi: 10.1080/07853890.2020.1808239. Epub 2020 Aug 31.
INTRODUCTION: As individuals age, the prevalence of neurocognitive and mental health disorders increases. Current biomedical treatments do not completely address the management of these conditions. Despite new pharmacological therapy the challenges of managing these diseases remain.There is increasing evidence that the Gut Microbiome (GM) and microbial dysbiosis contribute to some of the more prevalent mental health and neurocognitive disorders, such as depression, anxiety, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (BP), and dementia as well as the behavioural and psychological symptoms of dementia (BPSD) through the microbiota-gut-brain axis. Scoping review about the effect of gut microbiota on neurocognitive and mental health disorders. RESULTS: This scoping review found there is an evolving evidence of the involvement of the gut microbiota in the pathophysiology of neurocognitive and mental health disorders. This manuscript also discusses how the psychotropics used to treat these conditions may have an antimicrobial effect on GM, and the potential for new strategies of management with probiotics and faecal transplantation. CONCLUSIONS: This understanding can open up the need for a gut related approach in these disorders as well as unlock the door for the role of gut related microbiota management. KEY MESSAGES Challenges of managing mental health conditions remain in spite of new pharmacological therapy. Gut dysbiosis is seen in various mental health conditions. Various psychotropic medications can have an influence on the gut microbiota by their antimicrobial effect.
149Efficacy and safety of fecal microbiota transplantation for the treatment of diseases other than infection: a systematic review and meta-analysis.PubMed
Jessica Emily Green, Jessica A Davis, Michael Berk, et al.
Gut Microbes. 2020 Nov 9;12(1):1-25. doi: 10.1080/19490976.2020.1854640.
The intestinal microbiome has been identified as a key modifier for a variety of health conditions. Fecal Microbiota Transplantation (FMT) has emerged as a fast, safe, and effective means by which to modify the intestinal microbiome and potentially treat a variety of health conditions. Despite extensive research of FMT for CDI, there is a lack of clarity informed by systematic synthesis of data regarding the safety and efficacy of FMT for other health conditions. This systematic review used PRISMA guidelines and was prospectively registered with PROSPERO (CRD42018104243). In March 2020, a search of MEDLINE, EMBASE, and PsycINFO was conducted. We identified 26 eligible studies. A meta-analysis of FMT for active Ulcerative Colitis (UC) showed that FMT significantly improved rates of clinical remission (OR = 3.634, 95% CI = 1.940 to 6.808, I = 0%, < .001), clinical response (OR = 2.634, 95% CI = 1.441 to 4.815, I = 33%, = .002) and endoscopic remission (OR = 4.431, 95% CI = 1.901 to 10.324, I = 0%, = .001). With respect to Irritable Bowel Syndrome, a meta-analysis showed no significant change in symptoms following FMT ( = .739). Hepatic disorders, metabolic syndrome, and antibiotic-resistant organisms were conditions with emerging data on FMT. Serious adverse events (AE) were more often reported in control group participants (n = 43) compared with FMT group participants (n = 26). There were similar rates of mild to moderate AE in both groups. Preliminary data suggest that FMT is a potentially safe, well-tolerated and efficacious treatment for certain conditions other than CDI, with evidence for active UC being the most compelling.
150Parkinson's disease and gut microbiota: from clinical to mechanistic and therapeutic studies.PubMed
Xuxiang Zhang, Beisha Tang, Jifeng Guo
Transl Neurodegener. 2023 Dec 15;12(1):59. doi: 10.1186/s40035-023-00392-8.
Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases. The typical symptomatology of PD includes motor symptoms; however, a range of nonmotor symptoms, such as intestinal issues, usually occur before the motor symptoms. Various microorganisms inhabiting the gastrointestinal tract can profoundly influence the physiopathology of the central nervous system through neurological, endocrine, and immune system pathways involved in the microbiota-gut-brain axis. In addition, extensive evidence suggests that the gut microbiota is strongly associated with PD. This review summarizes the latest findings on microbial changes in PD and their clinical relevance, describes the underlying mechanisms through which intestinal bacteria may mediate PD, and discusses the correlations between gut microbes and anti-PD drugs. In addition, this review outlines the status of research on microbial therapies for PD and the future directions of PD-gut microbiota research.
151Alcohol Addiction, Gut Microbiota, and Alcoholism Treatment: A Review.PubMed
Shao-Cheng Wang, Yuan-Chuan Chen, Shaw-Ji Chen, et al.
Int J Mol Sci. 2020 Sep 3;21(17):6413. doi: 10.3390/ijms21176413.
Alcohol addiction is a leading risk factor for personal death and disability. In 2016, alcohol use caused 2.2% of female deaths and 6.8% of male deaths, and disability-adjusted life years (DALYs) were 2.3% in female and 8.9% in male. Individuals with alcohol use disorder are at high risk of anxiety, depression, impaired cognition performance, and illicit drug use and are comorbid with liver disease, such as alcoholic hepatitis and liver cirrhosis, which is a major cause of personal death and disability worldwide. Psychological interventions, such as cognitive behavior therapy and motivational interviewing, as well as medical treatments, such as disulfiram, naltrexone, acamprosate, and nalmefene, are used for the treatment of alcohol addiction in Europe and the United States. However, the effect of current interventions is limited, and the need for additional interventions is substantial. Alcohol use impairs the intestinal barrier and causes changes to the intestinal permeability as well as the gut microbiota composition. Emerging studies have tried to reveal the role of the gut-brain axis among individuals with alcohol use disorder with or without alcohol liver disease. Bacterial products penetrate the impaired intestinal barrier and cause central inflammation; changes to the gut microbiota impair enterohepatic circulation of bile acids; alcohol abuse causes shortage of vital nutrients such as thiamine. Several studies have suggested that probiotics, through either oral administration or fecal microbiota transplantation, increased intestinal levels of potentially beneficial bacteria such as bifidobacteria and lactobacilli, improving the levels of liver-associated enzymes in patients with mild alcoholic hepatitis, and demonstrating beneficial psychotropic effects on anxiety and depression. In addition to medications for alcohol addiction, gene editing therapy such as clustered regularly interspaced short palindromic repeats (CRISPRs) may be another potential research target. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are associated with ADH and ALDH genes, are major enzymes involved in alcohol metabolism, and gene editing approaches may have the potential to directly modify specific genes to treat alcoholism caused by genetic defects. Further research is needed to study the effect of the combined treatment for alcohol addiction.
152Gut liver brain axis in diseases: the implications for therapeutic interventions.PubMed
Mengyao Yan, Shuli Man, Benyue Sun, et al.
Signal Transduct Target Ther. 2023 Dec 6;8(1):443. doi: 10.1038/s41392-023-01673-4.
Gut-liver-brain axis is a three-way highway of information interaction system among the gastrointestinal tract, liver, and nervous systems. In the past few decades, breakthrough progress has been made in the gut liver brain axis, mainly through understanding its formation mechanism and increasing treatment strategies. In this review, we discuss various complex networks including barrier permeability, gut hormones, gut microbial metabolites, vagus nerve, neurotransmitters, immunity, brain toxic metabolites, β-amyloid (Aβ) metabolism, and epigenetic regulation in the gut-liver-brain axis. Some therapies containing antibiotics, probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), polyphenols, low FODMAP diet and nanotechnology application regulate the gut liver brain axis. Besides, some special treatments targeting gut-liver axis include farnesoid X receptor (FXR) agonists, takeda G protein-coupled receptor 5 (TGR5) agonists, glucagon-like peptide-1 (GLP-1) receptor antagonists and fibroblast growth factor 19 (FGF19) analogs. Targeting gut-brain axis embraces cognitive behavioral therapy (CBT), antidepressants and tryptophan metabolism-related therapies. Targeting liver-brain axis contains epigenetic regulation and Aβ metabolism-related therapies. In the future, a better understanding of gut-liver-brain axis interactions will promote the development of novel preventative strategies and the discovery of precise therapeutic targets in multiple diseases.
153Unexpected Roles for the Second Brain: Enteric Nervous System as Master Regulator of Bowel Function.PubMed
Sabine Schneider, Christina M Wright, Robert O Heuckeroth
Annu Rev Physiol. 2019 Feb 10;81:235-259. doi: 10.1146/annurev-physiol-021317-121515. Epub 2018 Oct 31.
At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system. The most carefully studied ENS functions include control of bowel motility, epithelial secretion, and blood flow, but the ENS also interacts with enteroendocrine cells, influences epithelial proliferation and repair, modulates the intestinal immune system, and mediates extrinsic nerve input. Here, we review the many different cell types that communicate with the ENS, integrating data about ENS function into a broader view of human health and disease. In particular, we focus on exciting new literature highlighting relationships between the ENS and its lesser-known interacting partners.
154From bugs to brain: unravelling the GABA signalling networks in the brain-gut-microbiome axis.PubMed
Delia Belelli, Jeremy J Lambert, Murphy Lam Yim Wan, et al.
Brain. 2025 May 13;148(5):1479-1506. doi: 10.1093/brain/awae413.
Convergent data across species paint a compelling picture of the critical role of the gut and its resident microbiota in several brain functions and disorders. The chemicals mediating communication along these sophisticated highways of the brain-gut-microbiome (BGM) axis include both microbiota metabolites and classical neurotransmitters. Amongst the latter, GABA is fundamental to brain function, mediating most neuronal inhibition. Until recently, GABA's role and specific molecular targets in the periphery within the BGM axis had received limited attention. Yet, GABA is produced by neuronal and non-neuronal elements of the BGM, and recently, GABA-modulating bacteria have been identified as key players in GABAergic gut systems, indicating that GABA-mediated signalling is likely to transcend physiological boundaries and species. We review the available evidence to better understand how GABA facilitates the integration of molecularly and functionally disparate systems to bring about overall homeostasis and how GABA perturbations within the BGM axis can give rise to multi-system medical disorders, thereby magnifying the disease burden and the challenges for patient care. Analysis of transcriptomic databases revealed significant overlaps between GABAAR subunits expressed in the human brain and gut. However, in the gut, there are notable expression profiles for a select number of subunits that have received limited attention to date but could be functionally relevant for BGM axis homeostasis. GABAergic signalling, via different receptor subtypes, directly regulates BGM homeostasis by modulating the excitability of neurons within brain centres responsible for gastrointestinal (GI) function in a sex-dependent manner, potentially revealing mechanisms underlying the greater prevalence of GI disturbances in females. Apart from such top-down regulation of the BGM axis, a diverse group of cell types, including enteric neurons, glia, enteroendocrine cells, immune cells and bacteria, integrate peripheral GABA signals to influence brain functions and potentially contribute to brain disorders. We propose several priorities for this field, including the exploitation of available technologies to functionally dissect components of these GABA pathways within the BGM, with a focus on GI and brain-behaviour-disease. Furthermore, in silico ligand-receptor docking analyses using relevant bacterial metabolomic datasets, coupled with advances in knowledge of GABAAR 3D structures, could uncover new ligands with novel therapeutic potential. Finally, targeted design of dietary interventions is imperative to advancing their therapeutic potential to support GABA homeostasis across the BGM axis.
155From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson's Disease.PubMed
Alba Montalbán-Rodríguez, Raquel Abalo, Laura López-Gómez
Int J Mol Sci. 2024 Jan 20;25(2):1294. doi: 10.3390/ijms25021294.
The brain-gut axis has been identified as an important contributor to the physiopathology of Parkinson's disease. In this pathology, inflammation is thought to be driven by the damage caused by aggregation of α-synuclein in the brain. Interestingly, the Braak's theory proposes that α-synuclein misfolding may originate in the gut and spread in a "prion-like" manner through the vagus nerve into the central nervous system. In the enteric nervous system, enteric glial cells are the most abundant cellular component. Several studies have evaluated their role in Parkinson's disease. Using samples obtained from patients, cell cultures, or animal models, the studies with specific antibodies to label enteric glial cells (GFAP, Sox-10, and S100β) seem to indicate that activation and reactive gliosis are associated to the neurodegeneration produced by Parkinson's disease in the enteric nervous system. Of interest, Toll-like receptors, which are expressed on enteric glial cells, participate in the triggering of immune/inflammatory responses, in the maintenance of intestinal barrier integrity and in the configuration of gut microbiota; thus, these receptors might contribute to Parkinson's disease. External factors like stress also seem to be relevant in its pathogenesis. Some authors have studied ways to reverse changes in EGCs with interventions such as administration of Tryptophan-2,3-dioxygenase inhibitors, nutraceuticals, or physical exercise. Some researchers point out that beyond being activated during the disease, enteric glial cells may contribute to the development of synucleinopathies. Thus, it is still necessary to further study these cells and their role in Parkinson's disease.
156Dietary Modulation of the Enteric Nervous System: From Molecular Mechanisms to Therapeutic Applications.PubMed
Xintong Wang, Wen Zhang, Huihui Wang, et al.
Nutrients. 2025 Nov 11;17(22):3519. doi: 10.3390/nu17223519.
The enteric nervous system (ENS), frequently referred to as the "second brain," is integral to maintaining gastrointestinal and systemic homeostasis. The structural and functional homeostasis of the ENS is crucial for both local intestinal processes (digestion, immunity) and systemic physiological equilibrium via the gut-brain axis, directly influencing overall health and disease. In recent years, dietary substances have attracted increasing scholarly attention for their potential to modulate the ENS, attributed to their safety and accessibility. This review commences with a systematic exploration of the anatomical structure of the ENS, including the myenteric and submucosal plexuses, its cellular constituents such as enteric neurons and enteric glial cells, and its core physiological functions, encompassing the regulation of gastrointestinal motility, the secretion-absorption balance, and the maintenance of immune homeostasis. Subsequently, it delineates the classification, distribution, and properties of essential dietary components, encompassing polyphenols, short-chain fatty acids, amino acids and their derivatives, as well as prebiotics and probiotics. Additionally, it examines the mechanisms through which these substances modulate the physiological functions of the ENS, including the regulation of intestinal motility, support for neuronal survival and network integrity, and the maintenance of neuro-immune homeostasis. The review concludes by highlighting current limitations-including reliance on rodent models, unclear human ENS mechanisms, and imprecise interventions-and proposes future directions focused on precision medicine, clinical translation, and advanced tools like single-cell sequencing and targeted delivery systems.
157The Effect of Curcumin on the Gut-Brain Axis: Therapeutic Implications.PubMed
Ayesheh Enayati, Aida Soghi, Alexandra E Butler, et al.
J Neurogastroenterol Motil. 2023 Oct 30;29(4):409-418. doi: 10.5056/jnm23065.
The gut-brain axis describes the bidirectional communication between the gut, the enteric nervous system, and the central nervous system. The gut-brain axis has attracted increasing attention owing to its regulatory effect on dysbiosis and a wide range of related diseases. Several types of nutrients, such as curcumin, have been proposed as regulators of the dysbiotic state, and preclinical experiments have suggested that curcumin is not only beneficial but also safe. This review focuses on the interplay between curcumin and the gut microbiota. Moreover, it provides a comprehensive review of the crosstalk between the gut-brain axis and disease, whilst also discussing curcumin-mediated gut-brain axis-dependent and -independent signaling about modulation of gut microbiota dysbiosis. This will help to define the utility of curcumin as a novel therapeutic agent to regulate intestinal microflora dysbiosis.
158Gut-Brain Axis, Neurodegeneration and Mental Health: A Personalized Medicine Perspective.PubMed
Alisha Chunduri, S Deepak Mohan Reddy, M Jahanavi, et al.
Indian J Microbiol. 2022 Dec;62(4):505-515. doi: 10.1007/s12088-022-01033-w. Epub 2022 Aug 10.
Neurological conditions such as neurodegenerative diseases and mental health disorders are a result of multifactorial underpinnings, leading to individual-based complex phenotypes. Demystification of these multifactorial connections will promote disease diagnosis and treatment. Personalized treatment rather than a one-size-fits-all approach would enable us to cater to the unmet healthcare needs based on protein-protein and gene-environment interactions. Gut-brain axis, as the name suggests, is a two-way biochemical communication pathway between the central nervous system (CNS) and enteric nervous system (ENS), enabling a mutual influence between brain and peripheral intestinal functions. The gut microbiota is a major component of this bidirectional communication, the composition of which is varied depending on the age, and disease conditions, among other factors. Gut microbiota profile is typically unique and personalized therapeutic intervention can aid in treating or delaying neurodegeneration and mental health conditions. Besides, research on the gut microbial influence on these conditions is gaining attention, and a better understanding of this concept can lead to identification of novel targeted therapies.
159Integrating Gut-Brain Axis: Exploring the Neurogastrointestinal Interactions and Therapeutic Potentials in Autism Spectrum Disorder.PubMed
Manjeet Kumar, Sidharth Mehan, Tarun Sharma, et al.
Endocr Metab Immune Disord Drug Targets. 2025 Apr 7. doi: 10.2174/0118715303369166250325110016.
This comprehensive review critically examines the gut-brain axis (GBA) and its implications in autism spectrum disorder (ASD). The GBA is a complex, bidirectional communication network that integrates the gastrointestinal tract, the central nervous system, and the gut microbiota. This axis is mediated through various physiological pathways, including the enteric nervous system (ENS), the vagus nerve, immune responses, and metabolic activities of gut microorganisms. ASD, a developmental disorder marked by social impairments and repetitive behaviors, presents with notable neurological irregularities. The review highlights the increased prevalence of gastrointestinal (GI) disturbances in individuals with ASD, suggesting a potential link between GI symptoms and the severity of ASD-related behaviors. This correlation is supported by evidence of altered gut microbiota composition in ASD, indicating significant interactions between the gut environment and neurological health. Moreover, the pathophysiology of ASD is explored with an emphasis on genetic and environmental contributions to neurodevelopmental impairments. Key topics include synaptic dysfunction, the roles of neurotransmitters like GABA and serotonin, and the impact of gut-brain interactions on ASD progression. Specifically, this review addresses how gut microbiota may influence metabolic alterations, immune dysregulation, oxidative stress, mitochondrial function, and neurotransmitter production in ASD. Emerging research on microbiome-based therapies for ASD is discussed, focusing on the potential of probiotics, prebiotics, and faecal microbiota transplantation (FMT) as novel interventions. Ethical considerations in this burgeoning field are also considered, highlighting the necessity for rigorous scientific inquiry and ethical oversight. The review advocates for a multidisciplinary approach to understanding and addressing the complexities of ASD. By integrating insights from genetics, neuroscience, psychology, and gastroenterology, a more comprehensive understanding of the role of GBA in ASD can be achieved. This interdisciplinary perspective is crucial for developing effective, individualized treatments and improving the quality of life for individuals with ASD.
160Microbiota-dependent early-life programming of gastrointestinal motility.PubMed
Mary E Frith, Purna C Kashyap, David R Linden, et al.
iScience. 2024 Sep 6;27(10):110895. doi: 10.1016/j.isci.2024.110895. eCollection 2024 Oct 18.
Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNA sequencing (RNA-seq) of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later-or not at all-showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early-life microbiome in later-life dysmotility.
161Review of research progress on intestinal microbiota based on metabolism and inflammation for depression.PubMed
Yunxiang Tan, Mengyu Xu, Deng Lin
Arch Microbiol. 2024 Mar 10;206(4):146. doi: 10.1007/s00203-024-03866-z.
Depression is a prevalent mental illness, affecting a significant portion of the global population. Recent research has highlighted the crucial role of the gut microbiota in both metabolic and central nervous health. By reviewing literature from various databases, including Pubmed, Science Direct, Web of Science, and Scopus, spanning the years 2005-2023, a comprehensive search was conducted using keywords such as "Depression" and "Gut Microbiota". The gut microbiota acts as a "second brain" in humans and can communicate bidirectionally with the brain through the Brain-gut-microbiota axis pathway. This communication involves the immune and nervous systems. However, there are challenges in detecting and treating depression effectively. To address these limitations, researchers have been exploring the relationship between gut microbiota and depression. Studies have shown that gut microbial metabolites, such as lipopolysaccharides and short-chain fatty acids, can induce pro-inflammatory cytokines that contribute to neuroinflammation and increase the risk of depression. The kynurenine pathway, triggered by gut microbial metabolites, has also been associated with neuroinflammation. Thus, investigating these microbial metabolites can provide insights into depression treatment. This review focuses on analyzing the connection between gut microbial metabolites, inflammation, and depression. It explores novel mechanisms contributing to depression, specifically focusing on the mediation of inflammation through the release of pro-inflammatory cytokines. The objective is to provide valuable insights into the mechanisms underlying depression and to propose potential treatments.
162A critical analysis of eating disorders and the gut microbiome.PubMed
Sydney M Terry, Jacqueline A Barnett, Deanna L Gibson
J Eat Disord. 2022 Nov 3;10(1):154. doi: 10.1186/s40337-022-00681-z.
The gut microbiota, also known as our "second brain" is an exciting frontier of research across a multitude of health domains. Gut microbes have been implicated in feeding behaviour and obesity, as well as mental health disorders including anxiety and depression, however their role in the development and maintenance of eating disorders (EDs) has only recently been considered. EDs are complex mental health conditions, shaped by a complicated interplay of factors. Perhaps due to an incomplete understanding of the etiology of EDs, treatment remains inadequate with affected individuals likely to face many relapses. The gut microbiota may be a missing piece in understanding the etiology of eating disorders, however more robust scientific inquiry is needed in the field before concrete conclusions can be made. In this spotlight paper, we critically evaluate what is known about the bi-directional relationship between gut microbes and biological processes that are implicated in the development and maintenance of EDs, including physiological functioning, hormones, neurotransmitters, the central nervous system, and the immune system. We outline limitations of current research, propose concrete steps to move the field forward and, hypothesize potential clinical implications of this research. Our gut is inhabited by millions of bacteria which have more recently been referred to as "our second brain". In fact, these microbes are thought to play a role in ED behaviour, associated anxiety and depression, and even affect our weight. Recent research has dove into this field with promising findings that have the potential to be applied clinically to improve ED recovery. The present paper discusses what is known about the gut microbiome in relation to EDs and the promising implications that leveraging this knowledge, through fecal microbiome transplants, probiotics, and microbiome-directed supplemental foods, could have on ED treatment.
163Diabetic gastrointestinal autonomic neuropathy: Integrating neuronal degeneration and gut microbial dysbiosis.PubMed
Mei-Xia Zhou, Yu Zhao, Chen-Ling Chu, et al.
World J Diabetes. 2025 Sep 15;16(9):110053. doi: 10.4239/wjd.v16.i9.110053.
Diabetic gastrointestinal autonomic neuropathy (DGAN) is a common and debilitating complication of diabetes, characterized by autonomic dysfunction in the gastrointestinal system. The complex pathophysiology of DGAN involves neuronal injury that is intrinsically linked to gut dysbiosis. Multiple factors, including hyperglycemia, oxidative stress, and inflammation, significantly contribute to neuronal damage, manifesting as symptoms such as delayed gastric emptying, diarrhea, and constipation. Recent studies have demonstrated that patients with diabetes experience substantial alterations in gut microbiota composition, potentially exacerbating gastrointestinal symptoms. Microbial metabolites may modulate neurotransmitter synthesis and release, directly affecting autonomic nerve function, while dysbiosis amplifies oxidative stress and inflammation, further compromising the enteric nervous system and worsening DGAN. Advances in multi-omics technologies now provide deeper insights into molecular mechanisms of DGAN and its interactions with microbiota. Early diagnosis leveraging biomarkers, gut microbiota analysis, and advanced imaging promises more effective interventions. Emerging therapeutic strategies targeting oxidative stress, inflammation, and gut microbiota represent promising approaches for managing DGAN. Future research should focus on large-scale, multi-ethnic studies and therapies targeting specific microbial metabolites to refine diagnosis and treatment approaches.
164[Unique characteristics of "the second brain" - The enteric nervous system].PubMed
Jun-Hua Li, Rui Duan, Liang Li, et al.
Sheng Li Xue Bao. 2020 Jun 25;72(3):382-390.
Enteric nervous system (ENS) is composed of intestinal submucosal and myenteric plexuses. ENS may independently regulate intestinal digestive and absorptive function, and it is also known as "the second brain" or gut brain. ENS has significant specificity relative to central nervous system (CNS) in properties and functional activities of neurons and neural circuits. ENS is connected with CNS through the feedback pathway (brain-gut-axis) of sympathetic and parasympathetic nerves and peripheral primary sensory afferent nerves to form the bidirectional brain-gut-axis, which may affect emotion, appetite and behavioral states of individuals. Gastrointestinal functional disorder (GIFD) induced by ENS dysfunction may not only cause abnormal gastrointestinal function but also has been implicated in cognitive and mood disorders, such as irritable bowel syndrome (IBS). GIFD would influence deeply the quality of life in patients. Nevertheless, in the worldwide, ENS has so far received much less attention as compared with CNS. The depth of research and scale of investment in ENS studies have been much lower than those in CNS studies. The situation in China is even more evident. From ENS research history, an outstanding problem is to ignore largely the unique properties of ENS and apply mechanically the hypotheses formed in CNS studies to ENS researches. In this review, the structure and function of ENS are briefly introduced, and the importance of extraordinary characteristics of ENS is illustrated by the problems encountered in our studies.
165The enteric nervous system: a second brain.PubMed
M D Gershon
Hosp Pract (1995). 1999 Jul 15;34(7):31-2, 35-8, 41-2 passim. doi: 10.3810/hp.1999.07.153.
Once dismissed as a simple collection of relay ganglia, the enteric nervous system is now recognized as a complex, integrative brain in its own right. Although we still are unable to relate complex behaviors such as gut motility and secretion to the activity of individual neurons, work in that area is proceeding briskly--and will lead to rapid advances in the management of functional bowel disease.
166Probiotics for Alzheimer's Disease: A Systematic Review.PubMed
Ruth Naomi, Hashim Embong, Fezah Othman, et al.
Nutrients. 2021 Dec 22;14(1):20. doi: 10.3390/nu14010020.
Alzheimer's disease (AD) is the most common form of neurodegenerative disorders affecting mostly the elderly. It is characterized by the presence of Aβ and neurofibrillary tangles (NFT), resulting in cognitive and memory impairment. Research shows that alteration in gut microbial diversity and defects in gut brain axis are linked to AD. Probiotics are known to be one of the best preventative measures against cognitive decline in AD. Numerous in vivo trials and recent clinical trials have proven the effectiveness of selected bacterial strains in slowing down the progression of AD. It is proven that probiotics modulate the inflammatory process, counteract with oxidative stress, and modify gut microbiota. Thus, this review summarizes the current evidence, diversity of bacterial strains, defects of gut brain axis in AD, harmful bacterial for AD, and the mechanism of action of probiotics in preventing AD. A literature search on selected databases such as PubMed, Semantic Scholar, Nature, and Springer link have identified potentially relevant articles to this topic. However, upon consideration of inclusion criteria and the limitation of publication year, only 22 articles have been selected to be further reviewed. The search query includes few sets of keywords as follows. (1) Probiotics OR gut microbiome OR microbes AND (2) Alzheimer OR cognitive OR aging OR dementia AND (3) clinical trial OR in vivo OR animal study. The results evidenced in this study help to clearly illustrate the relationship between probiotic supplementation and AD. Thus, this systematic review will help identify novel therapeutic strategies in the future as probiotics are free from triggering any adverse effects in human body.
167The role of the microbiota-gut-brain axis and intestinal microbiome dysregulation in Parkinson's disease.PubMed
Qing Li, Ling-Bing Meng, Li-Jun Chen, et al.
Front Neurol. 2023 May 25;14:1185375. doi: 10.3389/fneur.2023.1185375. eCollection 2023.
Parkinson's disease (PD) is a complex progressive neurodegenerative disease associated with aging. Its main pathological feature is the degeneration and loss of dopaminergic neurons related to the misfolding and aggregation of α-synuclein. The pathogenesis of PD has not yet been fully elucidated, and its occurrence and development process are closely related to the microbiota-gut-brain axis. Dysregulation of intestinal microbiota may promote the damage of the intestinal epithelial barrier, intestinal inflammation, and the upward diffusion of phosphorylated α-synuclein from the enteric nervous system (ENS) to the brain in susceptible individuals and further lead to gastrointestinal dysfunction, neuroinflammation, and neurodegeneration of the central nervous system (CNS) through the disordered microbiota-gut-brain axis. The present review aimed to summarize recent advancements in studies focusing on the role of the microbiota-gut-brain axis in the pathogenesis of PD, especially the mechanism of intestinal microbiome dysregulation, intestinal inflammation, and gastrointestinal dysfunction in PD. Maintaining or restoring homeostasis in the gut microenvironment by targeting the gut microbiome may provide future direction for the development of new biomarkers for early diagnosis of PD and therapeutic strategies to slow disease progression.
168The microbiome-gut-brain axis in Parkinson disease - from basic research to the clinic.PubMed
Ai Huey Tan, Shen Yang Lim, Anthony E Lang
Nat Rev Neurol. 2022 Aug;18(8):476-495. doi: 10.1038/s41582-022-00681-2. Epub 2022 Jun 24.
Evidence for a close bidirectional link between the brain and the gut has led to a paradigm shift in neurology, especially in the case of Parkinson disease (PD), in which gastrointestinal dysfunction is a prominent feature. Over the past decade, numerous high-quality preclinical and clinical publications have shed light on the highly complex relationship between the gut and the brain in PD, providing potential for the development of new biomarkers and therapeutics. With the advent of high-throughput sequencing, the role of the gut microbiome has been specifically highlighted. Here, we provide a critical review of the literature on the microbiome-gut-brain axis in PD and present perspectives that will be useful for clinical practice. We begin with an overview of the gut-brain axis in PD, including the potential roles and interrelationships of the vagus nerve, α-synuclein in the enteric nervous system, altered intestinal permeability and inflammation, and gut microbes and their metabolic activities. The sections that follow synthesize the proposed roles of gut-related factors in the development and progression of, in responses to PD treatment, and as therapeutic targets. Finally, we summarize current knowledge gaps and challenges and delineate future directions for the field.