1. 抑郁焦虑与免疫系统的交互作用基础
1.1 神经-免疫轴的生理调控机制
神经系统和免疫系统之间存在着复杂的双向调控网络，即“神经-免疫轴”，它在维持机体内环境稳态中发挥关键作用。这个轴的核心组成部分包括下丘脑-垂体-肾上腺（HPA）轴和自主神经系统（ANS）。HPA轴是机体应对应激的核心神经内分泌通路。当机体感知到应激时，下丘脑会释放促肾上腺皮质激素释放激素（CRH），CRH进而刺激垂体前叶分泌促肾上腺皮质激素（ACTH），最终ACTH作用于肾上腺皮质，促使其释放糖皮质激素（如皮质醇）1。糖皮质激素是强效的免疫抑制剂，能够抑制多种免疫细胞的功能和细胞因子的产生，从而调节免疫反应强度，避免过度炎症损伤12。此外，CRH本身也能直接或间接影响免疫细胞功能，例如，中枢注射CRH已被证明能抑制特异性抗体的产生3。
自主神经系统，特别是交感神经和副交感神经系统，也紧密调控着免疫功能。迷走神经作为副交感神经系统的重要组成部分，通过释放神经递质（如乙酰胆碱）与免疫细胞进行交流，对炎症反应具有重要的调节作用456。炎症性细胞因子能够与迷走神经元沟通，从而激活或抑制外周免疫反应5。神经递质，如5-羟色胺（5-HT）和去甲肾上腺素（NE），在免疫细胞功能调节中扮演着重要角色。淋巴细胞表面存在5-HT1A受体和β-肾上腺素能受体，5-HT能促进淋巴细胞增殖，而去甲肾上腺素则抑制其增殖7。5-HT和去甲肾上腺素的平衡能够影响T辅助细胞（Th1/Th2）的免疫应答，从而在细胞介导免疫和体液免疫之间进行调节8。这些神经内分泌和神经递质的相互作用共同构成了精密的神经-免疫调控网络，确保免疫系统在需要时能够有效运作，并在应激和疾病状态下维持动态平衡910。
1.2 抑郁焦虑状态下的神经内分泌异常
抑郁焦虑作为一种慢性应激状态，显著扰乱了神经内分泌系统的正常功能，进而对免疫细胞活性产生抑制作用。其中，下丘脑-垂体-肾上腺（HPA）轴的过度激活是核心特征之一 1112。在慢性应激和抑郁状态下，HPA轴持续活跃，导致糖皮质激素（如皮质醇）分泌量持续升高，其负反馈调节机制可能受损，表现为中枢糖皮质激素受体对负反馈抑制的敏感性降低，进一步加剧HPA轴的激活 1213。糖皮质激素水平的长期升高被认为是免疫抑制的重要原因，它能广泛影响免疫细胞的功能，包括T细胞、NK细胞和巨噬细胞等。
除了HPA轴的异常，抑郁焦虑状态还常伴随自主神经系统功能的紊乱。迷走神经作为微生物-肠-脑轴中的重要组成部分，在调节应激反应中发挥作用 14。有研究表明，社会孤立等应激因素可导致促炎性NF-κB转录因子结合位点基因的过表达，以及抗炎性糖皮质激素反应元件（GREs）基因的表达不足，这种变化独立于循环皮质醇水平，提示神经内分泌系统以外的机制也参与其中 15。
这些神经内分泌的改变直接干扰免疫细胞内的信号转导通路。例如，有研究通过启动子生物信息学分析发现，在主观社会隔离程度高的人群中，出现促炎性NF-κB/Rel转录因子结合位点基因的过表达 15。NF-κB是炎症和免疫反应中的关键转录因子，其活性的改变会直接影响免疫细胞的增殖、分化和效应功能。此外，JAK-STAT信号通路也可能受到影响。JAK-STAT通路在细胞因子受体信号转导中起着核心作用，调控着免疫细胞的生长、分化和功能。有研究通过生物信息学分析发现，在主观社会隔离程度高的人群中，JAK/STAT等转录控制通路显示出差异活性 15。例如，慢性应激引起的促炎细胞因子（如IL-1β, IL-6, TNF-α）升高，虽然看似增强免疫，但长期作用反而可能导致免疫失调，并反过来进一步刺激HPA轴，形成恶性循环，进一步加剧神经内分泌和免疫功能的紊乱 111316。此外，神经递质5-HT系统在慢性应激下也会发生改变，例如5HT2A受体功能增强而5HT1A受体功能减弱，这也被认为是导致焦虑和抑郁的重要机制，并可能间接影响免疫功能 13。
2. 抑郁焦虑对关键免疫细胞活性的抑制路径
2.1 T细胞亚群功能紊乱
抑郁焦虑状态对T细胞亚群的平衡和功能产生显著影响，导致免疫系统的功能紊乱，这在多种研究中得到了证实。其中一个关键的表现是Th1/Th2细胞平衡的失调。Th1细胞主要介导细胞免疫，分泌IFN-γ等细胞因子，而Th2细胞则主要介导体液免疫，分泌IL-4、IL-5、IL-10等。慢性应激，作为抑郁焦虑的重要诱因，已被观察到能导致Th2细胞比例显著增加，从而引起Th1/Th2平衡向Th2偏移，同时伴随促炎细胞因子IL-1α、IL-1β、IFN-γ和GM-CSF水平显著降低，而IL-2水平明显升高 17。这种Th1/Th2失衡可能导致机体在应对细胞内病原体感染和肿瘤免疫监视方面能力下降。
调节性T细胞（Treg细胞）是维持免疫耐受和抑制过度免疫反应的关键细胞亚群。抑郁焦虑状态常伴随Treg细胞功能或数量的改变。例如，有研究发现，焦虑和应激症状与循环Treg细胞及其亚群（如Helios阳性Treg细胞和TIM-3阳性Treg细胞）水平呈负相关 18。在重度抑郁症患者中，未经选择性5-羟色胺再摄取抑制剂（SSRI）治疗的患者，其外周Treg细胞的FOXP3表达和pSTAT5水平显著降低，表明Treg细胞的功能受损；而SSRI治疗后，这些指标有所改善 19。此外，有动物模型研究显示，Treg细胞耗竭会加剧小鼠的焦虑和抑郁样行为，并上调多种细胞因子（如IL-6、TNF-α、IL-2、IFN-γ、IL-4和IL-17A）的浓度 20。相反，也有研究发现类风湿关节炎患者在抑郁状态下Treg细胞数量扩张 21，这可能提示了不同疾病背景下Treg细胞在抑郁焦虑中的复杂性和异质性。
CD4+和CD8+记忆T细胞的功能衰减也是抑郁焦虑状态下T细胞功能障碍的体现。慢性应激可能影响T细胞的活化标记表达，例如，研究发现抑郁症患者表现出T细胞活化标记物（如CD2+CD25+、CD3+CD25+和HLA-DR+）的数量和百分比增加，同时伴随IFN-γ刺激性产生增加 22。然而，功能上，这些活化可能并非有效免疫应答的体现，而是免疫系统失调的标志。例如，高焦虑个体表现出较低的CTACK/CCL27、IL-12和IFN-γ基因表达，以及肿瘤浸润性辅助性T细胞（Th）和细胞毒性T淋巴细胞（CTL）数量减少 23，提示保护性免疫力受损。
细胞因子在介导抑郁焦虑引起的T细胞功能抑制中发挥核心作用。IL-6和TNF-α等促炎细胞因子在抑郁症中普遍升高 22。这些细胞因子可以介导多种免疫抑制效应，例如，IL-6、IL-1β和TNF-α等促炎细胞因子被发现参与多种癌症的发生、发展和复发 24。此外，Th17细胞（一种分泌IL-17的T细胞亚群，具有促炎作用）在抑郁症的病理生理学中也扮演重要角色。研究表明，Th17细胞的积累和Th17/Treg失衡在重度抑郁症和抑郁样行为动物模型中至关重要 252627。Th17细胞可能通过干扰谷氨酸信号、多巴胺产生以及其他免疫过程，进一步加剧抑郁症状并影响T细胞功能。这些复杂的相互作用共同构成了抑郁焦虑状态下T细胞亚群功能紊乱的机制。
2.2 NK细胞活性与免疫监视受损
抑郁焦虑状态对自然杀伤（NK）细胞的活性产生显著的抑制作用，这在多项研究中得到了证实 28。NK细胞是固有免疫系统的重要组成部分，主要负责非特异性杀伤肿瘤细胞和病毒感染细胞，在免疫监视中发挥关键作用。抑郁焦虑导致的慢性应激通常伴随着NK细胞脱颗粒能力下降，表现为细胞毒性作用减弱。
这种抑制作用的分子机制与糖皮质激素的过度释放密切相关。在应激状态下，下丘脑-垂体-肾上腺轴（HPA轴）的持续激活导致糖皮质激素（如皮质醇）水平升高 2。糖皮质激素通过与免疫细胞上的糖皮质激素受体结合，影响其增殖、细胞因子分泌和细胞毒性功能。例如，研究表明糖皮质激素可以降低NK细胞的数量和活性 2。此外，其他神经免疫调节因子也可能参与NK细胞的抑制。例如，P物质（Substance P, SP）作为一种神经免疫调节剂，在抑郁和HIV感染等NK细胞功能受损的病理状态下循环水平升高。研究发现，SP能通过神经激肽-1受体（NK1R）直接抑制NK细胞的细胞毒性，并降低脱颗粒作用，其机制可能涉及缩短靶细胞结合诱导的细胞内钙离子升高和减少触发受体诱导的pERK磷酸化 29。
抑郁焦虑对NK细胞活性的抑制具有重要的临床关联。首先，它可能导致机体免疫监视功能受损，增加肿瘤发生的风险或促进癌症进展。NK细胞是抗肿瘤免疫的第一道防线，其活性下降意味着肿瘤细胞更容易逃避免疫清除。例如，有研究发现，在口腔外科门诊患者中，对癌症的焦虑显著降低了NK细胞活性 30。慢性应激可能通过抑制NK细胞活性来促进白血病进展 31。其次，NK细胞活性的下降还会削弱机体对抗病毒感染的能力。NK细胞在病毒感染的早期阶段发挥关键作用，通过直接杀伤感染细胞和分泌细胞因子（如IFN-γ）来限制病毒复制和传播。抑郁焦虑状态下NK细胞功能的减弱，可能导致病毒感染的易感性增加或病毒清除能力下降。例如，巨细胞病毒（HCMV）感染者在运动后NK细胞动员受损，提示宿主感染史可能影响免疫系统对应激的反应 32。
总之，抑郁焦虑通过 HPA 轴的激活导致糖皮质激素升高，以及其他神经递质（如P物质）的调节，抑制了NK细胞的活性和脱颗粒能力，从而损害了机体的免疫监视功能，增加了肿瘤和病毒感染的风险。
2.3 脑内微胶质细胞的异常激活
抑郁焦虑状态下，脑内微胶质细胞（Microglia）的异常激活是其影响免疫细胞活性的一个关键路径。微胶质细胞是中枢神经系统（CNS）的常驻免疫细胞，在正常生理条件下，它们持续巡视大脑微环境，在神经发育、突触修剪以及清除细胞碎片方面发挥重要作用 333435。然而，在慢性应激、抑郁和焦虑等病理状态下，微胶质细胞会被异常激活，并呈现出不同的极化表型 3536。
抑郁焦虑常导致微胶质细胞向M1型（促炎表型）极化 35363738。M1型微胶质细胞通过释放一系列促炎细胞因子，如白细胞介素-1β (IL-1β)、白细胞介素-6 (IL-6) 和肿瘤坏死因子-α (TNF-α)，来介导神经炎症 3738394041424344。这些促炎因子对神经元功能和突触可塑性产生显著破坏作用。例如，IL-1β、IL-6和TNF-α的升高可导致突触传递增强或抑制，最终影响海马区的长时程增强（LTP）等关键的突触可塑性过程，进而损害学习和记忆功能 45。慢性应激诱导的微胶质细胞激活和促炎细胞因子释放，已被证明与抑郁症患者和动物模型中的神经元功能障碍及抑郁相关行为密切相关 464748。此外，神经元本身也可分泌含有miR-9-5p等miRNA的外泌体，促进微胶质细胞向M1型极化，形成恶性循环，加剧神经炎症和神经损伤 40。
微胶质细胞的异常激活不仅直接影响神经元，还可通过释放IL-1β、IL-18等因子间接抑制外周免疫细胞活性，形成神经-免疫交叉抑制机制。IL-1β和IL-18是重要的促炎细胞因子，它们的释放往往通过炎症小体（inflammasome）的激活，特别是NLRP3炎症小体途径 374249。这些细胞因子不仅在CNS内引起炎症反应，还可以通过血液循环进入外周，对全身免疫系统产生影响。例如，IL-1β被认为是连接神经炎症和HPA轴功能障碍的关键分子，进而影响外周免疫细胞。微胶质细胞持续激活，尤其是在血脑屏障（BBB）不完整的区域（如后脑区），可能导致慢性炎症状态并对外周免疫细胞的功能产生长期影响 50。多巴胺信号通路也参与调节髓系细胞（包括微胶质细胞）中IL-1β的产生，通过不同多巴胺受体的表达比例影响IL-1β的水平，进而可能放大炎症反应并影响免疫功能 42。
微胶质细胞M1型极化导致的促炎环境，进一步抑制了神经发生（neurogenesis）过程，尤其是在海马齿状回区域。海马神经发生对情绪调节和抗抑郁作用至关重要 3441。促炎细胞因子如IL-1β和TNF-α可以直接抑制神经干细胞的增殖和分化，从而减少新神经元的生成，加剧抑郁症状。一些研究显示，调节微胶质细胞极化（如促进M2型极化，即抗炎表型）能够缓解抑郁样行为，并改善海马神经发生 373851。例如，木兰醇通过诱导M2型极化和抑制NLRP3炎症小体信号通路来减轻抑郁样行为 37。埃斯氯胺酮（Esketamine）也通过抑制微胶质细胞M1型极化和改善BDNF-TrkB通路来预防术后情绪和认知功能障碍 36。因此，微胶质细胞的异常激活是抑郁焦虑引起免疫抑制和神经功能障碍的关键环节。
3. 肠道-脑轴在免疫抑制中的中介作用
3.1 肠嗜铬细胞（EC细胞）-5-HT信号的异常传导
肠道-脑轴是一个复杂的双向通讯系统，通过神经、内分泌和免疫途径连接肠道和大脑，调节包括情绪、应激反应和炎症在内的多种生理过程 5253。在抑郁焦虑状态下，肠道-脑轴的异常活动在中介免疫抑制中发挥着重要作用，其中肠嗜铬细胞（Enterochromaffin cells, EC细胞）及其产生的5-羟色胺（5-HT）信号是关键环节。
EC细胞是胃肠道黏膜内数量最多的内分泌细胞，尤其在十二指肠和直肠中密度最高 54。它们作为感受器，能够对肠腔内的压力、细菌产物以及膳食成分等物质作出反应 54。当EC细胞被激活时，会释放大量的5-HT。这些释放的5-HT作用于肠黏膜传入神经和肌间神经元的多种受体，从而启动分泌运动反射，引发恶心、呕吐、肠道分泌和蠕动增加，严重时可导致腹泻 54。
在应激和抑郁焦虑状态下，EC细胞的过度激活和5-HT的异常释放与肠道局部的免疫抑制密切相关。例如，在肠易激综合征（IBS）等疾病模型中，尤其是感染后IBS（PI-IBS），观察到直肠活检中EC细胞数量和粘膜5-HT含量显著增加 5455。这种现象与炎症反应有关，动物研究表明，炎症可以通过T淋巴细胞增加EC细胞数量和黏膜5-HT含量，而炎症细胞因子则会降低5-HT转运蛋白（SERT）的功能，进一步增加5-HT的生物利用度 54。
EC细胞释放的过量5-HT不仅影响肠道运动功能，还可能通过肠黏膜神经传入激活焦虑相关脑区。肠道中的5-HT能神经元直接与中枢神经系统相连，将肠道信号传递至大脑，从而影响情绪和行为 5254。例如，高水平的肠道5-HT可能通过迷走神经等传入通路，将“肠道不适”信号传递给大脑，诱发或加剧焦虑情绪。
此外，过量的5-HT还会抑制肠道局部免疫细胞的功能，尤其是黏膜T细胞。虽然5-HT在某些情境下对淋巴细胞具有促进增殖作用，但在肠道炎症或应激条件下，EC细胞释放的5-HT可能通过复杂的旁分泌或自分泌机制，影响肠道免疫细胞的活性和细胞因子分泌模式。例如，有研究表明，糖皮质激素（在应激中升高）能够显著降低肠黏膜T淋巴细胞的数量 55。尽管泼尼松龙未能显著改变EC细胞数量或改善感染后IBS症状，但它显著降低了固有层T淋巴细胞数量 55。这提示了肠道炎症和5-HT信号与局部免疫细胞活性之间的复杂相互作用。
3.2 肠道菌群代谢物的免疫调节失衡
肠道菌群及其代谢产物在抑郁焦虑导致的免疫抑制中扮演着中介角色。研究表明，抑郁症患者常表现出肠道菌群失调（dysbiosis），即肠道微生物组成和功能的改变 56。这种失调导致多种代谢产物的异常，其中短链脂肪酸（SCFAs）的减少和内毒素（LPS）的易位增加是关键。
短链脂肪酸（SCFAs），如丁酸盐、丙酸盐和乙酸盐，是肠道细菌发酵膳食纤维的主要产物，对维持肠道屏障完整性和免疫稳态至关重要 5758。它们不仅为肠上皮细胞提供能量，还具有抗炎和免疫调节作用。在抑郁焦虑状态下，肠道菌群多样性降低，特别是产生SCFAs的有益菌（如Faecalibacterium和Coprococcus）数量减少 5960。这导致SCFAs生成不足，削弱了其对肠道屏障的保护作用，可能使得肠道通透性增加。
与此同时，肠道菌群失调还可能引起内毒素（脂多糖，LPS）的易位增加。LPS是革兰氏阴性菌细胞壁的组成部分，正常情况下被肠道屏障有效阻隔在肠腔内。然而，在肠道通透性增加时，LPS可以进入宿主循环，引发全身性炎症反应 6162。抑郁焦虑患者血液中LPS水平的升高与炎症性抑郁症的发生相关 63。LPS通过激活 Toll 样受体 4 (TLR4) 信号通路，促进宿主免疫细胞（如巨噬细胞和单核细胞）释放大量促炎细胞因子，如IL-1β、IL-6和TNF-α 6465。这些促炎细胞因子不仅直接作用于外周免疫细胞，诱导其功能失调，还可以通过血脑屏障进入大脑，引发神经炎症，进一步加剧抑郁和焦虑症状 66。
LPS诱导的TLR4信号通路激活及其导致的系统性炎症，对T细胞功能具有抑制作用。促炎细胞因子如IL-6的升高，虽然在某些情况下可增强免疫应答，但长期慢性炎症反而会抑制T细胞增殖和分化，导致免疫疲劳，并干扰T细胞亚群的平衡 63。例如，高水平的LPS暴露可能导致T细胞对抗原刺激的反应性降低，或促使T细胞向非功能性或抑制性表型转化。这种“肠道-脑-免疫”负反馈环路的形成意味着肠道菌群失调引起的代谢产物异常不仅直接影响肠道免疫，还通过炎症介导的途径，对外周和中枢免疫系统产生广泛的抑制效应，进一步加剧抑郁焦虑的病理生理过程 67。例如，在溃疡性结肠炎患者中，抑郁和焦虑伴随着肠道微生物多样性降低，以及拟杆菌属（Bacteroides）和梭杆菌属（Fusobacterium）等菌属增加，而普雷沃氏菌属（Prevotella）和粪杆菌属（Faecalibacterium）减少，这与血清代谢产物和免疫蛋白的异常高度关联 68。微藻基水凝胶通过调节肠道菌群和肠道-脑轴，已被证明可以改善炎症性肠病及其相关的焦虑和抑郁症状 69。
3.3 性别差异的生物学基础
抑郁焦虑症在女性中的发病率是男性的两倍，且女性更容易受到与焦虑和抑郁相关的免疫抑制的影响 70。这种显著的性别差异，在很大程度上与肠道-脑轴中，特别是肠嗜铬细胞（EC细胞）-迷走神经通路的“紧张性激活”特征在女性中表现更为突出有关 7172。
女性EC细胞的生理特性似乎使其对某些刺激更为敏感，从而导致更多的5-HT释放。例如，研究显示，肥胖女性的十二指肠EC细胞在葡萄糖刺激下释放的5-HT量比体重正常的女性和男性高3到4倍 73。此外，胆霍乱毒素在雌性小鼠（处于动情期）中能迅速抑制结肠运动，而这种效应在雄性小鼠或处于非动情期的雌性小鼠中不明显，且这种性别特异性效应与结肠黏膜中含5-HT的EC细胞数量在动情期雌性中显著增加有关 74。这表明，在特定生理状态下，女性肠道EC细胞具有更高的活性和5-HT释放潜力。
这种EC细胞的“紧张性激活”通过迷走神经通路影响脑功能。肠道中的5-HT能神经元将信号传导至中枢神经系统，影响情绪和行为。女性EC细胞在应激下释放的过量5-HT可能通过迷走神经等传入通路，将肠道信号传递至大脑，从而更易诱发或加剧焦虑情绪。迷走神经张力与应激反应和情绪调节密切相关，而女性在应激反应中表现出与男性不同的神经内分泌特征，如HPA轴的反应性可能更高 72。这种神经通路上的性别差异，可能使得女性对肠道信号更为敏感，更容易将肠道紊乱转化为中枢情绪障碍。
进一步地，这种性别差异的肠道-脑轴激活对免疫系统产生特异性影响。抑郁焦虑状态下，女性更容易出现T细胞亚群比例异常等免疫变化 75。例如，在产后抑郁症女性中，正常生理状态下Treg细胞活性应增强以维持免疫耐受，但她们未能表现出这种生理性增强的T细胞活性，并且CD4+ T辅助记忆细胞数量也有所减少 76。此外，有研究表明，肠道菌群调节干预在性别特异性方面表现出差异，例如益生菌在青春期小鼠中可以预防脂多糖（LPS）诱导的免疫反应和应激引起的抑郁样行为（雌性）和焦虑样行为（雄性），提示肠道菌群对情绪和免疫的影响存在性别特异性 77。
促炎细胞因子在抑郁症中普遍升高，而女性似乎对这些炎症反应更为敏感。例如，新冠病毒感染者中，尽管炎症标志物水平较低，但女性更容易出现焦虑和抑郁症状 7879。这可能与女性免疫系统在面对炎症时，其响应模式和细胞因子表达谱与男性不同有关。炎症，作为免疫系统的重要组成部分，其在女性中可能扮演着更重要的角色，加剧了抑郁和焦虑的发生发展 75。抗炎细胞因子IL-10的表达变化与抑郁样行为有关，且这种行为改变在雌性小鼠中比雄性小鼠更显著，提示抗炎细胞因子与性激素之间可能存在相互作用 80。
综合来看，女性肠道EC细胞-迷走神经通路的“紧张性激活”特征，可能导致其在面对应激和炎症时，更容易产生过量的5-HT释放，并通过神经-免疫途径影响T细胞亚群的平衡，从而表现出性别特异性的免疫抑制和情绪障碍易感性。
4. 免疫抑制的临床关联与疾病负担
4.1 感染易感性与慢性炎症恶化
抑郁焦虑状态对免疫细胞活性的抑制，显著增加了机体对感染的易感性，并可能恶化慢性炎症性疾病的进程。这种效应主要通过影响固有免疫细胞，如中性粒细胞和巨噬细胞的功能来实现。
中性粒细胞是机体抵御细菌和真菌感染的第一道防线，其关键功能包括趋化（迁移至感染部位）和吞噬病原体。然而，抑郁焦虑相关的慢性应激会导致中性粒细胞趋化能力的下降。例如，高强度运动训练引起的生理应激，与中性粒细胞功能（包括吞噬活性和氧化爆发）的降低有关，这被认为是运动员对上呼吸道感染易感性增加的原因之一 818283。虽然此处为生理应激，但其机制与抑郁焦虑诱导的糖皮质激素升高和神经递质失衡具有相似性，暗示抑郁焦虑同样能通过影响中性粒细胞的迁移和功能而增加感染风险。在脓毒症等严重感染状态下，中性粒细胞的趋化能力受损是导致免疫功能障碍和预后不良的重要因素 8485。抑郁焦虑导致的免疫抑制可能模拟或加剧这种中性粒细胞功能障碍，使机体更难有效清除感染。
巨噬细胞是另一类重要的固有免疫细胞，负责吞噬病原体、清除细胞碎片和呈递抗原，在启动适应性免疫应答中发挥核心作用。抑郁焦虑状态下，巨噬细胞的吞噬功能可能减弱。慢性应激和高皮质醇水平已被证实会抑制巨噬细胞的活化和吞噬能力，从而影响病原体清除效率。这种免疫抑制效应不仅增加感染风险，还可能与多种慢性炎症性疾病的恶化相关联。
例如，银屑病是一种慢性炎症性皮肤病，其活动度与心理应激和抑郁焦虑存在密切关联。抑郁焦虑可能通过诱导促炎细胞因子（如IL-6、TNF-α）的持续释放，同时抑制抗炎细胞因子，进一步加剧银屑病的炎症反应。牙周病是常见的慢性感染性疾病，其进展也受系统性炎症和免疫状态的影响。抑郁焦虑通过影响免疫功能，可能导致牙周组织对细菌感染的抵抗力下降，从而加速牙周病的破坏进程。在炎症性肠病（IBD）患者中，焦虑和抑郁症状普遍存在，并与疾病的活动性和复发风险增加相关 86。此外，有研究表明，溃疡性结肠炎患者的抑郁症状与肠道微生物群的失调以及血清代谢产物的改变相关，进一步提示“肠道-脑-免疫”轴在慢性炎症性疾病中的关键作用。
综上所述，抑郁焦虑通过损害中性粒细胞的趋化能力和巨噬细胞的吞噬功能，使得机体在面对感染时防御力下降。同时，这种免疫抑制状态也可能加剧银屑病、牙周病和炎症性肠病等慢性炎症性疾病的活动度，形成恶性循环，给患者带来沉重的疾病负担。
4.2 癌症进展与免疫治疗耐药
抑郁焦虑对机体免疫细胞活性的抑制，不仅增加感染易感性，更在癌症的发生、发展以及对免疫治疗的响应中扮演了关键角色。临床研究已提供了确凿证据，表明抑郁焦虑状态与肿瘤进展加速和免疫检查点抑制剂（ICIs）疗效降低之间存在显著关联。
一个重要的机制涉及糖皮质激素的过度分泌。在慢性应激和抑郁焦虑状态下，下丘脑-垂体-肾上腺（HPA）轴持续激活，导致血浆皮质醇水平长期升高 8788。皮质醇作为一种强效免疫抑制剂，能够多方面抑制抗肿瘤免疫反应。例如，皮质醇升高会直接抑制CD8+ T细胞的功能和增殖，而CD8+ T细胞是ICIs发挥抗肿瘤作用的核心效应细胞。皮质醇还可以通过上调糖皮质激素诱导的转录因子Tsc22d3来阻断I型干扰素（IFN）反应，影响树突状细胞（DC）和IFN-γ T细胞的激活 88。这种抑制作用导致免疫细胞浸润肿瘤微环境的能力下降，从而削弱了机体对肿瘤的免疫清除能力。
多项临床研究印证了抑郁焦虑对癌症治疗效果的不利影响。一项针对非小细胞肺癌（NSCLC）患者的STRESS-LUNG前瞻性研究发现，基线存在情绪困扰（包括抑郁和/或焦虑症状）的患者，其中位无进展生存期（PFS）显著短于无情绪困扰的患者（7.9个月 vs 15.5个月），风险比（HR）为1.73 87。这意味着情绪困扰的患者对ICIs治疗的反应性更差，疾病进展更快。此外，情绪困扰组的客观缓解率（ORR）也较低（46.8% vs 62.1%），2年总生存率（OS）亦显著降低（46.5% vs 64.9%），死亡风险升高1.82倍 87。该研究的探索性分析还指出，情绪困扰组的血清皮质醇水平升高，且与较差的生存结局相关 87。另一项研究也发现，抑郁症可促进肺癌进展，这与肿瘤微环境中PD-L1表达增加和CD8+ T细胞水平下降有关 89。这些证据共同表明，抑郁焦虑通过升高皮质醇、抑制CD8+ T细胞浸润等机制，导致ICIs疗效降低。
除了直接的免疫抑制，抑郁焦虑还可能通过其他途径影响癌症进展。例如，长期的心理应激和抑郁焦虑会诱导慢性低度炎症反应，与无社会支持满意度人群相比，有更高社会支持满意度的人群其CRP、IL-6和TNF-α水平较低 90。炎症因子如IL-6和TNF-α的持续升高，能够促进肿瘤细胞的增殖、血管生成和转移，并可能诱导肿瘤微环境中的免疫抑制细胞（如髓源性抑制细胞MDSCs和调节性T细胞Tregs）的富集，进一步削弱抗肿瘤免疫。
鉴于抑郁焦虑对癌症患者预后和免疫治疗效果的显著影响，解决癌症患者的情绪困扰在癌症管理中具有重要意义 87。早期识别和干预患者的抑郁焦虑症状，可能通过改善免疫功能，进而提高ICIs的临床疗效，改善患者的长期生存。
4.3 自身免疫病的双向影响
抑郁焦虑与自身免疫性疾病之间存在复杂的双向影响关系：一方面，抑郁焦虑状态下免疫系统的紊乱可能诱发或加重自身免疫病；另一方面，自身免疫病的慢性炎症和疾病负担也常常导致患者出现抑郁焦虑症状。这种双向作用机制主要围绕调节性T细胞（Treg）功能不足与辅助性T细胞17（Th17）细胞过度活化之间的失衡展开。
Treg细胞在维持免疫耐受和抑制自身免疫反应中发挥核心作用，而Th17细胞则是一类重要的促炎性T细胞，其在多种自身免疫病的病理生理过程中扮演关键角色 9192。抑郁焦虑状态常伴随Th17细胞的增加和Treg细胞的减少或功能受损，导致Th17/Treg平衡失调，倾向于Th17优势 939495。例如，在系统性红斑狼疮（SLE）小鼠模型中，焦虑诱导的应激可导致小鼠IL-6表达显著增加，抗双链DNA抗体水平升高，尿蛋白含量增多，同时伴随着脾脏Treg细胞比例降低和Th17细胞比例升高，提示狼疮疾病进程加速 96。SLE患者本身就普遍存在高水平的压力、焦虑和抑郁 9798，且抑郁症状与SLE的疾病活动度之间存在关联 99。
这种Treg功能不足与Th17细胞过度活化的失衡，是许多自身免疫病发作或加重的关键因素。
类风湿关节炎（RA）：RA是一种慢性自身免疫性疾病，以关节滑膜炎症和骨质破坏为特征。Th17/Treg平衡失调在RA的发生发展中起着核心作用 92100。抑郁焦虑可加剧Th17/Treg失衡，促进炎症反应，从而可能诱发或加重RA的临床症状。此外，RA患者常伴有抑郁焦虑，而炎症水平与抗抑郁治疗效果差有关 101。
系统性红斑狼疮（SLE）：SLE是一种多系统受累的自身免疫病，其病理特征之一是免疫细胞，尤其是T细胞亚群的异常活化。Th17细胞的增多和Treg细胞功能的不足被认为是多种神经病理学疾病发病机制中的重要环节，这提示其在SLE中也可能发挥类似作用 102。抑郁焦虑不仅在SLE患者中普遍存在 99，还增加了SLE患者发生多种并发症的风险，包括心血管、肾脏、神经系统疾病以及抑郁症本身 103。焦虑和应激可能通过加剧Th17/Treg失衡来促进SLE的发生或恶化 96。炎症性细胞因子，如IL-6，在SLE和抑郁焦虑中均升高，这些因子进一步驱动Th17细胞的分化，形成恶性循环 96。
自身免疫病导致的慢性炎症也会反向加剧抑郁症状。自身免疫病患者体内的持续性炎症反应，表现为促炎细胞因子（如IL-1、IL-6、TNF-α）水平升高，这些细胞因子可以通过多种途径影响大脑功能，包括干扰神经递质代谢、损害神经可塑性、激活HPA轴以及诱导病态行为，从而导致抑郁焦虑的发生或加重 101104。此外，自身免疫病常常带来身体疼痛、功能障碍和生活质量下降，这些因素是导致抑郁焦虑的重要心理社会应激源。例如，纤维肌痛被认为可以预测重度抑郁症，而肌痛性脑脊髓炎/慢性疲劳综合征与抑郁焦虑之间存在双向关系 105。这种双向作用形成了一个恶性循环，使得自身免疫病患者的治疗更加复杂。
因此，理解抑郁焦虑与自身免疫病之间Th17/Treg失衡的复杂机制，对于开发兼顾情绪和免疫的综合治疗策略至关重要。
5. 靶向抑郁焦虑-免疫抑制的干预策略
5.1 抗抑郁药物的免疫调节效应
鉴于抑郁焦虑与免疫抑制之间复杂的交互作用，靶向这一机制的干预策略日益受到关注。抗抑郁药物，特别是选择性5-羟色胺再摄取抑制剂（SSRIs），除了其经典的神经递质调节作用外，还被发现具有显著的免疫调节效应，为改善抑郁焦虑相关的免疫抑制提供了新的视角。
SSRIs类药物，例如氟西汀，主要通过增加突触间隙中5-羟色胺（5-HT）的浓度发挥抗抑郁作用。然而，其免疫调节机制远不止于此。研究表明，氟西汀能够通过调节5-HT受体来影响免疫细胞功能，进而改善抑郁相关的免疫紊乱。例如，氟西汀已被证明可以改善调节性T细胞（Treg）的功能。Treg细胞是维持免疫耐受和抑制过度炎症反应的关键细胞。在抑郁症患者中，Treg细胞的功能常常受损，而SSRIs治疗可以逆转这种功能缺陷。此外，氟西汀还能抑制微胶质细胞的异常激活。微胶质细胞在抑郁焦虑引起的神经炎症中扮演关键角色，其M1型极化释放促炎细胞因子。氟西汀通过增加TNFAIP3 mRNA的表达来抑制IL-6水平，而TNFAIP3是TLR信号通路的负性调节因子，其低表达与重度抑郁症患者的炎症和TLR通路异常有关 106。这意味着氟西汀能够通过调节微胶质细胞的炎症反应，减轻神经炎症，从而对免疫系统产生积极影响。
除了SSRIs，一些新型抗抑郁药物或潜在的治疗策略也展现出免疫调节潜力。例如，酮替芬（ketotifen），一种抗组胺药，通过调节Th17/Treg平衡，可能成为治疗抑郁症的潜在药物。虽然酮替芬与传统的抗抑郁药物作用机制不同，但通过影响细胞因子网络，特别是Th17和Treg细胞之间的平衡，它可能改善抑郁相关的免疫失调。有研究表明，抗抑郁药物能够调节免疫反应，例如，通过降低促炎细胞因子IL-6、IL-10的水平或抑制NK细胞的细胞毒性，并可调节淋巴细胞增殖和凋亡 107。
值得注意的是，不同的抗抑郁药物对免疫系统的影响可能存在差异。例如，西替利嗪（cetirizine）作为一种抗组胺药，在体外研究中未显示出对T细胞增殖或活化标记物表达的影响 108。这表明免疫调节效应并非所有抗抑郁药物或相关药物的普遍特征，其具体机制需要深入研究。
总而言之，抗抑郁药物，特别是SSRIs，通过调节5-HT受体，改善Treg细胞功能和抑制微胶质细胞活化，发挥免疫调节效应，从而对抗抑郁焦虑相关的免疫抑制。对新型免疫调节药物（如酮替芬）的研究，将有助于开发更全面、更有效的抑郁焦虑治疗策略。
5.2 免疫调节疗法的应用
针对抑郁焦虑导致的免疫抑制，免疫调节疗法提供了创新的干预途径。这类疗法旨在直接或间接调节免疫系统，以期改善情绪障碍并恢复正常的免疫功能。其中，间充质干细胞（MSCs）疗法和益生菌/合生元干预是两个备受关注的方向。
间充质干细胞（MSCs）因其多向分化潜能、免疫调节特性和低免疫原性，在治疗多种疾病中展现出巨大潜力，包括抑郁症。MSCs可以通过多种机制发挥抗抑郁和免疫增强作用，其中激活“肺-迷走神经-脑轴”是一个新兴的解释。该轴线构成了肺部与中枢神经系统之间的关键通讯路径，MSCs可能通过影响肺部微环境，进而调节迷走神经活动。迷走神经是副交感神经系统的重要组成部分，其活化能够抑制炎症反应、调节HPA轴功能，并对情绪和认知产生积极影响。研究表明，MSCs移植可能通过改善炎症环境，减轻氧化应激，并通过迷走神经途径影响脑功能，从而改善抑郁样行为。此外，MSCs还被观察到能增强自然杀伤细胞（NK细胞）的活性。NK细胞是抗肿瘤和抗病毒免疫的关键组分，在抑郁焦虑状态下其活性常受到抑制。MSCs可能通过分泌细胞因子、趋化因子或其他生物活性分子，直接或间接促进NK细胞的增殖、活化和细胞毒性功能，从而增强机体的免疫监视能力。例如，有研究发现，MSCs能够分泌多种免疫调节因子，影响NK细胞的成熟和功能。
益生菌（Probiotics）和合生元（Synbiotics）作为调节肠道菌群的有效手段，在恢复“肠道-脑-免疫”稳态中发挥着越来越重要的作用。肠道菌群失调是抑郁焦虑的重要特征之一，而有益菌的补充可以改善这种失调，进而影响情绪和免疫功能 109110111112。益生菌通过多种机制发挥作用：
- 调节短链脂肪酸（SCFAs）的生成：益生菌，特别是产生丁酸盐、丙酸盐和乙酸盐等SCFAs的菌株，能够恢复肠道内SCFAs的水平 113。SCFAs对维持肠道屏障完整性、抑制炎症反应、调节免疫细胞功能至关重要。例如，丁酸盐被证明可以通过G蛋白偶联受体（GPCRs）或组蛋白去乙酰化酶（HDACs）抑制剂的方式，影响免疫细胞的分化和功能。通过增加SCFAs的生成，益生菌有助于减少肠道通透性，降低内毒素（LPS）易位，从而缓解全身性炎症 110112。
- 改善神经递质代谢：肠道菌群是多种神经递质（如5-HT、GABA）及其前体物质的重要来源。益生菌可以调节这些神经递质的合成和代谢，进而影响中枢神经系统的功能和情绪状态 110114。例如，一些益生菌菌株能够产生GABA，从而可能通过GABA能信号通路调节抑郁行为 110。
- 直接免疫调节：益生菌能够与肠道免疫细胞相互作用，调节细胞因子分泌，促进抗炎细胞因子（如IL-10）的生成，并抑制促炎细胞因子（如IL-6、TNF-α）的释放 112。这种免疫调节作用有助于纠正抑郁焦虑引起的免疫失衡，例如Th1/Th2平衡或Th17/Treg平衡的紊乱。
- 修复肠道屏障功能：抑郁焦虑常伴随肠道屏障功能受损，导致“肠漏”现象。益生菌通过增强紧密连接蛋白的表达，可以修复肠道屏障，减少有害物质进入血液循环，从而降低全身性炎症反应 112。
多项临床研究和动物实验已证实益生菌在改善抑郁焦虑症状方面的潜力。例如，一些特定的鼠李糖乳杆菌（Lactobacillus rhamnosus）菌株被发现可以缓解抑郁样行为 115。粪菌移植（FMT）作为一种更直接的菌群干预手段，也显示出改善抑郁症状的希望 116117118。此外，抗抑郁药物与益生菌的联合使用，可能通过调节肠道菌群来改善药物的吸收、代谢和活性，或减轻药物对肠道菌群的负面影响，从而增强治疗效果和减少副作用 109117。
总的来说，免疫调节疗法，特别是基于MSCs的干预和利用益生菌/合生元调节肠道菌群的策略，为缓解抑郁焦虑相关的免疫抑制提供了重要的治疗方向。这些方法通过多途径、多靶点作用，有望打破抑郁焦虑-免疫抑制的恶性循环，为患者带来更全面的身心健康改善。
5.3 心理干预与生活方式调整
除了药物和免疫调节疗法，心理干预和健康的生活方式调整在缓解抑郁焦虑相关的免疫抑制中也发挥着不可忽视的作用。这些非药物干预措施通过调节神经内分泌系统、减少应激反应以及直接影响免疫细胞功能，为改善患者的身心健康提供了有效途径。
认知行为疗法（CBT） 是目前治疗抑郁焦虑最常用的心理干预方法之一。CBT通过帮助患者识别、挑战并改变消极思维模式和行为，从而改善情绪状态。CBT对免疫系统的影响，特别是其如何改善T细胞增殖功能，与降低下丘脑-垂体-肾上腺（HPA）轴的活性密切相关。研究表明，HPA轴的过度激活是抑郁焦虑状态下免疫抑制的核心机制之一，导致皮质醇水平持续升高，进而抑制T细胞的增殖和功能。CBT被证实能有效降低HPA轴的过度激活。例如，一项随机对照试验发现，与等待列表对照组相比，接受6周CBT干预的个体表现出更强的皮质醇适应性（即对应激反应的皮质醇分泌下降），尽管基线皮质醇水平可能有所升高 119。HPA轴活性的降低意味着皮质醇对免疫细胞的抑制作用减弱，从而可能促进T细胞的正常增殖和功能恢复。此外，CBT还被发现能降低促炎细胞因子（如IL-6和TNF-α）的水平 120，这些细胞因子在抑郁症中普遍升高，并能抑制T细胞的活性。对于HIV感染者，认知行为干预被证实能改善抑郁、焦虑和应激症状，尽管对CD4细胞计数的直接影响有限，但长期来看，心理状态的改善对免疫功能有益 121122。心理治疗，尤其是CBT，也被证明在改善自身免疫病患者的预后中发挥作用 123。
运动干预 是另一种有效的生活方式调整，对抑郁焦虑相关的免疫抑制具有显著的缓解作用。规律的体育锻炼能够通过多种机制调节免疫系统和情绪状态。急性运动能诱导系统性抗炎环境，表现为血浆IL-10水平显著增加（在运动后1小时达到峰值），这可能主要由血浆IL-6水平的升高（在运动后立即达到峰值）介导 124。IL-10是一种重要的抗炎细胞因子，能够抑制促炎细胞因子的产生，对维持免疫稳态至关重要。长期规律的运动（例如，每周5次、每次30分钟的步行锻炼，持续6个月）能够发挥抗炎作用，表现为血浆IL-6/IL-10比值的降低，并下调T淋巴细胞和单核细胞的活化 124。这意味着运动可以通过调节细胞因子平衡，减轻抑郁焦虑引起的慢性低度炎症，从而改善免疫细胞功能。太极等运动形式也被发现能改善包括睡眠和焦虑在内的心理健康，并对自身免疫和免疫功能产生积极影响 125。此外，瑜伽等身心干预措施也被证明能够降低应激、焦虑和抑郁症状，对免疫系统和糖代谢均有益 126。
正念冥想（Mindfulness Meditation）和引导性意象（Guided Imagery） 等心身联系疗法也展现出改善免疫功能的潜力。正念冥想被发现能增加与积极情绪相关的左侧大脑前部激活，并显著提高流感疫苗的抗体滴度，提示其对免疫功能有积极影响 127128。引导性意象通过激活身心联系，能够增强个体的幸福感，减轻应激和焦虑，并有能力增强免疫系统 129。这些方法通过减轻心理应激，从而降低HPA轴的活性和促炎细胞因子的产生，进而对免疫系统产生有益的调节。
综上所述，认知行为疗法通过降低HPA轴活性和调节炎症反应，运动干预通过平衡细胞因子分泌和下调免疫细胞活化，以及其他心身疗法，都为缓解抑郁焦虑相关的免疫抑制提供了重要的非药物干预途径。这些干预策略的整合应用，有望为抑郁焦虑患者提供更全面的治疗效果，改善其免疫功能和整体健康状况。
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Neuroimmunomodulation. 2004;11(5):307-15. doi: 10.1159/000079411.
Lymphocytes possess serotonin 5-HT(1A) and beta-adrenergic receptors, which have been related to cell proliferation. In the present report, lymphocytes of rat blood were isolated by Ficoll-Hypaque gradients and differential adhesion to plastic. They were cultured in RPMI medium for 72 h in the presence of the mitogens lipopolysaccharide concanavalin A and anti-CD3 antibody. The latter two stimulated the proliferation of lymphocytes, but not the first. Serotonin (0.1-100 microM) was added alone or in the presence of suboptimal concentrations of concanavalin A (2 microg/ml) or anti-CD3 antibody (0.4 microg/ml). The 5-HT(1A) receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin and buspirone (0.1-100 microM) were also tested in the cultures. Serotonin, 8-hydroxy-2-(di-n-propylamino)tetralin and buspirone neither had any effect by themselves, nor modified the proliferation induced by the mitogens. Noradrenaline (25-1,000 microM) and the beta-adrenergic receptor agonist, isoproterenol (5-100 microM), produced a reduction of the activation induced by concanavalin A or anti-CD3 antibody in a dose-dependent manner. Increasing serotonin concentrations reduced the inhibitory effect of noradrenaline (300 microM). Variable concentrations of 8-hydroxy-2-(di-n-propylamino)tetralin or buspirone also reduced the inhibition produced by isoproterenol (100 microM). The antagonist of 5-HT(1A) receptors, WAY-100,478 (0.1-100 microM), inhibited concanavalin A- or anti-CD3 antibody-induced proliferation. Serotonin (0.1-100 microM) impaired the inhibitory effect of the 5-HT(1A) antagonist (10 microM). The inhibitor of tryptophan hydroxylase, p-chlorophenylalanine (50-1,000 microM), decreased the stimulatory effect of concanavalin A, serotonin (0.5-100 microM) and 8-hydroxy-2-(di-n-propylamino)tetralin (1-100 microM) reverted the effect of p-chlorophenylalanine (1,000 microM). The serotonin reuptake blockers zimelidine, imipramine and clomipramine decreased concanavalin A-induced proliferation. The concentrations of serotonin and noradrenaline increased in lymphocytes cultured in the presence of concanavalin A, probably as a mechanism for modifying the final effect on proliferation. The present results indicate that 5-HT(1A) receptors play a stimulatory role on rat blood lymphocytes, and they interact in a parallel and opposite manner with beta-adrenergic receptors. Furthermore, endogenous serotonin is relevant in displaying its stimulatory effect.
8Immunomodulation Mechanism of Antidepressants: Interactions between Serotonin/Norepinephrine Balance and Th1/Th2 Balance.PubMed
Matteo Martino, Giulio Rocchi, Andrea Escelsior, et al.
Curr Neuropharmacol. 2012 Jun;10(2):97-123. doi: 10.2174/157015912800604542.
Neurotransmitters and hormones regulate major immune functions, including the selection of T helper (Th)1 or Th2 cytokine responses, related to cell-mediated and humoral immunity, respectively. A role of imbalance and dynamic switching of Th1/Th2 system has been proposed, with relative displacement of the immune reserve in relation to complex interaction between Th1/Th2 and neuro-hormonal balance fluctuations, in the pathogenesis of various chronic human diseases, probably also including psychiatric disorders. Components of the stress system such as norepinephrine (NE) and glucocorticoids appear to mediate a Th2 shift, while serotonin (5-HT) and melatonin might mediate a Th1 shift. Some antidepressants would occur affecting these systems, acting on neurotransmitter balance (especially the 5-HT/NE balance) and expression levels of receptor subtypes, which in turn affect cytokine production and relative Th1/Th2 balance. It could be therefore hypothesized that the antidepressant-related increase in NE tone enhances the Th2 response, while the decrease in NE tone or the increase in 5-HT tone enhances the Th1 response. However, the neurotransmitter and Th1/Th2 balance modulation could be relative, aiming to restore physiological levels a previous imbalance in receptor sensitivity and cytokine production. The considerations on neuro-immunomodulation could represent an additional aid in the study of pathophysiology of psychiatric disorders and in the choice of specific antidepressants in specific clusters of symptoms, especially in comorbidity with internal pathologies. Furthermore limited data, reviewed here, have shown the effectiveness of some antidepressants as pure immunomodulators. However, these considerations are tentative and require experimental confirmation or refutation by future studies.
9[Functional anatomy of the hypothalamic-hypophysial system: neuroendocrine control mechanism].PubMed
S Daikoku
Kaibogaku Zasshi. 1993 Jun;68(3):288-304.
The hypothalamic neuroendocrine mechanisms involved in the regulation of the anterior pituitary functions were reviewed on the basis of the findings obtained mainly in rats. The hypothalamic-hypophysial system has long been considered as a hormonary associated organ system. Recent development of immunohistochemistry and molecular biology, however, has localized the hormone-synthesizing neurons in the hypothalamus, and disclosed the synaptic junctions between them, between those neurons and non-hormonal neurons in the hypothalamus, and further, between neurons in the hypothalamus and other brain parts as well as peripheral nervous systems. Based on these findings, we have designated five functional areas in the hypothalamus: septopreoptic, suprachiasmatic, magno- and parvicellular paraventricular, and arcuate-median eminence areas. The neuronal transmitters in the synaptic junctions were classical transmitters and hormonal or nonhormonal peptides. Some mutual synaptic connections were found between different hormonal peptide-synthesizing neurons within the same area and even between those in the different areas. Although the significance of the neuronal regulation system cooperating with the hormonal events is largely still uncertain, they may serve to integrate the functions of hypothalamic hormone-synthesizing neurons as a whole in adjusting the homeostasis of the internal milieu of the living body. Intimate relations have recently been reported between immune system and endocrine system or hypothalamic neuroendocrine system. In this connection, it is clear that the hypothalamus acts not only as the center for neuroendocrine regulation but also as the center of the neuroendocrine-immune regulation of the living body. To thereby understand the living and reproductive strategies of animals, further accurate knowledge on the neuronal connections within the hypothalamus is needed.
10Neuromodulation by the immune system: a focus on cytokines.PubMed
Andrea Francesca Salvador, Kalil Alves de Lima, Jonathan Kipnis
Nat Rev Immunol. 2021 Aug;21(8):526-541. doi: 10.1038/s41577-021-00508-z. Epub 2021 Mar 1.
Interactions between the immune system and the nervous system have been described mostly in the context of diseases. More recent studies have begun to reveal how certain immune cell-derived soluble effectors, the cytokines, can influence host behaviour even in the absence of infection. In this Review, we contemplate how the immune system shapes nervous system function and how it controls the manifestation of host behaviour. Interactions between these two highly complex systems are discussed here also in the context of evolution, as both may have evolved to maximize an organism's ability to respond to environmental threats in order to survive. We describe how the immune system relays information to the nervous system and how cytokine signalling occurs in neurons. We also speculate on how the brain may be hardwired to receive and process information from the immune system. Finally, we propose a unified theory depicting a co-evolution of the immune system and host behaviour in response to the evolutionary pressure of pathogens.
11Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems.PubMed
Anna Gądek-Michalska, Joanna Tadeusz, Paulina Rachwalska, et al.
Pharmacol Rep. 2013;65(6):1655-62. doi: 10.1016/s1734-1140(13)71527-5.
Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is accepted as one of the fundamental biological mechanisms that underlie major depression. This hyperactivity is caused by diminished feedback inhibition of glucocorticoid (GC)-induced reduction of HPA axis signaling and increased corticotrophin-releasing hormone (CRH) secretion from the hypothalamic paraventricular nucleus (PVN) and extra-hypothalamic neurons. During chronic stress-induced inhibition of systemic feedback, cytosolic glucocorticoid receptor (GR) levels were significantly changed in the prefrontal cortex (PFC) and hippocampus, both structures known to be deeply involved in the pathogenesis of depression. Cytokines secreted by both immune and non-immune cells can markedly affect neurotransmission within regulatory brain circuits related to the expression of emotions; cytokines may also induce hormonal changes similar to those observed following exposure to stress. Proinflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are implicated in the etiologies of clinical depression and anxiety disorders. Prolonged stress responses and cytokines impair neuronal plasticity and stimulation of neurotransmission. Exposure to acute stress and IL-1β markedly increased IL-1β levels in the PFC, hippocampus and hypothalamus, as well as overall HPA axis activity. Repeated stress sensitized the HPA axis response to IL-1β. Inflammatory responses in the brain contribute to cellular damage associated with neuropsychiatric diseases related to stress. Physical, psychological or combined-stress conditions evoke a proinflammatory response in the brain and other systems, characterized by a complex release of several inflammatory mediators including cytokines, prostanoids, nitric oxide (NO) and transcription factors. Induced CRH release involves IL-1, IL-6 and TNF-α, for stimulation adrenocorticotropic hormone (ACTH) release from the anterior pituitary. NO also participates in signal transduction pathways that result in the release of corticosterone from the adrenal gland. NO participates in multiple interactions between neuroendocrine and neuroimmune systems in physiological and pathological processes. Neuronal NO synthase (nNOS) modulates learning and memory and is involved in development of neuropsychiatric diseases, including depression. Nitric oxide generated in response to stress exposure is associated with depression-like and anxiety-like behaviors. In the central nervous system (CNS), prostaglandins (PG) generated by the cyclooxygenase (COX) enzyme are involved in the regulation of HPA axis activity. Prior exposure to chronic stress alters constitutive (COX-1) and inducible (COX-2) cyclooxygenase responses to homotypic stress differently in the PFC, hippocampus and hypothalamus. Both PG and NO generated within the PVN participate in this modulation. Acute stress affects the functionality of COX/PG and NOS/NO systems in brain structures. The complex responses of central and peripheral pathways to acute and chronic stress involve cytokines, NO and PG systems that regulate and turn off responses that would be potentially harmful for cellular homeostasis and overall health.
12Signaling pathways in brain involved in predisposition and pathogenesis of stress-related disease: genetic and kinetic factors affecting the MR/GR balance.PubMed
E Ronald De Kloet, Roel Derijk
Ann N Y Acad Sci. 2004 Dec;1032:14-34. doi: 10.1196/annals.1314.003.
Optimal regulation of the stress response is a prerequisite for adaptation, homeostasis, and health. There are two modes of operation in the stress response. First, an immediate response mode mediated by corticotrophin-releasing hormone-1 (CRH-1) receptors that organizes the behavioral, sympathetic, and hypothalamic-pituitary-adrenal (HPA) response to a stressor. Second, a slower mode, which facilitates behavioral adaptation, promotes recovery, and reestablishes homeostasis. Corticosteroid hormones are implicated in both stress system modes. On the one hand, cortisol and corticosterone determine the threshold or sensitivity of the fast responding mode, whereas the very same hormones in high concentrations facilitate termination of the stress response. In the brain, these actions exerted by the corticosteroid hormones are mediated by two distinct nuclear receptor types, that is, mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). Whereas MRs maintain neuronal homeostasis and limit the disturbance by stress, GRs help to recover after the challenge and to store the experience for coping with future encounters. Imbalance in MR/GR-mediated actions compromises homeostatic processes in these neurons, which is thought to underlie maladaptive behavior and HPA dysregulation that may lead to aberrant metabolism, impaired immune function, and altered cardiovascular control. The balance in MR/GR-mediated actions depends on bioavailability of corticosteroids, access to the receptors, the stoichiometry of co-regulators, and other proteins as well as genetic factors, among which single nucleotide polymorphisms (SNPs) of the GRs are extensively documented. Stress can bias the receptor signaling pathways, changing "good" corticosteroid actions into "bad" ones.
13The HPA and immune axes in stress: the involvement of the serotonergic system.PubMed
B E Leonard
Eur Psychiatry. 2005 Oct;20 Suppl 3:S302-6. doi: 10.1016/s0924-9338(05)80180-4.
The impact of acute and chronic stress on the hypothalamic-pituitary-adrenal (HPA) axis is reviewed and evidence presented that corticotrophin releasing factor (CRF) is the stress neurotransmitter which plays an important role in the activation of the central sympathetic and serotonergic systems. The activity of CRF is expressed through specific receptors (CRF 1 and 2) that are antagonistic in their actions and widely distributed in the limbic regions of the brain, as well as in the hypothalamus, and on immune cells. The mechanism whereby chronic stress, via the CRF induced activation of the dorsal raphe nucleus, can induce a change in the serotonergic system, involves an increase in the 5HT2A and a decrease in the 5HT1A receptor mediated function. Such changes contribute to the onset of anxiety and depression. In addition, the hypersecretion of glucocorticoids that is associated with chronic stress and depression desensitises the central glucocorticoid receptors to the negative feedback inhibition of the HPA axis. This indirectly results in the further activation of the HPA axis. The rise in pro-inflammatory cytokines that usually accompanies the chronic stress response results in a further stimulation of the HPA axis thereby adding to the stress response. While CRF would appear to play a pivotal role, evidence is provided that simultaneous changes in the serotonergic and noradrenergic systems, combined with the activation of peripheral and central macrophages that increase the pro-inflammatory cytokine concentrations in the brain and blood, also play a critical role in predisposing to anxiety and depression. Neurodegenerative changes in the brain that frequently occur in the elderly patient with major depression, could result from the activation of indoleaminedioxygenase (IDO), a widely distributed enzyme that converts tryptophan via the kynenine pathway to for the neurotoxic end product quinolinic acid.
14Stress & the gut-brain axis: Regulation by the microbiome.PubMed
Jane A Foster, Linda Rinaman, John F Cryan
Neurobiol Stress. 2017 Mar 19;7:124-136. doi: 10.1016/j.ynstr.2017.03.001. eCollection 2017 Dec.
The importance of the gut-brain axis in regulating stress-related responses has long been appreciated. More recently, the microbiota has emerged as a key player in the control of this axis, especially during conditions of stress provoked by real or perceived homeostatic challenge. Diet is one of the most important modifying factors of the microbiota-gut-brain axis. The routes of communication between the microbiota and brain are slowly being unravelled, and include the vagus nerve, gut hormone signaling, the immune system, tryptophan metabolism, and microbial metabolites such as short chain fatty acids. The importance of the early life gut microbiota in shaping later health outcomes also is emerging. Results from preclinical studies indicate that alterations of the early microbial composition by way of antibiotic exposure, lack of breastfeeding, birth by Caesarean section, infection, stress exposure, and other environmental influences - coupled with the influence of host genetics - can result in long-term modulation of stress-related physiology and behaviour. The gut microbiota has been implicated in a variety of stress-related conditions including anxiety, depression and irritable bowel syndrome, although this is largely based on animal studies or correlative analysis in patient populations. Additional research in humans is sorely needed to reveal the relative impact and causal contribution of the microbiome to stress-related disorders. In this regard, the concept of psychobiotics is being developed and refined to encompass methods of targeting the microbiota in order to positively impact mental health outcomes. At the 2016 Neurobiology of Stress Workshop in Newport Beach, CA, a group of experts presented the symposium "The Microbiome: Development, Stress, and Disease". This report summarizes and builds upon some of the key concepts in that symposium within the context of how microbiota might influence the neurobiology of stress.
15Social regulation of gene expression in human leukocytes.PubMed
Steve W Cole, Louise C Hawkley, Jesusa M Arevalo, et al.
Genome Biol. 2007;8(9):R189. doi: 10.1186/gb-2007-8-9-r189.
BACKGROUND: Social environmental influences on human health are well established in the epidemiology literature, but their functional genomic mechanisms are unclear. The present study analyzed genome-wide transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates. RESULTS: DNA microarray analysis identified 209 genes that were differentially expressed in circulating leukocytes from 14 high- versus low-lonely individuals, including up-regulation of genes involved in immune activation, transcription control, and cell proliferation, and down-regulation of genes supporting mature B lymphocyte function and type I interferon response. Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-kappaB/Rel transcription factors (p = 0.011). This reciprocal shift in pro- and anti-inflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/EBP, Oct, and GATA pathways. CONCLUSION: These data provide the first indication that human genome-wide transcriptional activity is altered in association with a social epidemiological risk factor. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolation.
16Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.PubMed
Andrew H Miller, Vladimir Maletic, Charles L Raison
Biol Psychiatry. 2009 May 1;65(9):732-41. doi: 10.1016/j.biopsych.2008.11.029. Epub 2009 Jan 15.
Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.
17Dysregulated immune system in chronic stress male rats is an outcome of altered mRNA expression, cytokines, and Th1/Th2 balance.PubMed
Zeju Luo, Yiheng Huang, Luhan Tang, et al.
Behav Brain Res. 2026 Feb 26;498:115921. doi: 10.1016/j.bbr.2025.115921. Epub 2025 Nov 6.
Chronic stress is known to cause immune system dysfunction, which can contribute to the development of various highly prevalent diseases. Nevertheless, the mechanisms underlying immune dysregulation during chronic stress remain poorly understood. In this study, we examined the effects of 35-day chronic unpredictable mild stress (CUMS) on behavioral patterns, lymphocyte subpopulation ratios, serum cytokine levels, and the peripheral blood leukocyte transcriptome in 20 male Sprague-Dawley rats. After 35 days of CUMS exposure, the rats exhibited established features of chronic unpredictable mild stress, including increased anxiety-like behavior and depression-like behavior. We found a significant increase in the proportion of Th2 cells among lymphocytes, leading to a Th1/Th2 imbalance. Additionally, serum levels of the pro-inflammatory cytokines IL-1α, IL-1β, IFN-γ, and GM-CSF were significantly decreased, whereas the concentration of IL-2 was markedly elevated. Transcriptomic profiling revealed broad alterations in gene expression after CUMS, particularly in pathways related to immune system function. Our findings indicate that chronic stress induces immune dysregulation through a Th1/Th2 imbalance and associated changes in key immune-related genes (including Maf, Irf4, Gfi1, and Bcl6b), suggesting a potential mechanism for stress-induced immune dysfunction.
18Regulatory T-cell phenotypes in prenatal psychological distress.PubMed
Kyle S Wiley, Dayoon Kwon, Delaney A Knorr, et al.
Brain Behav Immun. 2024 Feb;116:62-69. doi: 10.1016/j.bbi.2023.11.033. Epub 2023 Nov 26.
BACKGROUND: Experiencing symptoms of psychological distress during pregnancy is common and has been linked to dysregulated immune functioning. In this context, immunoregulatory function is especially relevant because of its crucial role in establishment and maintenance of healthy pregnancy. However, little research has examined associations between women's prenatal psychological distress and immunoregulatory biomarkers. We investigated how symptoms of depression, anxiety, and stress relate to circulating levels of regulatory T-cells (Tregs). MATERIALS AND METHODS: Pregnant Latina women were assessed at around 12 weeks of pregnancy (N = 82). These assessments included blood draws and self-report questionnaires assessing symptoms of depression, state anxiety, pregnancy-related anxiety, and perceived stress. Flow cytometry on PBMCs was used to quantify circulating Tregs, defined as CD3CD4CD25CD127FoxP3, and subpopulations positive for one of the following intra- or extracellular markers, CD45RA, CTLA-4, Helios, PD-1, TIM-3, and TIGIT. We collected 82 samples at 12 weeks. Multivariable linear regressions tested for associations between symptoms of psychological distress and Treg concentrations, adjusted for gestational age. RESULTS: State anxiety symptoms at 12 weeks were negatively associated with parent Treg cell levels (b = -4.02, p = 0.023) and subpopulations Helios (b = -3.29, p = 0.019) and TIM3 (b = -3.17, p = 0.008). Perceived stress was negatively associated with the PD-1 subpopulation at 12 weeks (b = -4.02, p = 0.023). Depression was not related to Tregs or the subpopulations. CONCLUSION: Our observation that symptoms of anxiety and stress are related to tolerogenic immunology suggests a possible biomechanism explaining correlations of maternal mood disorders with adverse outcomes for mothers and offspring.
19Diminished functional properties of T regulatory cells in major depressive disorder: The influence of selective serotonin reuptake inhibitor.PubMed
Leila Jahangard, Mahdi Behzad
J Neuroimmunol. 2020 Jul 15;344:577250. doi: 10.1016/j.jneuroim.2020.577250. Epub 2020 Apr 23.
The properties of CD4CD25 T regulatory cells (Tregs), and interleukin (IL)-2 pathway were investigated in major depressive disorder (MDD) patients treated with or without selective serotonin reuptake inhibitor (SSRI). The frequencies of FOXP3 and pSTAT5 in peripheral Tregs were found to be diminished in untreated patients (SSRI) versus HCs (p < .001 for both), while their percentages were increased in treated patients (SSRI) versus untreated patients (p < .001 and p = .04). The proliferation of CD4 T cells was higher in SSRIMDD patients versus HCs (p = .03). The SSRIMDD patients showed a lower concentration of supernatant TGF-β than HCs (p = .001), while the production of TGF-β was enhanced in SSRIMDD versus SSRIMDD patients (p = .003). The number of CD45RA-expressing Tregs, the expression of JAK1 and JAK3, and the levels of IL-2 and IL-10 were similar between the patients and HCs. The study results showed that untreated patients have an impaired IL-2 signaling pathway and defective Tregs, and SSRI treatment may improve the Tregs function.
20CD4+CD25+ regulatory T cell depletion modulates anxiety and depression-like behaviors in mice.PubMed
Soo-Jeong Kim, Hyojung Lee, Gihyun Lee, et al.
PLoS One. 2012;7(7):e42054. doi: 10.1371/journal.pone.0042054. Epub 2012 Jul 31.
Stress has been shown to suppress immune function and increase susceptibility to inflammatory disease and psychiatric disease. CD4(+)CD25(+) regulatory T (Treg) cells are prominent in immune regulation. This study was conducted to determine if anti-CD25 antibody (Ab) mediated depletion of Treg cells in mice susceptibility to stress-induced development of depression-like behaviors, as well as immunological and neurochemical activity. To accomplish this, an elevated plus-maze test (EPM), tail suspension test (TST), and forced swim test (FST) were used to examine depression-like behaviors upon chronic immobilization stress. Immune imbalance status was observed based on analysis of serum cytokines using a mouse cytometric bead array in conjunction with flow cytometry and changes in the levels of serotonin (5-HT) and dopamine (DA) in the brain were measured by high performance liquid chromatography (HPLC). The time spent in the open arms of the EPM decreased significantly and the immobility time in the FST increased significantly in the anti-CD25 Ab-treated group when compared with the non stressed wild-type group. In addition, interlukin-6 (IL-6), tumor necrosis factor-á (TNF-á), interlukin-2 (IL-2), interferon-gamma (IFN-γ), interlukin-4 (IL-4) and interlukin-17A (IL-17A) concentrations were significantly upregulated in the stressed anti-CD25 Ab-treated group when compared with the non stressed wild-type group. Furthermore, the non stressed anti-CD25 Ab-treated group displayed decreased 5-HT levels within the hippocampus when compared with the non stressed wild-type group. These results suggest that CD4(+)CD25(+) Treg cell depletion modulated alterations in depressive behavior, cytokine and monoaminergic activity. Therefore, controlling CD4(+)CD25(+) Treg cell function during stress may be a potent therapeutic strategy for the treatment of depression-like symptoms.
21Premature immunosenescence is associated with memory dysfunction in rheumatoid arthritis.PubMed
Laura Esteves Petersen, Rodrigo Grassi-Oliveira, Talita Siara, et al.
Neuroimmunomodulation. 2015;22(3):130-7. doi: 10.1159/000358437. Epub 2014 Apr 15.
BACKGROUND: Rheumatoid arthritis (RA) has been associated with premature immunosenescence and an increased prevalence of age-related morbidities including poor cognitive function. OBJECTIVE: We explored the relationships among lymphocyte subsets and memory in RA. METHODS: Thirty patients with RA and 19 age-matched healthy controls took part in this study. Cognitive function stress and depression scores were evaluated by structured clinical questionnaires. Lymphocytes were isolated and immunophenotyped by flow cytometry to investigate the following subsets: B cells, activated and naïve/memory T cells, regulatory FoxP3+ T (Treg) cells, Th17+ cells, NK cells and senescence-associated CD28- T cells. RESULTS: RA patients were more depressed than controls, but stress levels were similar in the 2 groups. Patients had impaired memory performance compared to controls, demonstrated by lower Mini-Mental State Examination scores and logical and working memories (all p < 0.0001). These group effects remained significant after correcting for depression and age. Patients had expansion of regulatory T cells, naïve CD4+ T cells and CD8+CD28- cells but reduced percentages of B cells and memory CD8+CD45RO+ T cells compared to controls. CD8+CD28- and CD8+CD45RO+ T cells were found to be negatively associated with memory. CONCLUSION: RA patients had reduced memory performance compared to healthy controls. Expansion of activated and senescence-associated T cells was correlated with poor memory performance.
22Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression.PubMed
Michael Maes
Prog Neuropsychopharmacol Biol Psychiatry. 2011 Apr 29;35(3):664-75. doi: 10.1016/j.pnpbp.2010.06.014. Epub 2010 Jun 20.
The first findings that depression is characterized by cell-mediated immune activation and inflammation were published between 1990-1993 (Maes et al.). Recently, it was reported that--based on meta-analysis results--depression is an inflammatory disorder because the plasma levels of two cytokines are increased, i.e. interleukin-(IL)-6 and tumor necrosis factor-α (TNFα). The same meta-analysis found that plasma IL-2 and interferon-(IFN)γ levels are not altered in depression, suggesting that there is no T cell activation in that illness. The present paper reviews the body of evidence that depression is accompanied by cell-mediated immune activation. The findings include: increased serum levels of the soluble IL-2 receptor (sIL-2R) and the sCD8 molecule; increased numbers and percentages of T cells bearing T cell activation markers, such as CD2+CD25+, CD3+CD25+, and HLA-DR+; increased stimulated production of IFNγ; higher neopterin and sTNFR-1 or sTNFR-2 levels; induction of indoleamine 2,3-dioxygenase (IDO) with lowered levels of plasma tryptophan and increased levels of tryptophan catabolites along the IDO pathway (TRYCATs); and glucocorticoid resistance in immune cells. Interferon-α (IFNα)-based immunotherapy shows that baseline and IFNα-induced activation of T cells, IDO activity and TRYCAT formation are related to the development of IFNα-induced depressive symptoms. Animal models of depression show that a cell-mediated immune response is related to the development of depression-like behavior. Antidepressants and mood stabilizers suppress different aspects of cell-mediated immunity and rather specifically target IFNγ production. This review shows that inflammation and cell-mediated immune activation are key factors in depression.
23High-anxious individuals show increased chronic stress burden, decreased protective immunity, and increased cancer progression in a mouse model of squamous cell carcinoma.PubMed
Firdaus S Dhabhar, Alison N Saul, Tyson H Holmes, et al.
PLoS One. 2012;7(4):e33069. doi: 10.1371/journal.pone.0033069. Epub 2012 Apr 25.
In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2-3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-γ gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). These results suggest that the deleterious effects of high trait anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship.
24Vagus nerve stimulation: Novel concept for the treatment of glioblastoma and solid cancers by cytokine (interleukin-6) reduction, attenuating the SASP, enhancing tumor immunity.PubMed
Steven Brem
Brain Behav Immun Health. 2024 Sep 17;42:100859. doi: 10.1016/j.bbih.2024.100859. eCollection 2024 Dec.
Immuno-oncology, specifically immune checkpoint inhibitors (ICIs), has revolutionized cancer care with dramatic, long-term responses and increased survival, including patients with metastatic cancer to the brain. Glioblastomas, and other primary brain tumors, are refractory to ICIs as monotherapy or in combination with standard therapy. The tumor microenvironment (TME) poses multiple biological hurdles: blood-brain barrier, immune suppression, heterogeneity, and tumor infiltration. Genomic analysis of the senescence-associated secretory phenotype (SASP) and preclinical models of glioma suggest that an exciting approach would entail reprogramming of the glioma microenvironment, attenuating the pro-inflammatory, pro-tumorigenic cytokines of the SASP, especially interleukin-6 (IL-6). A testable hypothesis now proposed is to modulate the immune system by harnessing the body's 'inflammatory reflex' to reduce cytokines. Vagus nerve stimulation can activate T cell immunity by the cholinergic, α7nicotinic acetylcholine receptor agonist (α7nAchR), and suppress IL-6 systemically, as well as other pro-inflammatory cytokines of the SASP, interleukin -1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). The hypothesis predicts that electrical activation of the vagus nerve, with cytokine reduction, in combination with ICIs, would convert an immune resistant ("cold") tumor to an immune responsive ("hot") tumor, and halt glioma progression. The hypothesis also envisions cancer as an immune "dysautonomia" whereby a therapeutic intervention, vagus nerve stimulation (VNS), resets the systemic and local cytokine levels. A prospective, randomized, phase II clinical trial, to confirm the hypothesis, is a logical, exigent, next step. Cytokine reduction by VNS could also be useful for other forms of human cancer, e.g., breast, colorectal, head and neck, lung, melanoma, ovarian, pancreatic, and prostate cancer, as the emerging field of "cancer neuroscience" shows a role for neural regulation of multiple tumor types. Because IL-6, and companion pro-inflammatory cytokines, participate in the initiation, progression, spread and recurrence of cancer, minimally invasive VNS could be employed to suppress glioma or cancer progression, while also mitigating depression and/or seizures, thereby enhancing quality of life. The current hypothesis reimagines glioma pathophysiology as a dysautonomia with the therapeutic objective to reset the autonomic nervous system and form an immune responsive state to halt tumor progression and prevent recurrence. VNS, as a novel method to control cancer, can be administered with ICIs, standard therapy, or in clinical trials, combined with emerging immunotherapy: dendritic cell, mRNA, or chimeric antigen receptor (CAR) T cell vaccines.
25Th17 Cells in Depression: Are They Crucial for the Antidepressant Effect of Ketamine?PubMed
Meiying Cui, Wanlin Dai, Jing Kong, et al.
Front Pharmacol. 2021 Apr 15;12:649144. doi: 10.3389/fphar.2021.649144. eCollection 2021.
Major depressive disorder is associated with inflammation and immune processes. Depressive symptoms correlate with inflammatory markers and alterations in the immune system including cytokine levels and immune cell function. Th17 cells are a T cell subset which exerts proinflammatory effects. Th17 cell accumulation and Th17/Treg imbalances have been reported to be critical in the pathophysiology of major depressive disorder and depressive-like behaviors in animal models. Th17 cells are thought to interfere with glutamate signaling, dopamine production, and other immune processes. Ketamine is a newly characterized antidepressant medication which has proved to be effective in rapidly reducing depressive symptoms. However, the mechanisms behind these antidepressant effects have not been fully elucidated. Literature about Th17 cells and their role in depression and the antidepressant effect of ketamine are reviewed, with the possible interaction networks discussed. The immune-modulating role of Th17 cells may participate in the antidepressant effect of ketamine. As Th17 cells play multiple roles in depression, it is important to explore the mechanisms of action of ketamine on Th17 cells and Th17/Treg cell balance. This provides new perspectives for strengthening the antidepressant effect of ketamine while reducing its side effects and adverse reactions.
26High-fat diet-induced obesity causes intestinal Th17/Treg imbalance that impairs the intestinal barrier and aggravates anxiety-like behavior in mice.PubMed
Yao Cai, Wenlin Deng, Qiuping Yang, et al.
Int Immunopharmacol. 2024 Mar 30;130:111783. doi: 10.1016/j.intimp.2024.111783. Epub 2024 Mar 7.
The prevalence of autism spectrum disorders (ASD) has been steadily increasing, and growing evidence suggests a link between high-fat diet (HFD), obesity, and ASD; however, the mechanism underlying this association remains elusive. Herein, BTBR T + tf/J (BTBR) inbred mice (a mouse ASD model) and C57Bl/6J (C57) mice were fed an HFD and normal diet (ND) for 8 weeks (groups: C57 + ND, C57 + HFD, BTBR + ND, and BTBR + HFD). Subsequently, mice underwent behavioral assessments, followed by intestinal tissues harvesting to detect expression of intestinal barrier proteins and inflammatory factors and immune cell numbers, and a correlation analysis. HFD-fed BTBR mice developed obesity, elevated blood sugar, significantly aggravated anxiety-like behaviors, impaired intestinal barrier function, intestinal inflammation with elevated CD4IL17 T (Th17) cells and reduced CD4Foxp3 T (Treg) cells, exhibiting reduced expression of proteins related to AMPK regulatory pathway (AMPK, p-AMPK, SIRT1). Correlation analysis revealed that the degree of behavioral anxiety, the degree of intestinal barrier damage, the severity of intestinal inflammation, and the degree of immune cell imbalance positively correlated with each other. Accordingly, HFD-induced obesity may cause intestinal Th17/Treg imbalance via the AMPK-SIRT1 pathway, leading to an inflammatory environment in the intestine, impairing intestinal barrier function, and ultimately aggravating anxiety-like behaviors in mice.
27Modeling an autism risk factor in mice leads to permanent immune dysregulation.PubMed
Elaine Y Hsiao, Sara W McBride, Janet Chow, et al.
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81. doi: 10.1073/pnas.1202556109. Epub 2012 Jul 16.
Increasing evidence highlights a role for the immune system in the pathogenesis of autism spectrum disorder (ASD), as immune dysregulation is observed in the brain, periphery, and gastrointestinal tract of ASD individuals. Furthermore, maternal infection (maternal immune activation, MIA) is a risk factor for ASD. Modeling this risk factor in mice yields offspring with the cardinal behavioral and neuropathological symptoms of human ASD. In this study, we find that offspring of immune-activated mothers display altered immune profiles and function, characterized by a systemic deficit in CD4(+) TCRβ(+) Foxp3(+) CD25(+) T regulatory cells, increased IL-6 and IL-17 production by CD4(+) T cells, and elevated levels of peripheral Gr-1(+) cells. In addition, hematopoietic stem cells from MIA offspring exhibit altered myeloid lineage potential and differentiation. Interestingly, repopulating irradiated control mice with bone marrow derived from MIA offspring does not confer MIA-related immunological deficits, implicating the peripheral environmental context in long-term programming of immune dysfunction. Furthermore, behaviorally abnormal MIA offspring that have been irradiated and transplanted with immunologically normal bone marrow from either MIA or control offspring no longer exhibit deficits in stereotyped/repetitive and anxiety-like behaviors, suggesting that immune abnormalities in MIA offspring can contribute to ASD-related behaviors. These studies support a link between cellular immune dysregulation and ASD-related behavioral deficits in a mouse model of an autism risk factor.
28Depression and immunity: a meta-analytic review.PubMed
T B Herbert, S Cohen
Psychol Bull. 1993 May;113(3):472-86. doi: 10.1037/0033-2909.113.3.472.
A meta-analysis indicated that clinical depression was associated with several large alterations in cellular immunity. Analyzing only methodologically sound studies, reliable immune alterations included lowered proliferative response of lymphocytes to mitogens (effect size rs = .24-.45), lowered natural killer cell activity (r = .28), and alterations in numbers of several white blood cell populations (rs = .11-.77). Immune alterations were greater in both older and hospitalized samples. There was also evidence of a linear relation between intensity of depressive affect and indicators of cellular immunity. Estimates of sample sizes needed to detect reliable effects for each immune outcome are provided. How neuroendocrine mechanisms or health practices might link depression to immunity is discussed, and design features needed to better understand these pathways are specified.
29Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor.PubMed
Linda Monaco-Shawver, Lynnae Schwartz, Florin Tuluc, et al.
J Leukoc Biol. 2011 Jan;89(1):113-25. doi: 10.1189/jlb.0410200. Epub 2010 Oct 12.
SP is a potent neuroimmunomodulator that functions through ligating members of the neurokinin receptor family, one of which, NK1R, is widely expressed in immune cells. As in humans, circulating SP levels are increased in pathologic states associated with impairment of NK cell functions, such as depression and HIV infection, we hypothesized that SP has a direct, inhibitory effect upon NK cells. We have studied a clonal human NK cell line (YTS) as well as ex vivo human NK cells and have determined that truncated and full-length NK1R isoforms are expressed in and SP bound by ex vivo NK cells and the YTS NK cell line. Incubation of YTS cells with 10⁻⁶ M SP and ex vivo NK cells with 10⁻⁵ M SP inhibited cytotoxic ability by ∼20% and reduced degranulation. This inhibitory effect upon cytotoxicity was partially prevented by the NK1R antagonist CP96,345. The treatment of YTS or ex vivo NK cells with SP neither down-modulated NCR expression nor affected triggering receptor-induced NF-κB activation. Preincubation of YTS cells with SP, however, did abbreviate the typically prolonged intracellular calcium increase induced by target cell engagement and reduced triggering receptor-induced pERK. Thus, SP has the potential to regulate NK cell functions and acts downstream from neurokinin receptors to modulate NK cell activation signaling. This mechanism may contribute to impairment of NK cell function in certain disease states associated with increased circulating SP. Antagonism of this system may present an opportunity to augment NK cell function therapeutically in selected human diseases.
30Anxiety and pain suppress the natural killer cell activity in oral surgery outpatients.PubMed
C Koga, K Itoh, M Aoki, et al.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Jun;91(6):654-8. doi: 10.1067/moe.2001.115465.
OBJECTIVE: Psychological stress has an influence on natural killer cell (NK) activity, which plays a central role in protection against microbial infection and cancer. Anxiety concerning cancer is a typical type of psychological stress observed in patients and is associated with various diseases. In this study, we examined whether anxiety about cancer reduces the NK activity or quality of life (QOL), or both, of outpatients. PATIENTS AND METHODS: NK activity was determined by means of a 4-hour 51 chromium-release assay, and a QOL questionnaire by the World Health Organization called QOL-BRIEF was also used. One hundred forty-four patients were asked a variety of questions about anxiety with respect to cancer and pain on their first visit to the outpatient clinic of our Department of Oral Surgery. RESULTS: The NK activity in patients with anxiety about cancer was significantly lower (P < .001) than that in those with no such anxiety. In contrast, NK activity was not influenced by any other factor tested, including differences in diseases and QOL scores. CONCLUSION: Anxiety about cancer may be one of the primary factors for suppression of NK activity in oral surgery outpatients.
31Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity.PubMed
Shelly Inbar, Elad Neeman, Roi Avraham, et al.
PLoS One. 2011 Apr 29;6(4):e19246. doi: 10.1371/journal.pone.0019246.
In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E(2) or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition.
32Human cytomegalovirus infection and the immune response to exercise.PubMed
Richard J Simpson, Austin B Bigley, Guillaume Spielmann, et al.
Exerc Immunol Rev. 2016;22:8-27.
Human cytomegalovirus (HCMV) is a ubiquitous -herpes virus that has co-evolved with its host since the very beginning of human life. The vast majority of adults worldwide carry the virus in a latent state, which is known to have striking effects on the composition and function of both T-cells and NK-cells. While there is evidence to suggest that prior exposure to HCMV can have beneficial effects in the immune competent host, poor control of the virus may contribute to T-cell exhaustion and the early onset of immunosenescence. The interaction between HCMV and exercise has garnered a lot of recent research attention. This stemmed from observations that people with HCMV redeploy greater numbers of CD8+ T-cells in response to a single exercise bout, while NK-cell mobilization is, conversely, impaired. Moreover, athletes with latent HCMV infection may be better protected against symptoms of upper respiratory illness (URI), and it has been suggested that the host's ability to control HCMV (i.e. keeping CMV in a latent state) may connect apparent bidirectional effects of exercise volume on host immunity and infection risk. This work has set a new paradigm that immune responses to both acute and chronic exercise might be governed by the infection history of the host. In this review, we summarize current knowledge on the effects of HCMV infection on T-cells and NK-cells and synthesize the literature on HCMV and the immune response to both single exercise bouts and prolonged periods of exercise training. We also discuss potential clinical and practical applications of this work including the use of HCMV reactivation as a biomarker of immune depression in athletes, its relevance in immunosenescence and the associated immune risk profile, and the potential for exercise to augment vaccine responses and the man ufacture of immune cells for adoptive transfer immunotherapy. Although research in this area is still in its infancy, we conclude that host infection history and the ability to regulate dormant pathogens is likely to play a key role in our understanding of how the immune system responds to both acute and chronic exercise across the entire exercise volume continuum.
33Synaptic pruning by microglia is necessary for normal brain development.PubMed
Rosa C Paolicelli, Giulia Bolasco, Francesca Pagani, et al.
Science. 2011 Sep 9;333(6048):1456-8. doi: 10.1126/science.1202529. Epub 2011 Jul 21.
Microglia are highly motile phagocytic cells that infiltrate and take up residence in the developing brain, where they are thought to provide a surveillance and scavenging function. However, although microglia have been shown to engulf and clear damaged cellular debris after brain insult, it remains less clear what role microglia play in the uninjured brain. Here, we show that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice. These findings link microglia surveillance to synaptic maturation and suggest that deficits in microglia function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.
34Roles of microglia in adult hippocampal neurogenesis in depression and their therapeutics.PubMed
Shaoyi Fang, Zhibin Wu, Yali Guo, et al.
Front Immunol. 2023 Oct 10;14:1193053. doi: 10.3389/fimmu.2023.1193053. eCollection 2023.
Adult hippocampal neurogenesis generates functional neurons from neural progenitor cells in the hippocampal dentate gyrus (DG) to complement and repair neurons and neural circuits, thus benefiting the treatment of depression. Increasing evidence has shown that aberrant microglial activity can disrupt the appropriate formation and development of functional properties of neurogenesis, which will play a crucial role in the occurrence and development of depression. However, the mechanisms of the crosstalk between microglia and adult hippocampal neurogenesis in depression are not yet fully understood. Therefore, in this review, we first introduce recent discoveries regarding the roles of microglia and adult hippocampal neurogenesis in the etiology of depression. Then, we systematically discuss the possible mechanisms of how microglia regulate adult hippocampal neurogenesis in depression according to recent studies, which involve toll-like receptors, microglial polarization, fractalkine-C-X3-C motif chemokine receptor 1, hypothalamic-pituitary-adrenal axis, cytokines, brain-derived neurotrophic factor, and the microbiota-gut-brain axis, etc. In addition, we summarize the promising drugs that could improve the adult hippocampal neurogenesis by regulating the microglia. These findings will help us understand the complicated pathological mechanisms of depression and shed light on the development of new treatment strategies for this disease.
35Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression.PubMed
Haixia Wang, Yi He, Zuoli Sun, et al.
J Neuroinflammation. 2022 Jun 6;19(1):132. doi: 10.1186/s12974-022-02492-0.
Major depressive disorder is a highly debilitating psychiatric disorder involving the dysfunction of different cell types in the brain. Microglia are the predominant resident immune cells in the brain and exhibit a critical role in depression. Recent studies have suggested that depression can be regarded as a microglial disease. Microglia regulate inflammation, synaptic plasticity, and the formation of neural networks, all of which affect depression. In this review, we highlighted the role of microglia in the pathology of depression. First, we described microglial activation in animal models and clinically depressed patients. Second, we emphasized the possible mechanisms by which microglia recognize depression-associated stress and regulate conditions. Third, we described how antidepressants (clinical medicines and natural products) affect microglial activation. Thus, this review aimed to objectively analyze the role of microglia in depression and focus on potential antidepressants. These data suggested that regulation of microglial actions might be a novel therapeutic strategy to counteract the adverse effects of devastating mental disorders.
36Esketamine Prevents Postoperative Emotional and Cognitive Dysfunction by Suppressing Microglial M1 Polarization and Regulating the BDNF-TrkB Pathway in Ageing Rats with Preoperative Sleep Disturbance.PubMed
Yuxin Wen, Jiawen Xu, Jiahong Shen, et al.
Mol Neurobiol. 2024 Aug;61(8):5680-5698. doi: 10.1007/s12035-023-03860-4. Epub 2024 Jan 15.
Postoperative depression (POD) and postoperative cognitive dysfunction (POCD) have placed heavy burden on patients' physical and mental health in recent years. Sleep disturbance before surgery is a common phenomenon that has been increasingly believed to affect patients' recovery, especially in aged patients, while little attention has been paid to sleep disruption before surgery and the potential mechanism remains ambiguous. Ketamine has been reported to attenuate POCD after cardiac surgery and elicit rapid-acting and sustained antidepressant actions. The present study aimed to clarify the effect of esketamine's (the S-enantiomer of ketamine) protective effects and possible mechanisms of action in POCD and POD. Our results showed that sleep disturbance before surgery exacerbated microglial M1 polarization and microglial BDNF-TrkB signalling dysfunction induced by surgery, resulting in postoperative emotional changes and cognitive impairments. Notably, treatment with esketamine reversed the behavioural abnormalities through inhibiting the M1 polarization of microglia and the inflammatory response thus improving BDNF-TrkB signalling in vivo and vitro. In addition, esketamine administration also reversed the impaired hippocampal synaptic plasticity which has been perturbed by sleep disturbance and surgery. These findings warrant further investigations into the interplay of esketamine and may provide novel ideas for the implication of preoperative preparations and the prevention of postoperative brain-related complications.
37Magnolol attenuates depressive-like behaviors by polarizing microglia towards the M2 phenotype through the regulation of Nrf2/HO-1/NLRP3 signaling pathway.PubMed
Weiwei Tao, Yuwen Hu, Zhaoyang Chen, et al.
Phytomedicine. 2021 Oct;91:153692. doi: 10.1016/j.phymed.2021.153692. Epub 2021 Jul 30.
PURPOSE: Magnolol (MA) exhibits anti-depressant effect by inhibiting inflammation. However, its effect on microglia polarization remains not fully understood. Herein, our study was performed to evaluate the effect of MA on microglia polarization in chronic unpredictable mild stress (CUMS)-induced depression and explore its potential mechanism. STUDY DESIGN: The CUMS procedure was conducted, and the mice were intragastrically treated with MA. BV2 cells were pretreated with MA prior to LPS/ATP challenge. METHODS: The levels of TNF-α, IL-1β, IL-6 and IL-4, IL-10 in brain and BV2 cells were examined by ELISA. The mRNA expressions of Arg1, Ym1, Fizz1 and Klf4 in brains were measured. ROS content was determined using flow cytometry. Immunofluorescence was employed to evaluate Iba-1 level, Nrf2 nuclear translocation, Iba-1CD16/32 and Iba-1CD206 cell population. The protein expressions of Nrf2, HO-1, NLRP3, caspase-1 p20 and IL-1β in brains and BV2 cells were investigated by western blot. Nrf2 siRNA was induced in experiments to explore the role of Nrf2 in MA-mediated microglia polarization. The ubiquitination of Nrf2 was visualized by Co-IP. RESULTS: The treatment with MA notably relieved depressive like behaviors, suppressed pro-inflammatory cytokines, promoted anti-inflammatory cytokines and the transcription of M2 phenotype microglia-specific indicators. MA upregulated the expression of Nrf2, HO-1, downregulated the expression of NLRP3, caspase-1 p20, IL-1β both in vivo and in vitro. MA also reduced ROS concentration, promoted Nrf2 nucleus translocation and prevented Nrf2 ubiquitination. Nrf2 Knockdown by siRNA abolished the MA-mediated microglia polarization. CONCLUSION: The present research demonstrated that MA attenuated CUMS-stimulated depression by inhibiting M1 polarization and inducing M2 polarization via Nrf2/HO-1/NLRP3 signaling.
38Echinacoside exerts antidepressant-like effects through enhancing BDNF-CREB pathway and inhibiting neuroinflammation regulating microglia M1/M2 polarization and JAK1/STAT3 pathway.PubMed
Renrui Lu, Li Zhang, Huihui Wang, et al.
Front Pharmacol. 2023 Jan 4;13:993483. doi: 10.3389/fphar.2022.993483. eCollection 2022.
The present study was performed to investigate the antidepressant effect of echinacoside (ECH) using chronic unpredictable mild stress (CUMS) induced depression mice and lipopolysaccharide (LPS)-stimulated N9 microglial cells. CUMS treatment was performed on C57BL/6 mice for 28 days, followed by gavaging with different doses of echinacoside (15 and 60 mg/kg) for 21 consecutive days. Sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were measured to assess the effects of echinacoside on CUMS-Induced Depressive-Like Behaviors. After that, the pathological changes of hippocampus were determined by Hematoxylin and eosin (HE) staining and Nissl staining; the neurotransmitters, pro-inflammatory cytokines and indoleamine 2,3-dioxygenase (IDO) levels, and the hypothalamic-pituitary-adrenal (HPA) axis activity were determined by enzyme linked immunosorbent assay (ELISA); Iba 1were evaluated by Immunofluorescence assay; Key protein expression levels of CREB/BDNF signal pathway were measured by western blotting. Subsequently, N9 cells were stimulated with 1 μg/ml LPS to induce N9 microglia activation, and were treated with 5-20 μM of echinacoside for 24 h. After that, the levels of NO, interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), IL-4, IL-10, and transforming growth factor beta (TGF-β) in N9 cell culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA) kits; morphology and Iba 1 expression level were observed by high-content screening assay; the M1 markers of CD11b, CD86 and M2 markers of CD206 were analyzed by imaging flow cytometry. Results show that treatment with echinacoside reversed CUMS-increased immobility time in OFT, TST, FST and reversed CUMS-reduced sucrose preference in SPT. In addition, echinacoside reduced the levels of pro-inflammatory cytokines and Iba 1. Moreover, echinacoside significantly increased p-CREB/CREB ratio and BDNF level in hippocampus. Furthermore, echinacoside reduced the secretion of inflammatory factors and inhibited microglia M1 polarization in N9 cells. In conclusion, echinacoside may be beneficial for the treatment of depression diseases through regulating the microglia balance by inhibiting the polarization of microglia to M1 phenotype, and improving hippocampal neurogenesis by the CREB-BDNF signaling pathway.
39Microglia in depression: current perspectives.PubMed
Xiaoning Jia, Zhihua Gao, Hailan Hu
Sci China Life Sci. 2021 Jun;64(6):911-925. doi: 10.1007/s11427-020-1815-6. Epub 2020 Oct 14.
Major depressive disorder (MDD) is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain. Accumulating studies started to reveal that microglia, the primary resident immune cells, play an important role in the development and progression of depression. Microglia respond to stress-triggered neuroinflammation, and through the release of proinflammatory cytokines and their metabolic products, microglia may modulate the function of neurons and astrocytes to regulate depression. In this review, we focused on the role of microglia in the etiology of depression. We discussed the dynamic states of microglia; the correlative and causal evidence of microglial abnormalities in depression; possible mechanisms of how microglia sense depression-related stress and modulate depression state; and how antidepressive therapies affect microglia. Understanding the role of microglia in depression may shed light on developing new treatment strategies to fight against this devastating mental illness.
40Neuron secrete exosomes containing miR-9-5p to promote polarization of M1 microglia in depression.PubMed
Xian Xian, Li-Li Cai, Yang Li, et al.
J Nanobiotechnology. 2022 Mar 9;20(1):122. doi: 10.1186/s12951-022-01332-w.
BACKGROUND: Neuroinflammation is an important component mechanism in the development of depression. Exosomal transfer of MDD-associated microRNAs (miRNAs) from neurons to microglia might exacerbate neuronal cell inflammatory injury. RESULTS: By sequence identification, we found significantly higher miR-9-5p expression levels in serum exosomes from MDD patients than healthy control (HC) subjects. Then, in cultured cell model, we observed that BV2 microglial cells internalized PC12 neuron cell-derived exosomes while successfully transferring miR-9-5p. MiR-9-5p promoted M1 polarization in microglia and led to over releasing of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which exacerbated neurological damage. Furthermore, we identified suppressor of cytokine signaling 2 (SOCS2) as a direct target of miR-9-5p. Overexpression of miR-9-5p suppressed SOCS2 expression and reactivated SOCS2-repressed Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways. Consistently, we confirmed that adeno-associated virus (AAV)-mediated overexpression of miR-9-5p polarized microglia toward the M1 phenotype and exacerbated depressive symptoms in chronic unpredictable mild stress (CUMS) mouse mode. CONCLUSION: MiR-9-5p was transferred from neurons to microglia in an exosomal way, leading to M1 polarization of microglia and further neuronal injury. The expression and secretion of miR-9-5p might be novel therapeutic targets for MDD.
41Neuroinflammation, memory, and depression: new approaches to hippocampal neurogenesis.PubMed
Anbiao Wu, Jiyan Zhang
J Neuroinflammation. 2023 Nov 27;20(1):283. doi: 10.1186/s12974-023-02964-x.
As one of most common and severe mental disorders, major depressive disorder (MDD) significantly increases the risks of premature death and other medical conditions for patients. Neuroinflammation is the abnormal immune response in the brain, and its correlation with MDD is receiving increasing attention. Neuroinflammation has been reported to be involved in MDD through distinct neurobiological mechanisms, among which the dysregulation of neurogenesis in the dentate gyrus (DG) of the hippocampus (HPC) is receiving increasing attention. The DG of the hippocampus is one of two niches for neurogenesis in the adult mammalian brain, and neurotrophic factors are fundamental regulators of this neurogenesis process. The reported cell types involved in mediating neuroinflammation include microglia, astrocytes, oligodendrocytes, meningeal leukocytes, and peripheral immune cells which selectively penetrate the blood-brain barrier and infiltrate into inflammatory regions. This review summarizes the functions of the hippocampus affected by neuroinflammation during MDD progression and the corresponding influences on the memory of MDD patients and model animals.
42Dopamine-driven increase in IL-1β in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV.PubMed
Stephanie M Matt, Rachel Nolan, Samyuktha Manikandan, et al.
J Neuroinflammation. 2025 Mar 23;22(1):91. doi: 10.1186/s12974-025-03403-9.
The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1β in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1β in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1β. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1β gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1β signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1β in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1β, will be critical to effectively tailor medication regimens.
43Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala.PubMed
Zhi-Heng Zheng, Jiang-Long Tu, Xiao-Han Li, et al.
Brain Behav Immun. 2021 Jan;91:505-518. doi: 10.1016/j.bbi.2020.11.007. Epub 2020 Nov 6.
Increasing evidence indicates that excessive inflammatory responses play a crucial role in the pathophysiology of psychiatric diseases, including depression and anxiety disorders. The dysfunctional neural plasticity in amygdala has long been proposed as the vital cause for the progression of psychiatric disorders. However, the effect of neuroinflammation on the functional changes of the amygdala remains largely unknown. Here, by using a mouse model of inflammation induced by lipopolysaccharide (LPS) injection, we investigated the effect of LPS-induced neuroinflammation on the synaptic and non-synaptic plasticity in basolateral amygdala (BLA) projection neurons (PNs) and their contribution to the LPS-induced anxiety- and depressive-like behavior. The results showed that LPS treatment led to the activation of microglia and production of proinflammatory cytokines in the BLA. Furthermore, LPS treatment increased excitatory but not inhibitory synaptic transmission due to the enhanced presynaptic glutamate release, thus leading to the shift of excitatory/inhibitory balance towards excitatory. In addition, the intrinsic neuronal excitability of BLA PNs was also increased by LPS treatment through the loss of expression and function of small-conductance, calcium-activated potassium channel. Chronic fluoxetine pretreatment significantly prevented these neurophysiological changes induced by LPS, and alleviated anxiety and depressive-like behavior, indicating that LPS-induced neuronal dysregulation of BLA PNs may contribute to the development of psychiatry disorders. Collectively, these findings provide evidence that dysregulation of synaptic and non-synaptic transmission in the BLA PNs may account for neuroinflammation-induced anxiety- and depressive-like behavior.
44Microglia-Derived Interleukin-6 Triggers Astrocyte Apoptosis in the Hippocampus and Mediates Depression-Like Behavior.PubMed
Shi-Yu Shen, Ling-Feng Liang, Tian-Le Shi, et al.
Adv Sci (Weinh). 2025 Mar;12(11):e2412556. doi: 10.1002/advs.202412556. Epub 2025 Jan 30.
In patients with major depressive disorder (MDD) and animal models of depression, key pathological hallmarks include activation of microglia as well as atrophy and loss of astrocytes. Under certain pathological conditions, microglia can inflict damage to neurons and astrocytes. However, the precise mechanisms underlying how activated microglia induced astrocyte atrophy and loss remain enigmatic. In this study, a depression model induced by chronic social defeat stress (CSDS) is utilized. The results show that CSDS induces significant anxiety- and depression-like behaviors, along with notable astrocyte atrophy and apoptosis, microglial activation, and elevated levels of microglial interleukin-6 (IL-6). Subsequent studies demonstrate that IL-6 released from activated microglia promotes astrocyte apoptosis. Furthermore, the knockdown of the P2X7 receptor (P2X7R) in microglia, which is implicated in the stress response, reduces stress-induced microglial activation, IL-6 release, and astrocyte apoptosis. Direct inhibition of microglia by minocycline corroborates these effects. The selective knockdown of IL-6 in microglia and IL-6 receptors in astrocytes effectively mitigates depression-like behaviors and reduces astrocyte atrophy. This study identifies microglial IL-6 as a key factor that contributes to astrocyte apoptosis and depressive symptoms. Consequently, the IL-6/IL-6R pathway has emerged as a promising target for the treatment of depression.
45Effects of central and peripheral inflammation on hippocampal synaptic plasticity.PubMed
Massimiliano Di Filippo, Davide Chiasserini, Fabrizio Gardoni, et al.
Neurobiol Dis. 2013 Apr;52:229-36. doi: 10.1016/j.nbd.2012.12.009. Epub 2013 Jan 4.
The central nervous system (CNS) and the immune system are known to be engaged in an intense bidirectional crosstalk. In particular, the immune system has the potential to influence the induction of brain plastic phenomena and neuronal networks functioning. During direct CNS inflammation, as well as during systemic, peripheral, inflammation, the modulation exerted by neuroinflammatory mediators on synaptic plasticity might negatively influence brain neuronal networks functioning. The aim of the present study was to investigate, by using electrophysiological techniques, the ability of hippocampal excitatory synapses to undergo synaptic plasticity during the initial clinical phase of an experimental model of CNS (experimental autoimmune encephalomyelitis, EAE) as well as following a systemic inflammatory trigger. Moreover, we compared the morphologic, synaptic and molecular consequences of central neuroinflammation with those accompanying peripheral inflammation. Hippocampal long-term potentiation (LTP) has been studied by extracellular field potential recordings in the CA1 region. Immunohistochemistry was performed to investigate microglia activation. Western blot and ELISA assays have been performed to assess changes in the subunit composition of the synaptic glutamate NMDA receptor and the concentration of pro-inflammatory cytokines in the hippocampus. Significant microglial activation together with an impairment of CA1 LTP was present in the hippocampus of mice with central as well as peripheral inflammation. Interestingly, exclusively during EAE but not during systemic inflammation, the impairment of hippocampal LTP was paralleled by a selective reduction of the NMDA receptor NR2B subunit levels and a selective increase of interleukin-1β (IL1β) levels. Both central and peripheral inflammation-triggered mechanisms can activate CNS microglia and influence the function of CNS synapses. During direct CNS inflammation these events are accompanied by detectable changes in synaptic glutamate receptors subunit composition and in the levels of the pro-inflammatory cytokine IL1β.
46Neuroinflammation and depression: A review.PubMed
Romain Troubat, Pascal Barone, Samuel Leman, et al.
Eur J Neurosci. 2021 Jan;53(1):151-171. doi: 10.1111/ejn.14720. Epub 2020 Mar 20.
Some recent clinical and preclinical evidence suggests that neuroinflammation is a key factor that interacts with the three neurobiological correlates of major depressive disorder: depletion of brain serotonin, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and alteration of the continuous production of adult-generated neurons in the dentate gyrus of the hippocampus. This review discusses the main players in brain immunity as well as how inflammation interacts with the above three mechanisms. It is reported that kynurenine (KYN) pathway alteration in favour of its excitotoxic component and HPA axis dysregulation have the common effect of increasing extracellular glutamate levels and glutamate neurotransmission, which can impact hippocampal neurogenesis. This pathophysiological cascade appears to be triggered or sustained and reinforced by any chronic inflammatory condition involving increased circulating markers of inflammation that are able to cross the blood-brain barrier and activate microglia; it can also be the consequence of primary brain neuroinflammation, such as in neurodegenerative disorders with early manifestations that are frequently depressive symptoms. Further recent data indicate that primary microglial activation may also result from a direct impact of chronic stress on vascular function. The intricated dynamic crosstalk between neuroinflammation and other relevant neurobiological correlates of depression add to evidence that neuroinflammation may be a key therapeutic target for future therapeutic strategies in major depressive disorder.
47Chronic psychosocial stress triggers microglial-/macrophage-induced inflammatory responses leading to neuronal dysfunction and depressive-related behavior.PubMed
Alexandros G Kokkosis, Miguel M Madeira, Zachary Hage, et al.
Glia. 2024 Jan;72(1):111-132. doi: 10.1002/glia.24464. Epub 2023 Sep 7.
Chronic environmental stress and traumatic social experiences induce maladaptive behavioral changes and is a risk factor for major depressive disorder (MDD) and various anxiety-related psychiatric disorders. Clinical studies and animal models of chronic stress have reported that symptom severity is correlated with innate immune responses and upregulation of neuroinflammatory cytokine signaling in brain areas implicated in mood regulation (mPFC; medial Prefrontal Cortex). Despite increasing evidence implicating impairments of neuroplasticity and synaptic signaling deficits into the pathophysiology of stress-related mental disorders, how microglia may modulate neuronal homeostasis in response to chronic stress has not been defined. Here, using the repeated social defeat stress (RSDS) mouse model we demonstrate that microglial-induced inflammatory responses are regulating neuronal plasticity associated with psychosocial stress. Specifically, we show that chronic stress induces a rapid activation and proliferation of microglia as well as macrophage infiltration in the mPFC, and these processes are spatially related to neuronal activation. Moreover, we report a significant association of microglial inflammatory responses with susceptibility or resilience to chronic stress. In addition, we find that exposure to chronic stress exacerbates phagocytosis of synaptic elements and deficits in neuronal plasticity. Importantly, by utilizing two different CSF1R inhibitors (the brain penetrant PLX5622 and the non-penetrant PLX73086) we highlight a crucial role for microglia (and secondarily macrophages) in catalyzing the pathological manifestations linked to psychosocial stress in the mPFC and the resulting behavioral deficits usually associated with depression.
48Stress induced microglial activation contributes to depression.PubMed
Bingjin Li, Wei Yang, Tongtong Ge, et al.
Pharmacol Res. 2022 May;179:106145. doi: 10.1016/j.phrs.2022.106145. Epub 2022 Feb 24.
Major depressive disorder (MDD) is a debilitating neuropsychological disorder, which has caused serious health and socio-economic burdens worldwide. A growing body of evidence indicates that inflated neuroinflammation and aberrant microglial activity are associated with depressive-like symptoms. In the central nervous system (CNS), microglia constantly survey the internal environment, playing crucial roles in injury response and pathogen defense. From developmental stage through the whole adult life, microglia dynamically sculpt neural circuits by modulation of synaptic plasticity or engulfment of redundant synapses. Dysregulated microglia may impact these fundamental biophysiological processes and contribute to the pathogenesis of depressive disorder. In this review, we discuss candidate mechanisms by which stress induces microglia to deviate from its fine-tuned homeostasis in clinical and preclinical studies. These triggering factors include the neuroendocrine system, the noradrenergic system, gut-brain axis, and unbalanced pro- v.s. anti-inflammatory milieu composed of diversified cytokines and neurotransmitters. We argue that functional changes in microglia can strongly influence neuronal network activity due to dysregulated secretion of cytokines and elevated release of neurotoxic metabolites, therefore contributing to the pathological outcomes in stress. Understanding the role that microglia play in the etiology of depression may provide a tantalizing therapeutic target and help with the development of novel intervention strategies against this devastating mental health problem.
49The Role of the Inflammasome in Neurodegenerative Diseases.PubMed
Federica Piancone, Francesca La Rosa, Ivana Marventano, et al.
Molecules. 2021 Feb 11;26(4):953. doi: 10.3390/molecules26040953.
Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1β and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases.
50Sustained microglial activation in the area postrema of collagen-induced arthritis mice.PubMed
Takayuki Matsushita, Kazuhiro Otani, Yohsuke Oto, et al.
Arthritis Res Ther. 2021 Oct 29;23(1):273. doi: 10.1186/s13075-021-02657-x.
BACKGROUND: Central nervous system (CNS)-mediated symptoms, such as fatigue, depression, and hyperalgesia, are common complications among patients with rheumatoid arthritis (RA). However, it remains unclear how the peripheral pathology of RA spreads to the brain. Accumulated evidence showing an association between serum cytokine levels and aberrant CNS function suggests that humoral factors participate in this mechanism. In contrast to the well-known early responses of microglia (CNS-resident immune cells) in the area postrema [AP; a brain region lacking a blood-brain barrier (BBB)] to experimental inflammation, microglial alterations in the AP during chronic inflammation like RA remain unclear. Therefore, to determine whether microglia in the AP can react to persistent autoimmune-arthritis conditions, we analyzed these cells in a mouse model of collagen-induced arthritis (CIA). METHODS: Microglial number and morphology were analyzed in the AP of CIA and control mice (administered Freund's adjuvant or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: "pre-onset" [post-immunization day (PID) 21], "establishment" (PID 35), and "chronic" (PID 56 and 84). Quantitative analyses of microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1β (IL-1β) mRNA expression was analyzed by multiple fluorescent in situ hybridization and real-time polymerase chain reaction. Behavioral changes were assessed by sucrose preference test. RESULTS: Microglia in the AP significantly increased in density and exhibited changes in morphology during the establishment and chronic phases, but not the pre-onset phase. Non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of highly activated microglia increased in the CIA group during establishment and chronic phases. Moreover, the density of IL-1β-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1β expression in brain regions containing the AP. CONCLUSIONS: Our findings demonstrate that microglia in the AP can sustain their activated state during persistent autoimmune arthritis, which suggests that chronic inflammation, such as RA, may affect microglia in brain regions lacking a BBB and have various neural consequences.
51Rifaximin-mediated gut microbiota regulation modulates the function of microglia and protects against CUMS-induced depression-like behaviors in adolescent rat.PubMed
Haonan Li, Yujiao Xiang, Zemeng Zhu, et al.
J Neuroinflammation. 2021 Nov 4;18(1):254. doi: 10.1186/s12974-021-02303-y.
BACKGROUND: Chronic unpredictable mild stress (CUMS) can not only lead to depression-like behavior but also change the composition of the gut microbiome. Regulating the gut microbiome can have an antidepressant effect, but the mechanism by which it improves depressive symptoms is not clear. Short-chain fatty acids (SCFAs) are small molecular compounds produced by the fermentation of non-digestible carbohydrates. SFCAs are ubiquitous in intestinal endocrine and immune cells, making them important mediators of gut microbiome-regulated body functions. The balance between the pro- and anti-inflammatory microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. Non-absorbable antibiotic rifaximin can regulate the structure of the gut microbiome. We hypothesized that rifaximin protects against stress-induced inflammation and depression-like behaviors by regulating the abundance of fecal microbial metabolites and the microglial functions. METHODS: We administered 150 mg/kg rifaximin intragastrically to rats exposed to CUMS for 4 weeks and investigated the composition of the fecal microbiome, the content of short-chain fatty acids in the serum and brain, the functional profiles of microglia and hippocampal neurogenesis. RESULTS: Our results show that rifaximin ameliorated depressive-like behavior induced by CUMS, as reflected by sucrose preference, the open field test and the Morris water maze. Rifaximin increased the relative abundance of Ruminococcaceae and Lachnospiraceae, which were significantly positively correlated with the high level of butyrate in the brain. Rifaximin increased the content of anti-inflammatory factors released by microglia, and prevented the neurogenic abnormalities caused by CUMS. CONCLUSIONS: These results suggest that rifaximin can regulate the inflammatory function of microglia and play a protective role in pubertal neurodevelopment during CUMS by regulating the gut microbiome and short-chain fatty acids.
52Bidirectional 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.
53Bidirectional regulation of the brain-gut-microbiota axis following traumatic brain injury.PubMed
Xinyu You, Lin Niu, Jiafeng Fu, et al.
Neural Regen Res. 2025 Aug 1;20(8):2153-2168. doi: 10.4103/NRR.NRR-D-24-00088. Epub 2024 Jul 10.
JOURNAL/nrgr/04.03/01300535-202508000-00002/figure1/v/2024-09-30T120553Z/r/image-tiff Traumatic brain injury is a prevalent disorder of the central nervous system. In addition to primary brain parenchymal damage, the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury; however, the underlying pathogenesis remains unclear, and effective intervention methods are lacking. Intestinal dysfunction is a significant consequence of traumatic brain injury. Being the most densely innervated peripheral tissue in the body, the gut possesses multiple pathways for the establishment of a bidirectional "brain-gut axis" with the central nervous system. The gut harbors a vast microbial community, and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal, hormonal, and immune pathways. A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications. We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury, with a specific focus on the complex biological processes of peripheral nerves, immunity, and microbes triggered by traumatic brain injury, encompassing autonomic dysfunction, neuroendocrine disturbances, peripheral immunosuppression, increased intestinal barrier permeability, compromised responses of sensory nerves to microorganisms, and potential effector nuclei in the central nervous system influenced by gut microbiota. Additionally, we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury. This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the "brain-gut-microbiota axis."
54Serotonin and GI clinical disorders.PubMed
Robin Spiller
Neuropharmacology. 2008 Nov;55(6):1072-80. doi: 10.1016/j.neuropharm.2008.07.016. Epub 2008 Jul 19.
Serotonin is widely distributed throughout the gut within both the enteric nerves and enterochromaffin (EC) cells. EC cells are located in the gut mucosa with maximal numbers in the duodenum and rectum where they act as signal transducers, responding to pressure and luminal substances both bacterial and dietary. Activation leads to serotonin release which acts on a range of receptors on mucosal afferent and myenteric interneurones to initiate secretomotor reflexes. These cause nausea and vomiting as well as intestinal secretion, propulsion and if pronounced, diarrhoea. Inflammation in animal models acts via T lymphocytes to increase EC cell numbers and mucosal serotonin (5-HT) content while inflammatory cytokines decrease serotonin transporter (SERT) function. Inflammation due to coeliac disease and following gastrointestinal infection increases mucosal 5-HT availability by a combination of increased EC cells and depressed SERT. Irritable bowel syndrome (IBS) developing after gastrointestinal infection and IBS with diarrhoea is associated with excess 5-HT. The associated diarrhoeal symptoms respond well to 5-HT(3) receptor antagonists. These drugs also inhibit the nausea and vomiting occurring in patients undergoing chemotherapy which cause a marked increase in release of 5-HT as well as other mediators. Other conditions including IBS-C and constipation may have inadequate 5-HT release and benefit from both 5-HT(3) and 5-HT(4) receptor agonists.
55Randomized, double-blind, placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome.PubMed
S P Dunlop, D Jenkins, K R Neal, et al.
Aliment Pharmacol Ther. 2003 Jul 1;18(1):77-84. doi: 10.1046/j.1365-2036.2003.01640.x.
BACKGROUND: Post-infectious irritable bowel syndrome is associated with increased serotonin-containing enterochromaffin cells and lymphocytes in rectal biopsies. Animal studies have suggested that steroids reduce the lymphocyte response and suppress some of the post-infectious changes in neuromuscular function. AIM: To evaluate whether steroids reduce the number of enterochromaffin cells and improve the symptoms of post-infectious irritable bowel syndrome. METHODS: Twenty-nine patients with post-infectious irritable bowel syndrome underwent a randomized, double-blind, placebo-controlled trial of 3 weeks of oral prednisolone, 30 mg/day. Mucosal enterochromaffin cells, T lymphocytes and mast cells were assessed in rectal biopsies before and after treatment, and bowel symptoms were recorded in a daily diary. RESULTS: Initial enterochromaffin cell counts were increased and correlated with initial lamina propria T-lymphocyte counts (r = 0.460, P = 0.014). Enterochromaffin cell counts did not change significantly after either prednisolone (- 0.8% +/- 9.2%) or placebo (7.9% +/- 7.9%) (P = 0.5). Although lamina propria T-lymphocyte counts decreased significantly after prednisolone (22.0% +/- 5.6%, P = 0.003), but not after placebo (11.5% +/- 8.6%, P = 0.1), this was not associated with any significant treatment-related improvement in abdominal pain, diarrhoea, frequency or urgency. CONCLUSIONS: Prednisolone does not appear to reduce the number of enterochromaffin cells or cause an improvement in symptoms in post-infectious irritable bowel syndrome. Other approaches to this persistent condition are indicated.
56Gut microbiota and its metabolites in depression: from pathogenesis to treatment.PubMed
Lanxiang Liu, Haiyang Wang, Xueyi Chen, et al.
EBioMedicine. 2023 Apr;90:104527. doi: 10.1016/j.ebiom.2023.104527. Epub 2023 Mar 22.
Major depressive disorder is one of the most disabling mental disorders worldwide. Increasing preclinical and clinical studies have highlighted that compositional and functional (e.g., metabolite) changes in gut microbiota, known as dysbiosis, are associated with the onset and progression of depression via regulating the gut-brain axis. However, the gut microbiota and their metabolites present a double-edged sword in depression. Dysbiosis is involved in the pathogenesis of depression while, at the same time, offering a novel therapeutic target. In this review, we describe the association between dysbiosis and depression, drug-microbiota interactions in antidepressant treatment, and the potential health benefits of microbial-targeted therapeutics in depression, including dietary interventions, fecal microbiota transplantation, probiotics, prebiotics, synbiotics, and postbiotics. With the emergence of microbial research, we describe a new direction for future research and clinical treatment of depression.
57The Role of Gut Microbiota in Anxiety, Depression, and Other Mental Disorders as Well as the Protective Effects of Dietary Components.PubMed
Ruo-Gu Xiong, Jiahui Li, Jin Cheng, et al.
Nutrients. 2023 Jul 23;15(14):3258. doi: 10.3390/nu15143258.
The number of individuals experiencing mental disorders (e.g., anxiety and depression) has significantly risen in recent years. Therefore, it is essential to seek prevention and treatment strategies for mental disorders. Several gut microbiota, especially Firmicutes and Bacteroidetes, are demonstrated to affect mental health through microbiota-gut-brain axis, and the gut microbiota dysbiosis can be related to mental disorders, such as anxiety, depression, and other mental disorders. On the other hand, dietary components, including probiotics (e.g., and ), prebiotics (e.g., dietary fiber and alpha-lactalbumin), synbiotics, postbiotics (e.g., short-chain fatty acids), dairy products, spices (e.g., , curcumin, and capsaicin), fruits, vegetables, medicinal herbs, and so on, could exert protective effects against mental disorders by enhancing beneficial gut microbiota while suppressing harmful ones. In this paper, the mental disorder-associated gut microbiota are summarized. In addition, the protective effects of dietary components on mental health through targeting the gut microbiota are discussed. This paper can be helpful to develop some dietary natural products into pharmaceuticals and functional foods to prevent and treat mental disorders.
58Nutraceuticals in Psychiatric Disorders: A Systematic Review.PubMed
Paola Bozzatello, Roberta Novelli, Cristiana Montemagni, et al.
Int J Mol Sci. 2024 Apr 28;25(9):4824. doi: 10.3390/ijms25094824.
Correct nutrition and diet are directly correlated with mental health, functions of the immune system, and gut microbiota composition. Diets with a high content of some nutrients, such as fibers, phytochemicals, and short-chain fatty acids (omega-3 fatty acids), seem to have an anti-inflammatory and protective action on the nervous system. Among nutraceuticals, supplementation of probiotics and omega-3 fatty acids plays a role in improving symptoms of several mental disorders. In this review, we collect data on the efficacy of nutraceuticals in patients with schizophrenia, autism spectrum disorders, major depression, bipolar disorder, and personality disorders. This narrative review aims to provide an overview of recent evidence obtained on this topic, pointing out the direction for future research.
59The gut microbiota in anxiety and depression - A systematic review.PubMed
Carra A Simpson, Carmela Diaz-Arteche, Djamila Eliby, et al.
Clin Psychol Rev. 2021 Feb;83:101943. doi: 10.1016/j.cpr.2020.101943. Epub 2020 Oct 29.
Growing evidence indicates the community of microorganisms throughout the gastrointestinal tract, (i.e., gut microbiota), is associated with anxiety and depressive disorders. We present the first systematic review of the gut microbiota in anxiety disorders, along with an update in depression. Consideration of shared underlying features is essential due to the high rates of comorbidity. Systematic searches, following PRISMA guidelines, identified 26 studies (two case-control comparisons of the gut microbiota in generalised anxiety disorder, 18 in depression, one incorporating both anxiety/depression, and five including symptom-only measures). Alpha and beta diversity findings were inconsistent; however, differences in bacterial taxa indicated disorders may be characterised by a higher abundance of proinflammatory species (e.g., Enterobacteriaceae and Desulfovibrio), and lower short-chain fatty acid producing-bacteria (e.g., Faecalibacterium). Several taxa, and their mechanisms of action, may relate to anxiety and depression pathophysiology via communication of peripheral inflammation to the brain. Although the gut microbiota remains a promising target for prevention and therapy, future research should assess confounders, particularly diet and psychotropic medications, and should examine microorganism function.
60Perturbations in Gut Microbiota Composition in Psychiatric Disorders: A Review and Meta-analysis.PubMed
Viktoriya L Nikolova, Megan R B Smith, Lindsay J Hall, et al.
JAMA Psychiatry. 2021 Dec 1;78(12):1343-1354. doi: 10.1001/jamapsychiatry.2021.2573.
IMPORTANCE: Evidence of gut microbiota perturbations has accumulated for multiple psychiatric disorders, with microbiota signatures proposed as potential biomarkers. However, no attempts have been made to evaluate the specificity of these across the range of psychiatric conditions. OBJECTIVE: To conduct an umbrella and updated meta-analysis of gut microbiota alterations in general adult psychiatric populations and perform a within- and between-diagnostic comparison. DATA SOURCES: Cochrane Library, PubMed, PsycINFO, and Embase were searched up to February 2, 2021, for systematic reviews, meta-analyses, and original evidence. STUDY SELECTION: A total of 59 case-control studies evaluating diversity or abundance of gut microbes in adult populations with major depressive disorder, bipolar disorder, psychosis and schizophrenia, anorexia nervosa, anxiety, obsessive compulsive disorder, posttraumatic stress disorder, or attention-deficit/hyperactivity disorder were included. DATA EXTRACTION AND SYNTHESIS: Between-group comparisons of relative abundance of gut microbes and beta diversity indices were extracted and summarized qualitatively. Random-effects meta-analyses on standardized mean difference (SMD) were performed for alpha diversity indices. MAIN OUTCOMES AND MEASURES: Alpha and beta diversity and relative abundance of gut microbes. RESULTS: A total of 34 studies provided data and were included in alpha diversity meta-analyses (n = 1519 patients, n = 1429 control participants). Significant decrease in microbial richness in patients compared with control participants were found (observed species SMD = -0.26; 95% CI, -0.47 to -0.06; Chao1 SMD = -0.5; 95% CI, -0.79 to -0.21); however, this was consistently decreased only in bipolar disorder when individual diagnoses were examined. There was a small decrease in phylogenetic diversity (SMD = -0.24; 95% CI, -0.47 to -0.001) and no significant differences in Shannon and Simpson indices. Differences in beta diversity were consistently observed only for major depressive disorder and psychosis and schizophrenia. Regarding relative abundance, little evidence of disorder specificity was found. Instead, a transdiagnostic pattern of microbiota signatures was found. Depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were consistently shared between major depressive disorder, bipolar disorder, psychosis and schizophrenia, and anxiety, suggesting these disorders are characterized by a reduction of anti-inflammatory butyrate-producing bacteria, while pro-inflammatory genera are enriched. The confounding associations of region and medication were also evaluated. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found that gut microbiota perturbations were associated with a transdiagnostic pattern with a depletion of certain anti-inflammatory butyrate-producing bacteria and an enrichment of pro-inflammatory bacteria in patients with depression, bipolar disorder, schizophrenia, and anxiety.
61Acute Endotoxemia-Induced Respiratory and Intestinal Dysbiosis.PubMed
Evy Goossens, Jianhui Li, Chana Callens, et al.
Int J Mol Sci. 2022 Oct 1;23(19):11602. doi: 10.3390/ijms231911602.
Systemic inflammatory response syndrome (SIRS) is a severe condition characterized by systemic inflammation, which may lead to multiple organ failure, shock and death. SIRS is common in burn patients, pancreatitis and sepsis. SIRS is often accompanied by intestinal dysbiosis. However, the mechanism, role and details of microbiome alterations during the early phase of acute SIRS are not completely understood. The current study aimed to characterize the dynamic alterations of both the intestinal and respiratory microbiome at two timepoints during the early phase of acute SIRS (4 and 8 h after LPS) and link these to the host response in a mouse model of a LPS-induced lethal SIRS. Acute SIRS had no effect on the microbiome in the large intestine but induced a rapid dysbiosis in the small intestine, which resembled the microbiome alterations commonly observed in SIRS patients. Later in the disease progression, a dysbiosis of the respiratory microbiome was observed, which was associated with the MMP9 expression in the lungs. Although similar bacteria were increased in both the lung and the small intestine, no evidence for a gut-lung translocation was observed. Gut dysbiosis is commonly observed in diseases involving inflammation in the gut. However, whether the inflammatory response associated with SIRS and sepsis can directly cause gut dysbiosis was still unclear. In the current study we provide evidence that a LPS-induced SIRS can directly cause dysbiosis of the small intestinal and respiratory microbiome.
62How Toll-like receptors influence Parkinson's disease in the microbiome-gut-brain axis.PubMed
Ziyi Zhang, Zhihui Liu, Ao Lv, et al.
Front Immunol. 2023 May 3;14:1154626. doi: 10.3389/fimmu.2023.1154626. eCollection 2023.
Recently, a large number of experimenters have found that the pathogenesis of Parkinson's disease may be related to the gut microbiome and proposed the microbiome-gut-brain axis. Studies have shown that Toll-like receptors, especially Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4), are key mediators of gut homeostasis. In addition to their established role in innate immunity throughout the body, research is increasingly showing that the Toll-like receptor 2 and Toll-like receptor 4 signaling pathways shape the development and function of the gut and enteric nervous system. Notably, Toll-like receptor 2 and Toll-like receptor 4 are dysregulated in Parkinson's disease patients and may therefore be identified as the core of early gut dysfunction in Parkinson's disease. To better understand the contribution of Toll-like receptor 2 and Toll-like receptor 4 dysfunction in the gut to early α-synuclein aggregation, we discussed the structural function of Toll-like receptor 2 and Toll-like receptor 4 and signal transduction of Toll-like receptor 2 and Toll-like receptor 4 in Parkinson's disease by reviewing clinical, animal models, and studies. We also present a conceptual model of the pathogenesis of Parkinson's disease, in which microbial dysbiosis alters the gut barrier as well as the Toll-like receptor 2 and Toll-like receptor 4 signaling pathways, ultimately leading to a positive feedback loop for chronic gut dysfunction, promoting α-synuclein aggregation in the gut and vagus nerve.
63Immunoregulatory role of the gut microbiota in inflammatory depression.PubMed
Penghong Liu, Zhifen Liu, Jizhi Wang, et al.
Nat Commun. 2024 Apr 8;15(1):3003. doi: 10.1038/s41467-024-47273-w.
Inflammatory depression is a treatment-resistant subtype of depression. A causal role of the gut microbiota as a source of low-grade inflammation remains unclear. Here, as part of an observational trial, we first analyze the gut microbiota composition in the stool, inflammatory factors and short-chain fatty acids (SCFAs) in plasma, and inflammatory and permeability markers in the intestinal mucosa of patients with inflammatory depression (ChiCTR1900025175). Gut microbiota of patients with inflammatory depression exhibits higher Bacteroides and lower Clostridium, with an increase in SCFA-producing species with abnormal butanoate metabolism. We then perform fecal microbiota transplantation (FMT) and probiotic supplementation in animal experiments to determine the causal role of the gut microbiota in inflammatory depression. After FMT, the gut microbiota of the inflammatory depression group shows increased peripheral and central inflammatory factors and intestinal mucosal permeability in recipient mice with depressive and anxiety-like behaviors. Clostridium butyricum administration normalizes the gut microbiota, decreases inflammatory factors, and displays antidepressant-like effects in a mouse model of inflammatory depression. These findings suggest that inflammatory processes derived from the gut microbiota can be involved in neuroinflammation of inflammatory depression.
64LPS-induced systemic inflammation disrupts brain activity in a region- and vigilance-state specific manner.PubMed
Susan Leemburg, Annu Kala, Athira Nataraj, et al.
Brain Behav Immun. 2025 Aug;128:713-724. doi: 10.1016/j.bbi.2025.05.002. Epub 2025 May 9.
Sepsis-associated encephalopathy (SAE) is a common complication of sepsis and the systemic inflammatory response syndrome that leads to lasting consequences in survivors. It manifests as early EEG changes that are region-, time- and state-specific, possibly reflecting distinct mechanisms of injury. Here, we investigated the effects of 5 mg/kg lipopolysaccharide (LPS) on hippocampal and cortical sleep-wake states, oscillatory and non-oscillatory neuronal activity, as well as on within- and between-state dynamics using state-space analysis. LPS induced rapid-onset severe temporal and spatial vigilance state fragmentation, which preceded all other spectral changes by ∼90 min. Thereafter, LPS led to specific destabilization and increased delta oscillatory activity in wakefulness, but not NREM sleep, although state transitions remained largely normal. Instead, reduced NREM delta power resulted from aperiodic spectrum changes. LPS specifically reduced higher frequency hippocampal gamma oscillations (60-80 Hz peak) in wakefulness, but not cortical high gamma or lower frequency gamma oscillations. These results suggest that disruption of sleep-wake patterns could serve as an early indicator of sepsis and associated encephalopathy, independent of spectral changes. Moreover, treatment aimed at stabilizing vigilance states in early stages of sepsis might prove to be a novel option preventing the development of further pathological neurophysiology, as well as limiting inflammation-related brain damage.
65Gut-brain relationship in dementia and Alzheimer's disease: Impact on stress and immunity.PubMed
Upasana Mukherjee, P Hemachandra Reddy
Ageing Res Rev. 2025 Sep;111:102843. doi: 10.1016/j.arr.2025.102843. Epub 2025 Jul 23.
Alzheimer's disease (AD) is increasingly recognized as a condition shaped not only by central nervous system pathology but also by complex, bidirectional interactions between the gut, brain, and immune system. This review synthesizes emerging evidence on gut-brain-immune dysregulation in AD, with particular attention to how chronic stress, microbial imbalance, and neuroimmune signaling converge to influence disease risk and progression. We move beyond traditional microbiome-focused perspectives to incorporate non-microbial gut-derived mediators, including enteroendocrine hormones, bile acids, and vagal neuropeptides, which contribute to immune modulation, neurotransmission, and brain homeostasis. Importantly, we highlight that AD-related neurodegeneration can also feedback to impair gastrointestinal function and microbial composition, creating a self-reinforcing pathological loop. The review integrates recent findings on the role of host genetic polymorphisms, such as APOE4 and TREM2, in modulating gut permeability, immune tone, and microbiota profiles-emphasizing a systems biology model in which genome-microbiome interactions shape AD susceptibility. We also explore how single-cell omics technologies and multi-organ frameworks are redefining our understanding of gut-brain-immune circuits at cellular resolution. The translational section critically evaluates current and potential therapeutic strategies, including dietary, microbial, behavioral, and endocrine interventions, while addressing the challenges of applying preclinical findings to diverse human populations across the disease spectrum. By incorporating age-, stage-, and genotype-specific considerations, this review offers a comprehensive and timely synthesis of the gut-brain-stress axis in AD, positioning it as a key frontier in mechanistic research and precision therapeutic development.
66A Review of Traumatic Brain Injury and the Gut Microbiome: Insights into Novel Mechanisms of Secondary Brain Injury and Promising Targets for Neuroprotection.PubMed
Caroline S Zhu, Ramesh Grandhi, Thomas Tyler Patterson, et al.
Brain Sci. 2018 Jun 19;8(6):113. doi: 10.3390/brainsci8060113.
The gut microbiome and its role in health and disease have recently been major focus areas of research. In this review, we summarize the different ways in which the gut microbiome interacts with the rest of the body, with focus areas on its relationships with immunity, the brain, and injury. The gut⁻brain axis, a communication network linking together the central and enteric nervous systems, represents a key bidirectional pathway with feed-forward and feedback mechanisms. The gut microbiota has a central role in this pathway and is significantly altered following injury, leading to a pro-inflammatory state within the central nervous system (CNS). Herein, we examine traumatic brain injury (TBI) in relation to this axis and explore potential interventions, which may serve as targets for improving clinical outcomes and preventing secondary brain injury.
67Brain-gut-microbiota axis in depression: A historical overview and future directions.PubMed
Lijia Chang, Yan Wei, Kenji Hashimoto
Brain Res Bull. 2022 May;182:44-56. doi: 10.1016/j.brainresbull.2022.02.004. Epub 2022 Feb 11.
Depression is the most common mental disorder and a leading cause of disability worldwide. Despite abundant research, the precise mechanisms underlying the pathophysiology of depression remain elusive. Accumulating evidence from preclinical and clinical studies suggests that alterations in the gut microbiota, microbe-derived short-chain fatty acids, D-amino acids and metabolites play a key role in the pathophysiology of depression via the brain-gut-microbiota axis, including the neural and immune systems. Notably, the brain-gut-microbiota axis might play a crucial role in susceptibility versus resilience in rodents exposed to stress. Vagotomy is reported to block depression-like phenotypes in rodents after fecal microbiota transplantation of "depression-related" microbiome, suggesting that the vagus nerve influences depression through the brain-gut-microbiota axis. In this article, we review recent findings regarding the brain-gut-microbiota axis in depression and discuss its potential as a therapeutic target for depression.
68Depression and anxiety in patients with active ulcerative colitis: crosstalk of gut microbiota, metabolomics and proteomics.PubMed
Xiaomin Yuan, Biqing Chen, Zhenglan Duan, et al.
Gut Microbes. 2021 Jan-Dec;13(1):1987779. doi: 10.1080/19490976.2021.1987779.
Patients with ulcerative colitis (UC) have a high prevalence of mental disorders, such as depression and anxiety. Gut microbiota imbalance and disturbed metabolism have been suggested to play an important role in either UC or mental disorders. However, little is known about their detailed multi-omics characteristics in patients with UC and depression/anxiety. In this prospective observational study, 240 Chinese patients were enrolled, including 129 patients with active UC (69 in Phase 1 and 60 in Phase 2; divided into depression/non-depression or anxiety/non-anxiety groups), 49 patients with depression and anxiety (non-UC), and 62 healthy people. The gut microbiota of all subjects was analyzed using 16S rRNA sequencing. The serum metabolome and proteome of patients with UC in Phase 2 were analyzed using liquid chromatography/mass spectrometry. Associations between multi-omics were evaluated by correlation analysis. The prophylactic effect of candidate metabolites on the depressive-like behavior of mice with colitis was investigated. In total, 58% of patients with active UC had depression, while 50% had anxiety. Compared to patients with UC without depression/anxiety, patients with UC and depression/anxiety had lower fecal microbial community richness and diversity, with more , and but less and . Most metabolites (e.g., glycochenodeoxycholate) were increased in the serum, while few metabolites, including 2'-deoxy-D-ribose and L-pipecolic acid, were decreased, accompanied by a general reduction in immunoglobulin proteins. These related bacteria, metabolites, and proteins were highly connected. A prophylactic administration of 2'-deoxy-D-ribose and L-pipecolic acid significantly reduced the depressive-like behaviors in mice with colitis and alleviated the inflammatory cytokine levels in their colon, blood and brain. This study has identified a comprehensive multi-omics network related to depression and anxiety in active UC. It is composed of a certain set of gut microbiota, metabolites, and proteins, which are potential targets for clinical intervention for patients with UC and depression/anxiety.
69Microalgae-Based Hydrogel for Inflammatory Bowel Disease and Its Associated Anxiety and Depression.PubMed
Danni Zhong, Kangyu Jin, Ruoxi Wang, et al.
Adv Mater. 2024 Jun;36(24):e2312275. doi: 10.1002/adma.202312275. Epub 2024 Mar 18.
Patients diagnosed with inflammatory bowel disease (IBD) exhibit a notable prevalence of psychiatric disorders, such as anxiety and depression. Nevertheless, the etiology of psychiatric disorders associated with IBD remains uncertain, and an efficacious treatment approach has yet to be established. Herein, an oral hydrogel strategy (SP@Rh-gel) is proposed for co-delivery of Spirulina platensis and rhein to treat IBD and IBD-associated anxiety and depression by modulating the microbiota-gut-brain axis. SP@Rh-gel improves the solubility, release characteristics and intestinal retention capacity of the drug, leading to a significant improvement in the oral therapeutic efficacy. Oral administration of SP@Rh-gel can reduce intestinal inflammation and rebalance the disrupted intestinal microbial community. Furthermore, SP@Rh-gel maintains intestinal barrier integrity and reduces the release of pro-inflammatory factors and their entry into the hippocampus through the blood-brain barrier, thereby inhibiting neuroinflammation and maintaining neuroplasticity. SP@Rh-gel significantly alleviates the colitis symptoms, as well as anxiety- and depression-like behaviors, in a chronic colitis mouse model. This study demonstrates the significant involvement of the microbiota-gut-brain axis in the development of IBD with psychiatric disorders and proposes a safe, simple, and highly efficient therapeutic approach for managing IBD and comorbid psychiatric disorders.
70Sex Differences in Depression and Anxiety.PubMed
Pavlina Pavlidi, Nikolaos Kokras, Christina Dalla
Curr Top Behav Neurosci. 2023;62:103-132. doi: 10.1007/7854_2022_375.
Depression and anxiety disorders carry a tremendous worldwide burden and emerge as a significant cause of disability among western societies. Both disorders are known to disproportionally affect women, as they are twice more likely to be diagnosed and moreover, they are also prone to suffer from female-specific mood disorders. Importantly, the prevalence of these affective disorders has notably risen after the COVID pandemic, especially in women. In this chapter, we describe factors that are possibly contributing to the expression of such sex differences in depression and anxiety. For this, we overview the effect of transcriptomic and genetic factors, the immune system, neuroendocrine aspects, and cognition. Furthermore, we also provide evidence of sex differences in antidepressant response and their causes. Finally, we emphasize the importance to consider sex as a biological variable in preclinical and clinical research, which may facilitate the discovery and development of new and more efficacious antidepressant and anxiolytic pharmacotherapies for both women and men.
71Gut enterochromaffin cells drive visceral pain and anxiety.PubMed
James R Bayrer, Joel Castro, Archana Venkataraman, et al.
Nature. 2023 Apr;616(7955):137-142. doi: 10.1038/s41586-023-05829-8. Epub 2023 Mar 22.
Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents an important component of chronic visceral pain. For the growing population afflicted by irritable bowel syndrome, GI hypersensitivity and pain persist long after tissue injury has resolved. Irritable bowel syndrome also exhibits a strong sex bias, afflicting women three times more than men. Here, we focus on enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium. EC cells detect and transduce noxious stimuli to nearby mucosal nerve endings but involvement of this signalling pathway in visceral pain and attendant sex differences has not been assessed. By enhancing or suppressing EC cell function in vivo, we show that these cells are sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterial short-chain fatty acid associated with GI inflammation. Remarkably, prolonged EC cell activation produced persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Furthermore, perturbing EC cell activity promoted anxiety-like behaviours which normalized after blockade of serotonergic signalling. Sex differences were noted across a range of paradigms, indicating that the EC cell-mucosal afferent circuit is tonically engaged in females. Our findings validate a critical role for EC cell-mucosal afferent signalling in acute and persistent GI pain, in addition to highlighting genetic models for studying visceral hypersensitivity and the sex bias of gut pain.
72Sex Differences in Stress Response: Classical Mechanisms and Beyond.PubMed
Georgia E Hodes, Debra Bangasser, Ioannis Sotiropoulos, et al.
Curr Neuropharmacol. 2024;22(3):475-494. doi: 10.2174/1570159X22666231005090134.
Neuropsychiatric disorders, which are associated with stress hormone dysregulation, occur at different rates in men and women. Moreover, nowadays, preclinical and clinical evidence demonstrates that sex and gender can lead to differences in stress responses that predispose males and females to different expressions of similar pathologies. In this curated review, we focus on what is known about sex differences in classic mechanisms of stress response, such as glucocorticoid hormones and corticotrophin-releasing factor (CRF), which are components of the hypothalamicpituitary- adrenal (HPA) axis. Then, we present sex differences in neurotransmitter levels, such as serotonin, dopamine, glutamate and GABA, as well as indices of neurodegeneration, such as amyloid β and Tau. Gonadal hormone effects, such as estrogens and testosterone, are also discussed throughout the review. We also review in detail preclinical data investigating sex differences caused by recentlyrecognized regulators of stress and disease, such as the immune system, genetic and epigenetic mechanisms, as well neurosteroids. Finally, we discuss how understanding sex differences in stress responses, as well as in pharmacology, can be leveraged into novel, more efficacious therapeutics for all. Based on the supporting evidence, it is obvious that incorporating sex as a biological variable into preclinical research is imperative for the understanding and treatment of stress-related neuropsychiatric disorders, such as depression, anxiety and Alzheimer's disease.
73Sugar Responses of Human Enterochromaffin Cells Depend on Gut Region, Sex, and Body Mass.PubMed
Amanda L Lumsden, Alyce M Martin, Emily W Sun, et al.
Nutrients. 2019 Jan 22;11(2):234. doi: 10.3390/nu11020234.
Gut-derived serotonin (5-HT) is released from enterochromaffin (EC) cells in response to nutrient cues, and acts to slow gastric emptying and modulate gastric motility. Rodent studies also evidence a role for gut-derived 5-HT in the control of hepatic glucose production, lipolysis and thermogenesis, and in mediating diet-induced obesity. EC cell number and 5-HT content is increased in the small intestine of obese rodents and human, however, it is unknown whether EC cells respond directly to glucose in humans, and whether their capacity to release 5-HT is perturbed in obesity. We therefore investigated 5-HT release from human duodenal and colonic EC cells in response to glucose, sucrose, fructose and α-glucoside (αMG) in relation to body mass index (BMI). EC cells released 5-HT only in response to 100 and 300 mM glucose (duodenum) and 300 mM glucose (colon), independently of osmolarity. Duodenal, but not colonic, EC cells also released 5-HT in response to sucrose and αMG, but did not respond to fructose. 5-HT content was similar in all EC cells in males, and colonic EC cells in females, but 3 to 4-fold higher in duodenal EC cells from overweight females ( < 0.05 compared to lean, obese). Glucose-evoked 5-HT release was 3-fold higher in the duodenum of overweight females ( < 0.05, compared to obese), but absent here in overweight males. Our data demonstrate that primary human EC cells respond directly to dietary glucose cues, with regional differences in selectivity for other sugars. Augmented glucose-evoked 5-HT release from duodenal EC is a feature of overweight females, and may be an early determinant of obesity.
74A sexually dimorphic effect of cholera toxin: rapid changes in colonic motility mediated via a 5-HT3 receptor-dependent pathway in female C57Bl/6 mice.PubMed
Gayathri K Balasuriya, Elisa L Hill-Yardin, Michael D Gershon, et al.
J Physiol. 2016 Aug 1;594(15):4325-38. doi: 10.1113/JP272071. Epub 2016 May 12.
KEY POINTS: Cholera causes more than 100,000 deaths each year as a result of severe diarrhoea, vomiting and dehydration due to the actions of cholera toxin; more females than males are affected. Cholera toxin induces hypersecretion via release of mucosal serotonin and over-activation of enteric neurons, but its effects on gastrointestinal motility are not well characterized. We found that cholera toxin rapidly and reversibly reduces colonic motility in female mice in oestrus, but not in males or females in prooestrus, an effect mediated by 5-HT in the colonic mucosa and by 5-HT3 receptors. We show that the number of mucosal enterochromaffin cells containing 5-HT changes with the oestrous cycle in mice. These findings indicate that cholera toxin's effects on motility are rapid and depend on the oestrous cycle and therefore can help us better understand differences in responses in males and female patients. ABSTRACT: Extensive studies of the mechanisms responsible for the hypersecretion produced by cholera toxin (CT) have shown that this toxin produces a massive over-activation of enteric neural secretomotor circuits. The effects of CT on gastrointestinal motility, however, have not been adequately characterized. We investigated effects of luminal CT on neurally mediated motor activity in ex vivo male and female mouse full length colon preparations. We used video recording and spatiotemporal maps of contractile activity to quantify colonic migrating motor complexes (CMMCs) and resting colonic diameter. We compared effects of CT in female colon from wild-type and mice lacking tryptophan hydroxylase (TPH1KO). We also compared CMMCs in colons of female mice in oestrus with those in prooestrus. In female (but not male) colon, CT rapidly, reversibly and concentration-dependently inhibits CMMC frequency and induces a tonic constriction. These effects were blocked by granisetron (5-HT3 antagonist) and were absent from TPH1KO females. CT effects were prominent at oestrus but absent at prooestrus. The number of EC cells containing immunohistochemically demonstrable serotonin (5-HT) was 30% greater in female mice during oestrus than during prooestrus or in males. We conclude that CT inhibits CMMCs via release of mucosal 5-HT, which activates an inhibitory pathway involving 5-HT3 receptors. This effect is sex- and oestrous cycle-dependent and is probably due to an oestrous cycle-dependent change in the number of 5-HT-containing EC cells in the colonic mucosa.
75Inflaming sex differences in mood disorders.PubMed
Jennifer R Rainville, Georgia E Hodes
Neuropsychopharmacology. 2019 Jan;44(1):184-199. doi: 10.1038/s41386-018-0124-7. Epub 2018 Jun 19.
Men and women often experience different symptoms or rates of occurrence for a variety of mood disorders. Many of the symptoms of mood disorders overlap with autoimmune disorders, which also have a higher prevalence in women. There is a growing interest in exploring the immune system to provide biomarkers for diagnosis of mood disorders, along with new targets for developing treatments. This review examines known sex differences in the immune system and their relationship to mood disorders. We focus on immune alterations associated with unipolar depression, bipolar depression, and anxiety disorders. We describe work from both basic and clinical research examining potential immune mechanisms thought to contribute to stress susceptibility and associated mood disorders. We propose that sex and age are important, intertwined factors that need to be included in future experimental designs if we are going to harness the power of the immune system to develop a new wave of treatments for mood disorders.
76T-cell defects and postpartum depression.PubMed
Lauren M Osborne, Janneke Gilden, Astrid M Kamperman, et al.
Brain Behav Immun. 2020 Jul;87:397-403. doi: 10.1016/j.bbi.2020.01.007. Epub 2020 Jan 8.
BACKGROUND: Most studies of immune dysregulation in perinatal mood and anxiety disorders have focused on peripheral cytokines, but literature from non-perinatal mood disorders also implicates T-cell defects. We sought to characterize proportions of T-cell subtypes in women with postpartum depression. MATERIALS AND METHODS: We enrolled 21 women with postpartum depression (PPD), 39 healthy postpartum controls, and 114 healthy non-postpartum women. Blood was collected in sodium-heparin EDTA tubes and was analyzed using flow cytometry. We conducted statistical tests including linear regression analysis that were aimed at determining differences in proportions of T cell populations among groups. RESULTS: Mean counts of T-cells (all CD3+ T cells), T-helper cells, (CD3+CD4+ T cells), and T-cytotoxic cells (CD3+CD8+ T cells) were significantly increased in healthy postpartum women compared to healthy non-postpartum controls (p < 0.001, p = 0.007, and p = 0.002, respectively), but not in women with PPD. The increases in healthy postpartum women were driven by increases in T1 cells and T regulatory cells, increases that were nonexistent or attenuated in women with postpartum depression. Mean counts of CD4+ T-helper memory cells were also increased in healthy postpartum women (p = 0.009), but slightly decreased in women with PPD (p = 0.066), when compared to healthy non-postpartum controls. CONCLUSIONS: Our study confirms that the postpartum period in healthy women is a time of enhanced T cell activity. Women with postpartum depression failed to show physiological enhanced T-cell activity postpartum, and future research is needed to elucidate etiological mechanisms and consequences.
77Probiotic consumption during puberty mitigates LPS-induced immune responses and protects against stress-induced depression- and anxiety-like behaviors in adulthood in a sex-specific manner.PubMed
Emma Murray, Rupali Sharma, Kevin B Smith, et al.
Brain Behav Immun. 2019 Oct;81:198-212. doi: 10.1016/j.bbi.2019.06.016. Epub 2019 Jun 15.
Puberty/adolescence is a significant period of development and a time with a high emergence of psychiatric disorders. During this period, there is increased neuroplasticity and heightened vulnerability to stress and inflammation. The gut microbiome regulates stress and inflammatory responses and can alter brain chemistry and behaviour. However, the role of the gut microbiota during pubertal development remains largely uninvestigated. The current study examined gut manipulation with probiotics during puberty in CD1 mice on lipopolysaccharide (LPS)-induced immune responses and enduring effects on anxiety- and depression-like behaviours and stress-reactivity in adulthood. Probiotics reduced LPS-induced sickness behaviour at 12 h in females and at 48 h following LPS treatment in males. Probiotics also reduced LPS-induced changes in body weight at 48 h post-treatment in females. Probiotic treatment also prevented LPS-induced increases in pro- and anti-inflammatory peripheral cytokines at 8 h following LPS treatment, reduced central cytokine mRNA expression in the hypothalamus, hippocampus and PFC, and prevented LPS-induced changes to in the gut microbiota. A single exposure to LPS during puberty resulted in enduring depression-like behaviour in female mice, and anxiety-like behaviour in male mice in adulthood. However, pubertal exposure to probiotics prevented enduring LPS-induced depression-like behaviour in females and anxiety-like behaviors in males. Moreover, probiotics altered toll-like receptor-4 activity in the paraventricular nucleus of the hypothalamus (PVN) in males in response to a novel stressor in adulthood. Our results suggest that the gut microbiome plays an important role in pubertal neurodevelopment. These findings indicate that exposure to probiotics during puberty mitigates inflammation and decreases stress-induced vulnerabilities to emotional behaviours later in life, in a sex-specific manner.
78Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors.PubMed
Mario Gennaro Mazza, Rebecca De Lorenzo, Caterina Conte, et al.
Brain Behav Immun. 2020 Oct;89:594-600. doi: 10.1016/j.bbi.2020.07.037. Epub 2020 Jul 30.
Infection-triggered perturbation of the immune system could induce psychopathology, and psychiatric sequelae were observed after previous coronavirus outbreaks. The spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID-19) pandemic could be associated with psychiatric implications. We investigated the psychopathological impact of COVID-19 in survivors, also considering the effect of clinical and inflammatory predictors. We screened for psychiatric symptoms 402 adults surviving COVID-19 (265 male, mean age 58), at one month follow-up after hospital treatment. A clinical interview and a battery of self-report questionnaires were used to investigate post-traumatic stress disorder (PTSD), depression, anxiety, insomnia, and obsessive-compulsive (OC) symptomatology. We collected sociodemographic information, clinical data, baseline inflammatory markers and follow-up oxygen saturation levels. A significant proportion of patients self-rated in the psychopathological range: 28% for PTSD, 31% for depression, 42% for anxiety, 20% for OC symptoms, and 40% for insomnia. Overall, 56% scored in the pathological range in at least one clinical dimension. Despite significantly lower levels of baseline inflammatory markers, females suffered more for both anxiety and depression. Patients with a positive previous psychiatric diagnosis showed increased scores on most psychopathological measures, with similar baseline inflammation. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, positively associated with scores of depression and anxiety at follow-up. PTSD, major depression, and anxiety, are all high-burden non-communicable conditions associated with years of life lived with disability. Considering the alarming impact of COVID-19 infection on mental health, the current insights on inflammation in psychiatry, and the present observation of worse inflammation leading to worse depression, we recommend to assess psychopathology of COVID-19 survivors and to deepen research on inflammatory biomarkers, in order to diagnose and treat emergent psychiatric conditions.
79Factors related to mental health of inpatients with COVID-19 in Wuhan, China.PubMed
Yanyu Hu, Yingying Chen, Yixiong Zheng, et al.
Brain Behav Immun. 2020 Oct;89:587-593. doi: 10.1016/j.bbi.2020.07.016. Epub 2020 Jul 15.
OBJECTIVE: To evaluate the mental health status of hospitalized patients with coronavirus disease 2019 (COVID-19) and to explore the related factors. METHOD: This was a cross-sectional survey among COVID-19 inpatients in two isolation wards of a designated hospital in Wuhan, China, from March 7, 2020, to March 24, 2020. Participants' demographic data, clinical data and levels of circulating inflammatory markers were collated. Mental health symptoms were evaluated with questionnaires, which included the Insomnia Severity Index (ISI) scale, the 9-item Patient Health Questionnaire (PHQ-9), the 7-item Generalized Anxiety Disorder (GAD-7) scale, and questions about patients' self-perceived illness severity. Multivariate linear regression analysis was performed to explore factors that associated with mental symptoms, and a structural equation model (SEM) was used to assess the possible relationships between those factors and the patients' mental health. RESULTS: Among the 85 participants, 45.9% had symptoms of depression (PHQ-9 ≥ 5), 38.8% had anxiety (GAD-7 ≥ 5), and 54.1% had insomnia (ISI ≥ 8). According to multivariate regression analysis, female sex, a higher level of interleukin (IL)-1β and greater self-perceived illness severity were all significantly associated with a higher PHQ-9 score, higher GAD-7 score and higher ISI score. In addition, the disease duration and the neutrophil to lymphocyte ratio (NLR) were positively related to patients' self-perceived illness severity. The results of the SEM analyses suggested that sex (β = 0.313, P < 0.001), self-perceived illness severity (β = 0.411, P < 0.001) and levels of inflammatory markers (β = 0.358, P = 0.002) had direct effects on patients' mental health. The disease duration (β = 0.163, P = 0.003) and levels of inflammatory markers (β = 0.101, P = 0.016) also indirectly affected patients' mental health, with self-perceived illness severity acting as a mediator. CONCLUSION: A majority of COVID-19 infected inpatients reported experiencing mental health disturbances. Female sex, disease duration, levels of inflammatory markers and self-perceived illness severity are factors that could be used to predict the severity of patients' mental symptoms.
80IL-10 modulates depressive-like behavior.PubMed
Ana Raquel Mesquita, Margarida Correia-Neves, Susana Roque, et al.
J Psychiatr Res. 2008 Dec;43(2):89-97. doi: 10.1016/j.jpsychires.2008.02.004. Epub 2008 Apr 18.
The role of pro-inflammatory cytokines in psychiatric disorders has been the focus of great research attention in recent years. Paradoxically, the same is not true for anti-inflammatory cytokines. In the present study, we assessed the behavioral profile of animals with altered expression of the anti-inflammatory cytokine IL-10. We performed a battery of tests to assess anxiety, depressive-like and cognitive behaviors in mice overexpressing IL-10 (PMT10) and IL-10(-/-) animals; in the later mice we also tested the behavioral effect of IL-10 administration. In the forced-swimming test, IL-10(-/-) females displayed increased depressive-like behavior; importantly, this phenotype was reverted by the injection of IL-10. Moreover, mice overexpressing IL-10 presented a decreased depressive-like behavior. Despite the presence of a similar trend, male animals did not reach significant differences in depressive-like behavior. Assessment in the open-field showed that the absence of IL-10 decreased the percentage of time spent in the center of the arena in both male and female mice, while male animals overexpressing IL-10 revealed an opposite behavior. For both sexes, imbalance in IL-10 levels did not affect spatial reference memory. In conclusion, variations in IL-10 expression are associated with an altered depressive-like behavior, but do not influence cognitive performance. Interestingly, IL-10 imbalance produced more profound behavioral changes in females than in male animals. This is in accordance with clinical data demonstrating an increased susceptibility of women to mood disorders, suggesting an interplay between anti-inflammatory cytokines and sexual steroids.
81Immunity in athletes.PubMed
L T Mackinnon
Int J Sports Med. 1997 Mar;18 Suppl 1:S62-8. doi: 10.1055/s-2007-972701.
There is a general perception among athletes, coaches and sports physicians that athletes are susceptible to infectious illness, such as upper respiratory tract infection (URTI), during intensive training and major competition; recent epidemiological evidence is consistent with this perception. Recent studies have focused on the effects of exercise on immune parameters in order to better understand mechanisms by which exercise training may influence resistance to infection. Intensive exercise has been shown to transiently alter a number of immune parameters including circulating leukocyte and subset numbers, plasma cytokine concentrations, natural killer cell activity, secretory immunoglobulin A secretion rate, and neutrophil and macrophage phagocytic activity. Many of these changes persist for several hours or even days after intensive exercise. Some athletes have been shown to exhibit low resting or postexercise values on some nonspecific immune parameters compared with clinical norms, such as complement, acute phase proteins, and neutrophil activation. In addition, extended periods of intensive exercise training have been associated with progressive decreases in some immune parameters such as neutrophil function and certain subclasses of serum and secretory immunoglobulin. These data suggest the possibility of clinically relevant immune suppression in well-trained athletes. Psychological stress associated with training and competition at the elite level may be an additive factor to the effects of intensive exercise on immune function.
82Exercise, immunology and upper respiratory tract infections.PubMed
E M Peters
Int J Sports Med. 1997 Mar;18 Suppl 1:S69-77. doi: 10.1055/s-2007-972702.
The literature reveals a paradoxical response of the immune and host defense systems to endurance exercise apparent stimulation following long-term regular training and suppression in response to acute exposure to exhaustive endurance exercise. Several epidemiological surveys have confirmed a clinical manifestation of immunosuppression in the form of increased incidence of upper respiratory tract infection symptoms following participation in competitive marathon and ultramarathon running events. Prerace training status and racing intensity have been related to the incidence of this symptomatology during the postrace fortnight. Nutritional intervention studies have shown the antioxidant nutrient, vitamin C, to be effective in reducing the incidence of upper respiratory tract infection symptoms following competitive distance events. Laboratory studies have revealed this vitamin to be the first line of defense in neutralizing the auto-oxidative activity of phagocytes. It is hypothesized that exercise-induced neuroendocrine stimulation of the oxidative burst in neutrophils increases the rate of release of reactive oxygen species and that these are, in turn, neutralized by high plasma ascorbate levels. Enhancing intrinsic antioxidant defense by increasing exogenous antioxidant intake is thus theorized to be of long-term benefit to serious endurance athletes engaged in heavy training and competition.
83Exercise immunology: nutritional countermeasures.PubMed
D C Nieman
Can J Appl Physiol. 2001;26 Suppl:S45-55. doi: 10.1139/h2001-041.
In contrast to moderate physical activity, prolonged and intensive exertion causes numerous changes in immunity that reflect physiologic stress and suppression, and an increased risk of upper respiratory tract infection. Enzymes in immune cells require the presence of micronutrients, leading to attempts by investigators to alter changes in immunity following heavy exertion through use of nutritional supplements, primarily zinc, dietary fat, vitamin C and other antioxidants, glutamine, and carbohydrate. Except for carbohydrate supplementation, none of these nutrients has emerged as an effective countermeasure to exercise-induced immunosuppression. Data from several studies of endurance athletes suggest that carbohydrate compared to placebo ingestion is associated with an attenuated cortisol, growth hormone, and epinephrine response to heavy exertion, fewer perturbations in blood immune cell counts, lower granulocyte and monocyte phagocytosis and oxidative burst activity, and a diminished pro- and anti-inflammatory cytokine response. Overall, the hormonal and immune responses to carbohydrate compared to placebo ingestion during intensive exercise suggest that physiologic stress and inflammation are diminished, although clinical significance awaits further research.
84Neutrophil in Reverse Migration: Role in Sepsis.PubMed
Jingjing Ji, Jie Fan
Front Immunol. 2021 Mar 15;12:656039. doi: 10.3389/fimmu.2021.656039. eCollection 2021.
Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. During the development and progression of sepsis, polymorphonuclear neutrophils (PMNs) are the most abundantly recruited innate immune cells at sites of infection, playing critical roles in the elimination of local infection and healing of the injury. PMN reverse migration (rM) describes the phenomenon in which PMNs migrate away from the inflammatory site back into the vasculature following the initial PMN infiltration. The functional role of PMN rM within inflammatory scenarios requires further exploration. Current evidence suggests that depending on the context, PMN rM can be both a protective response, by facilitating an efficient resolution to innate immune reaction, and also a tissue-damaging event. In this review, we provide an overview of current advancements in understanding the mechanism and roles of PMN rM in inflammation and sepsis. A comprehensive understanding of PMN rM may allow for the development of novel prophylactic and therapeutic strategies for sepsis.
85Recent advances in neutrophil chemotaxis abnormalities during sepsis.PubMed
Yu-Ying Zhou, Bing-Wei Sun
Chin J Traumatol. 2022 Nov;25(6):317-324. doi: 10.1016/j.cjtee.2022.06.002. Epub 2022 Jun 13.
Sepsis remains one of the leading causes of death globally, in spite of advanced developments in intensive care and better understandings of pathophysiology related to sepsis. There is no special treatment or drug available for sepsis, currently. Under normal circumstances, neutrophil is a major player in acute infection control. However, during sepsis, the migration abilities and antimicrobial functions of neutrophils are impaired, resulting in a dysregulated immune response. Recent studies have indeed demonstrated that blocking or reversing neutrophil migration and impaired antibacterial function can improve the outcomes in septic animal models. This article systemically synthesized information regarding related factors and signaling involved in the functions of neutrophils in sepsis. This review also discussed the possibility that neutrophils be used as a marker for specific diagnosis and/or prediction of the outcomes of sepsis.
86A Review of Inflammatory Bowel Disease: A Model of Microbial, Immune and Neuropsychological Integration.PubMed
P Tavakoli, U Vollmer-Conna, D Hadzi-Pavlovic, et al.
Public Health Rev. 2021 May 5;42:1603990. doi: 10.3389/phrs.2021.1603990. eCollection 2021.
Inflammatory bowel diseases (IBDs) are complex chronic inflammatory disorders of the gastro-intestinal (GI) tract with uncertain etiology. IBDs comprise two idiopathic disorders: Crohn's disease (CD) and ulcerative colitis (UC). The aetiology, severity and progression of such disorders are still poorly understood but thought to be influenced by multiple factors (including genetic, environmental, immunological, physiological, psychological factors and gut microbiome) and their interactions. The overarching aim of this review is to evaluate the extent and nature of the interrelationship between these factors with the disease course. A broader conceptual and longitudinal framework of possible neuro-visceral integration, core microbiome analysis and immune modulation assessment may be useful in accurately documenting and characterizing the nature and temporal continuity of crosstalk between these factors and the role of their interaction (s) in IBD disease activity. Characterization of these interactions holds the promise of identifying novel diagnostic, interventions, and therapeutic strategies. A search of published literature was conducted by exploring PubMed, EMBASE, MEDLINE, Medline Plus, CDSR library databases. Following search terms relating to key question were set for the search included: "Inflammatory bowel diseases," "gut microbiota," "psychological distress and IBD," "autonomic reactivity and IBD," "immune modulation," "chronic inflammation," "gut inflammation," "enteric nervous system," "gut nervous system," "Crohn's disease," "Ulcerative colitis", "depression and IBD", "anxiety and IBD", "quality of life in IBD patients," "relapse in IBDs," "remission in IBDs," "IBD disease activity," "brain-gut-axis," "microbial signature in IBD," "validated questionnaires in IBD," "IBD activity indices," "IBD aetiology," "IBDs and stress," "epidemiology of IBDs", "autonomic nervous system and gut inflammation", "IBD and environment," "genetics of IBDs," "pathways of immune response in IBDs," "sleep disturbances in IBD," "hypothalamic-pituitary-adrenal axis (HPA)," "sympatho-adrenal axis," "CNS and its control of gut function" "mucosal immune response," "commensal and pathogenic bacteria in the gut," "innate and adaptive immunity." Studies evaluating any possible associations between gut microbiome, psychological state, immune modulation, and autonomic function with IBDs were identified. Commonly cited published literatures with high quality research methodology/results and additional articles from bibliographies of recovered papers were examined and included where relevant. Although there is a substantial literature identifying major contributing factors with IBD, there has been little attempt to integrate some factors over time and assess their interplay and relationship with IBD disease activity. Such contributing factors include genetic and environmental factors, gut microbiota composition and function, physiological factors, psychological state and gut immune response. Interdependences are evident across psychological and biological factors and IBD disease activity. Although from the available evidence, it is implausible that a single explanatory model could elucidate the interplay between such factors and the disease course as well as the sequence of the effect during the pathophysiology of IBD. Longitudinal monitoring of IBD patients and integrating data related to the contributing/risk factors including psychological state, physiological conditions, inflammatory/immune modulations, and microbiome composition/function, could help to explain how major factors associate and interrelate leading to exacerbation of symptoms and disease activity. Identifying the temporal trajectory of biological and psychosocial disturbances may also help to assess their effects and interdependence on individuals' disease status. Moreover, this allows greater insight into understanding the temporal progressions of subclinical events as potential ground for disease severity in IBD. Furthermore, understanding the interaction between these risk factors may help better interventions in controlling the disease, reducing the costs related to disease management, further implications for clinical practice and research approaches in addition to improving patients' mental health and quality of life.
87Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.PubMed
Yue Zeng, Chun-Hong Hu, Yi-Zheng Li, et al.
Nat Med. 2024 Jun;30(6):1680-1688. doi: 10.1038/s41591-024-02929-4. Epub 2024 May 13.
Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .
88Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity.PubMed
Heng Yang, Lin Xia, Jian Chen, et al.
Nat Med. 2019 Sep;25(9):1428-1441. doi: 10.1038/s41591-019-0566-4. Epub 2019 Sep 9.
Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.
89Depression promotes lung carcinoma progression by regulating the tumor microenvironment in tumor-bearing models of C57BL/6J mice.PubMed
Sainan Cui, Huiyuan Lin, Yongfei Cui, et al.
Neurosci Lett. 2021 May 29;754:135851. doi: 10.1016/j.neulet.2021.135851. Epub 2021 Mar 26.
Psychological stress is a common etiology among patients with lung cancer and serves as a potential indication of poor prognosis and advanced cancer clinical stage. Evidence indicates that depression is positively correlated with the evolvement of lung carcinoma. Nevertheless, the mechanisms underlying the effects of mental disorder on lung cancer have not been considerably and systemically explored. We hypothesized that mental disorder may affect the adjustment of the tumor microenvironment and immune cells. We used the chronic unpredictable mild stress (CUMS) procedure to induce depressed mice models and established tumor-bearing models of C57BL/6 J mice. Results revealed that the worsening of lung cancer was notably hastened in the CUMS + tumor group. Notably, the expression of PD-L1 in tumor issues increased in the tumor microenvironment, accompanied with a decline in the levels of CD8. On the basis of the date of tumor migration, our results indicated that MMPs and VEGF significantly increased after CUMS + tumor treatment. Thus, we demonstrated that modulation of the tumor microenvironment is pivotal for depression-promoted lung cancer migration.
90Social Relationships, Inflammation, and Cancer Survival.PubMed
Courtney E Boen, David A Barrow, Jeannette T Bensen, et al.
Cancer Epidemiol Biomarkers Prev. 2018 May;27(5):541-549. doi: 10.1158/1055-9965.EPI-17-0836. Epub 2018 Feb 23.
Social stressors, such as social relationship deficits, have been increasingly linked to chronic disease outcomes, including cancer. However, critical gaps exist in our understanding of the nature and strength of such links, as well as the underlying biological mechanisms relating social relationships to cancer progression and survival. Utilizing novel questionnaire and biomarker data from the UNC Health Registry/Cancer Survivorship Cohort, this study examines the associations between diverse measures of social support and mortality risk among individuals with cancer ( = 1,004). We further assess the role of multiple serum markers of inflammation, including high-sensitivity C-reactive protein (CRP), IL6, TNFα, and VEGF, as potential mediators in the social relationship-cancer link. The findings revealed that one's appraisal of their social support was associated with cancer mortality, such that individuals reporting higher levels of social support satisfaction had lower mortality risk than individuals reporting lower levels of satisfaction. The amount of support received, on the other hand, was not predictive of cancer survival. We further found evidence that inflammatory processes may undergird the link between social support satisfaction and mortality among individuals with cancer, with individuals reporting higher levels of social support satisfaction having lower levels of CRP, IL6, and TNFα. These results provide new knowledge of the biosocial processes producing population disparities in cancer outcomes. Our study offers new insights for intervention efforts aimed at promoting social connectedness as a means for improving cancer survival. .
91The role of Th17 cells in the pathophysiology of pregnancy and perinatal mood and anxiety disorders.PubMed
Lauren M Osborne, Amitoj Brar, Sabra L Klein
Brain Behav Immun. 2019 Feb;76:7-16. doi: 10.1016/j.bbi.2018.11.015. Epub 2018 Nov 19.
T cells play a key role in adaptive immune responses, and shifts among T cell classes occur in normal pregnancy. There is evidence for the role of T17 cells and dysregulation of the T17/T cell balance in morbidities and autoimmune diseases during pregnancy. Because T17 responses may play a role in depression and anxiety outside of pregnancy, we hypothesize that T17 responses and the balance of T17/T activity may also contribute to the development of depression and anxiety during pregnancy. To explore this hypothesis, this review has three main aims: 1) to evaluate systematically the role of T17 cells and cytokines during pregnancy; 2) to compare changes in the ratio of T17/T cells during pregnancy morbidities with the changes that occur in depression and anxiety outside of pregnancy; and 3) to provide a basis for further research on T17 cells in perinatal mood and anxiety disorders, with an eye toward the development of novel therapeutics. We also review the limited literature concerning perinatal mood and anxiety disorders, and hypothesize about the potential role of T17 cells in these illnesses. Understanding the pathophysiology of perinatal mood and anxiety disorders will aid development of novel therapeutics that address immunological mechanisms, in addition to the serotonin system, which are targetable molecules in treating depression and anxiety during pregnancy.
92Research progress of targeted therapy regulating Th17/Treg balance in bone immune diseases.PubMed
Xiaxia Wang, Bai Sun, Yujie Wang, et al.
Front Immunol. 2024 Jan 30;15:1333993. doi: 10.3389/fimmu.2024.1333993. eCollection 2024.
Rheumatoid arthritis (RA) and postmenopausal osteoporosis (PMOP) are common bone-immune diseases. The imbalance between helper (Th17) and regulatory T cells (Tregs) produced during differentiation of CD4 T cells plays a key regulatory role in bone remodelling disorders in RA and PMOP. However, the specific regulatory mechanism of this imbalance in bone remodelling in RA and PMOP has not been clarified. Identifying the regulatory mechanism underlying the Th17/Treg imbalance in RA and PMOP during bone remodelling represents a key factor in the research and development of new drugs for bone immune diseases. In this review, the potential roles of Th17, Treg, and Th17/Treg imbalance in regulating bone remodelling in RA and PMOP have been summarised, and the potential mechanisms by which probiotics, traditional Chinese medicine compounds, and monomers maintain bone remodelling by regulating the Th17/Treg balance are expounded. The maintenance of Th17/Treg balance could be considered as an therapeutic alternative for the treatment of RA and PMOP. This study also summarizes the advantages and disadvantages of conventional treatments and the quality of life and rehabilitation of patients with RA and PMOP. The findings presented her will provide a better understanding of the close relationship between bone immunity and bone remodelling in chronic bone diseases and new ideas for future research, prevention, and treatment of bone immune diseases.
93Targeting the Adaptive Immune System in Depression: Focus on T Helper 17 Cells.PubMed
Eléonore Beurel, Eva M Medina-Rodriguez, Richard S Jope
Pharmacol Rev. 2022 Apr;74(2):373-386. doi: 10.1124/pharmrev.120.000256.
There is a vital need to understand mechanisms contributing to susceptibility to depression to improve treatments for the 11% of Americans who currently suffer from this debilitating disease. The adaptive immune system, comprising T and B cells, has emerged as a potential contributor to depression, as demonstrated in the context of lymphopenic mice. Overall, patients with depression have reduced circulating T and regulatory B cells, "immunosuppressed" T cells, and alterations in the relative abundance of T cell subtypes. T helper (Th) cells have the capacity to differentiate to various lineages depending on the cytokine environment, antigen stimulation, and costimulation. Regulatory T cells are decreased, and the Th1/Th2 ratio and the Th17 cells are increased in patients with depression. Evidence for changes in each Th lineage has been reported to some extent in patients with depression. However, the evidence is strongest for the association of depression with changes in Th17 cells. Th17 cells produce the inflammatory cytokine interleukin (IL)-17A, and the discovery of Th17 cell involvement in depression evolved from the well established link that IL-6, which is required for Th17 cell differentiation, contributes to the onset, and possibly maintenance, of depression. One intriguing action of Th17 cells is their participation in the gut-brain axis to mediate stress responses. Although the mechanisms of action of Th17 cells in depression remain unclear, neutralization of IL-17A by anti-IL-17A antibodies, blocking stress-induced production, or release of gut Th17 cells represent feasible therapeutic approaches and might provide a new avenue to improve depression symptoms. SIGNIFICANCE STATEMENT: Th17 cells appear as a promising therapeutic target for depression, for which efficacious therapeutic options are limited. The use of neutralizing antibodies targeting Th17 cells has provided encouraging results in depressed patients with comorbid autoimmune diseases.
94Compound 511 ameliorates MRSA-induced lung injury by attenuating morphine-induced immunosuppression in mice via PI3K/AKT/mTOR pathway.PubMed
Zhonghao Li, Qinmei Sun, Qingyang Liu, et al.
Phytomedicine. 2023 Jan;108:154475. doi: 10.1016/j.phymed.2022.154475. Epub 2022 Sep 25.
BACKGROUND: Opioids are widely used in clinical practice. However, their long-term administration causes respiratory depression, addiction, tolerance, and severe immunosuppression. Traditional Chinese medicine (TCM) can alleviate opioid-induced adverse effects. Compound 511 is particularly developed for treating opioid addiction, based on Jiumi Liangfang, an ancient Chinese drug treatment and rehabilitation monograph completed in 1833 A.D. It is an herbal formula containing eight plants, each of them contributing to the overall pharmacological effect of the product: Panax ginseng C. A. Meyer (8.8%), Astragalus membranaceus (Fisch.) (18.2%), Datura metel Linn. (10.95%), Corydalis yanhusuo W. T. Wang (14.6%), Acanthopanar gracilistμlus W. W. Smith (10.95%), Ophiopogon japonicus (Linn. f.) Ker-Gawl. (10.95%), Gynostemma pentaphyllum (Thunb.) Makino (10.95%), Polygala arvensis Willd. (14.6%). This formula effectively ameliorates opioid-induced immunosuppression. However, the underlying mechanism remains unclear. PURPOSE: To reveal the effects of Compound 511 on the immune response of morphine-induced immunosuppressive mice and their potential underlying molecular mechanism. This study provides information for a better clinical approach and scientific use of opioids. METHODS: Immunosuppression was induced in mice by repeated morphine administration. Th1/Th2/Th17/Treg cell levels were measured using flow cytometry. Splenic transcription factors of Th1/Th2/Th17/Treg and outputs of the regulatory PI3K/AKT/mTOR signaling pathway were determined. Subsequently, methicillin-resistant Staphylococcus aureus (MRSA) was administered intranasally to morphine-induced immunosuppressive mice pretreated with Compound 511. Their lung inflammatory status was assessed using micro-computer tomography (CT), hematoxylin and eosin (H&E) staining, and enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to morphine, Compound 511 significantly decreased the immune organ indexes of mice, corrected the Th1/Th2 and Treg/Th17 imbalance in the immune organs and peripheral blood, reduced the mRNA levels of FOXP3 and GATA3, and increased those of STAT3 and T-bet in the spleen. It improved immune function and reduced MRSA-induced lung inflammation. CONCLUSION: Compound 511 ameliorates opioid-induced immunosuppression by regulating the balance of Th1/Th2 and Th17/Treg via PI3K/AKT/mTOR signaling pathway. Thus, it effectively reduces susceptibility of morphine-induced immunosuppressive mice to MRSA infection.
95Xiaoyaosan alleviates chronic psychological stress-induced TH17/Treg imbalance via modulation of the FKBP5/NF-κB axis.PubMed
Yi Zhang, Xiao-Ru Luo, Yu-Hang Zhou, et al.
J Ethnopharmacol. 2025 Aug 29;352:120184. doi: 10.1016/j.jep.2025.120184. Epub 2025 Jun 21.
ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyaosan (XYS), a classical herbal formulation indicated for "depression syndrome", can improve chronic stress-related mood disorders and immune disorders through multi-target modulation of inflammatory mediators, although its precise mechanism in regulating Th17/Treg balance remains to be clarified. AIM OF THE STUDY: This study aims to elucidate the regulatory impact of XYS on the peripheral Th17/Treg immunological imbalance generated by chronic psychological stress through modulation of the FKBP5/NF-κB signaling pathway, thereby establishing a mechanistic foundation for developing innovative interventions with dual stress-adaptogenic and immunoregulatory properties. MATERIALS AND METHODS: FKBP5 knockout (FKBP5) and C57BL/6 mice underwent a 35-day chronic unpredictable mild stress (CUMS) paradigm. C57BL/6 mice were subsequently treated with XYS (1.61, 3.22, and 6.44 g/kg/d), fluoxetine (3 mg/kg/d). Behavioral phenotyping included the Open Field Test (OFT), Tail Suspension Test (TST), Forced Swimming Test (FST) and Sucrose preference test (SPT). Serum inflammatory cytokines (IL-17A, IL-23, IL-10, TNF-α) measured by enzyme-linked immunosorbent test (ELISA). Splenic Th17/Treg subset ratios were analyzed using multicolor flow cytometry. Western blotting evaluated FKBP5 expression and NF-κB pathway dynamics (IκB-α degradation, P65 nuclear translocation). UPLC-HRMS-based phytochemical profiling coupled with molecular docking elucidated XYS-FKBP5 interactions. FKBP5/IKKα/β complex formation was validated through confocal immunofluorescence (IF) colocalization and reciprocal co-immunoprecipitation (CO-IP) assays. RESULTS: CUMS mice exhibited significant depression-like behaviors and hippocampal neuronal damage, concomitant with elevated serum corticosterone levels and Th17/Treg immune dysregulation. Medium- and high-dose XYS interventions substantially ameliorated these behavioral abnormalities, reversed hippocampal pathological alterations, suppressed pro-inflammatory responses, and rectified Th17/Treg imbalance. Crucially, XYS exerted therapeutic effects through targeted suppression of FKBP5-IKK complex interaction, effectively blocking NF-κB nuclear translocation, thereby restoring Th17/Treg homeostasis. CONCLUSION: XYS ameliorates chronic psychological stress-induced Th17/Treg immune imbalance through FKBP5-targeted suppression of NF-κB hyperactivation. This multicomponent synergistic mechanism establishes a novel therapeutic strategy for stress-associated inflammatory comorbidities, particularly depression with immune dysregulation.
96Effects of environmentally-induced anxiety on autoimmunity in the MRL/lpr mouse.PubMed
Fan Zhang, Qiong Zhang, Ruo-Nan Dang, et al.
Lupus Sci Med. 2025 Jun 19;12(1):e001528. doi: 10.1136/lupus-2025-001528.
OBJECTIVE: To investigate the interplay between anxiety disorders and SLE using lupus-prone MRL-lpr mice and MRL/MPJ control mice exposed to predator stress, and to elucidate the potential mechanisms underlying this interaction. METHODS: We conducted an experiment where 16 MRL-lpr mice and 16 MRL/MPJ control mice were randomly assigned to four groups and exposed to predator stress (cat exposure) or served as unexposed controls for 2 months. Anxiety levels were evaluated using the elevated plus maze (EPM) and open field test (OFT). Physiological responses were assessed through measurements of body weight, interleukin-6 (IL-6) levels, anti-double-stranded DNA (dsDNA) antibody titres and urine protein content. Additionally, the splenic index and the proportions of regulatory T (Treg) and T helper 17 (Th17) cells were analysed to further understand the immune responses. RESULTS: Both mouse strains exhibited increased anxiety levels as assessed by the EPM and OFT. However, MRL-lpr mice demonstrated a heightened sensitivity to predator stress-induced anxiety compared with MRL/MPJ mice. Biochemical analyses revealed that while MRL/MPJ mice showed a typical inflammatory response to predator stress, characterised by elevated IL-6 levels, this did not exacerbate immune dysregulation or renal damage. In contrast, MRL-lpr mice exhibited markedly increased IL-6 expression, elevated anti-dsDNA antibody levels, higher urine protein content, decreased Treg proportions and increased Th17 proportions in the spleen, suggesting an accelerated progression of lupus disease. CONCLUSIONS: Our findings emphasise that lupus-prone MRL-lpr mice display a greater vulnerability to the detrimental consequences of predator stress compared with MRL/MPJ control mice.
97Psychological impact of life events in systemic lupus erythematosus patients - Differences between flares and remission.PubMed
Raquel Faria, Daniel Guimarães de Oliveira, Rute Alves, et al.
Lupus. 2024 Sep;33(10):1139-1144. doi: 10.1177/09612033241266987. Epub 2024 Jul 21.
BACKGROUND: Stress has been linked to worsening symptoms and increased disease activity in patients with Systemic lupus erythematosus (SLE). Life-events are individual stress points, and there is conflicting evidence regarding their role in SLE activity and disease perception. METHODS: Adult SLE patients were recruited for the study. Clinical and laboratory features of SLE were recorded, and previous diagnosis of anxiety or depression were retrieved from patients' electronic charts. Flares were defined by the Systemic Lupus Erythematosus Disease Activity (SLEDAI) flare Index, and flares during the previous year were documented. During a routine visit, they completed validated Portuguese translations of the 10-item Perceived Stress Scale (PSS-10), Hospital Anxiety and Depression Scale (HADS) and Life Experience Survey (LES) for the previous year. RESULTS: A total of 47 female SLE patients were recruited. Ten patients (21.3%) had experienced recent flares. Patients with recent flares reported fewer life events, with lower positive, negative, and total weightings sums compared to those without recent flares. Although 42.2% of patients perceived pathological levels of stress in the previous month, 48.9% had anxiety symptoms, and 34% were at high risk for an anxiety disorder, these psychometric measures did not differ significantly between the recent flare and no-flare groups. CONCLUSIONS: There is a high prevalence of pathological levels of stress among SLE patients. SLE patients with recent flares report less psychological impact from life events, both positive and negative, independent of other psychological or pharmacological factors.
98Social determinants of depression in systemic lupus erythematosus: A systematic scoping review.PubMed
Rachel S Bergmans, Emma Loewenstein, Deena Aboul-Hassan, et al.
Lupus. 2023 Jan;32(1):23-41. doi: 10.1177/09612033221135145. Epub 2022 Oct 22.
Social determinants of health (SDOH) influence inequities in systemic lupus erythematosus (SLE). While these inequities contribute to overall disease experience, there is little consensus guiding our understanding of the psychological implications of SDOH in SLE. Given the paucity of evidence in this area, the aim of this scoping review was to systematically assess the volume and features of available research literature on associations of SDOH with depression in SLE over the past 20 years, from 1 January 2000 to 16 November 2021. We developed a search strategy for PubMed and EMBASE that included keywords for depression and lupus. After screening 2188 articles, we identified 22 original articles that met our inclusion criteria. At least one SDOH was associated with depression in two of the six studies with unadjusted estimates and 13 of the 16 studies with adjusted estimates. Results provide consistent but sparse evidence that SDOH are associated with depression in SLE. Additionally, depression epidemiology in SLE may differ from the general population such that depression risk is more similar across genders and racial/ethnic groups. More work is needed to identify the SDOH that have the greatest impact on depression and mental health among SLE patients, as well as how and when to intervene.
99Depressed Symptomatology in Systemic Lupus Erythematosus Patients.PubMed
Sara R Kellahan, Xinliang Huang, Daphne Lew, et al.
Arthritis Care Res (Hoboken). 2023 Apr;75(4):749-757. doi: 10.1002/acr.24833. Epub 2022 Dec 2.
OBJECTIVE: Depression is a prevalent (24-30%) and significant comorbidity in patients with systemic lupus erythematosus (SLE). In the present study, we leveraged the longitudinal SLE cohort at the Washington University Lupus Clinic to address 1) what is the longitudinal course of depressed affect among outpatients with SLE and 2) what is the longitudinal relationship between SLE disease activity and depressed affect? METHODS: Longitudinal data from patients with American College of Rheumatology- or Systemic Lupus International Collaborating Clinics-classified SLE were analyzed. Depressed symptoms were assessed at each visit using the Center for Epidemiologic Studies Depression Scale, Revised (CESD-R), and SLE disease activity was measured via the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Group-based trajectory modeling (GBTM) and linear mixed models were used for analysis. RESULTS: The study sample (n = 144) was 56.3% Black and 38.9% White. GBTM revealed 5 distinct groups of patients who demonstrated consistent trends in depression over time. Members of groups 4 (n = 44, 30.6%) and 5 (n = 44, 30.6%) demonstrated CESD-R scores consistent with depression. Of note, Black patients were much more common in group 5 (n = 32, 72.7%, P < 0.02). Analyses identified an association between SLEDAI disease activity and depression scores in multivariate analysis but did not show significance in GBTM and univariate analysis. CONCLUSIONS: The majority (61.2%) of patients had CESD-R scores consistent with persistent depressed affect or major depression over a period of up to 4 years. The lack of a consistent relationship of CESD-R with SLE disease activity highlights the need to regularly monitor, treat, and better understand the causes behind this comorbidity.
100Differential immunological profiles in seronegative versus seropositive rheumatoid arthritis: Th17/Treg dysregulation and IL-4.PubMed
Baochen Li, Rui Su, Qiaoling Guo, et al.
Front Immunol. 2024 Sep 3;15:1447213. doi: 10.3389/fimmu.2024.1447213. eCollection 2024.
BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease with various subtypes. Among these, seronegative rheumatoid arthritis (SnRA), distinguished by its distinctive seronegative antibody phenotype, presents clinical diagnosis and treatment challenges. This study aims to juxtapose the immunological features of SnRA with seropositive rheumatoid arthritis (SpRA) to investigate potential mechanisms contributing to differences in antibody production. METHODS: This study included 120 patients diagnosed with RA and 78 patients diagnosed with psoriatic arthritis (PsA), comprising 41 cases of SnRA and 79 cases of SpRA. Clinical, serological, and immune data were collected from all participants to systematically identify and confirm the most pivotal immunological distinctions between SnRA and SpRA. RESULTS: (1) SpRA demonstrates more pronounced T-helper 17 cells (Th17)/Regulatory T cells (Treg) dysregulation, vital immunological differences from SnRA. (2) SpRA exhibits higher inflammatory cytokine levels than SnRA and PsA. (3) Lymphocyte subset ratios and cytokine overall distribution in SnRA close to PsA. (4) Interleukin-4 (IL-4) emerges as the central immunological disparity marker between SnRA and SpRA. CONCLUSION: Th17/Treg imbalance is one of the vital immunological disparities between SnRA and SpRA. Interestingly, PsA and SnRA display similar peripheral blood immunological profiles, providing immunological evidence for these two diseases' clinical and pathological similarities. Furthermore, IL-4 emerges as the central immunological disparity marker between SnRA and SpRA, suggesting its potential role as a triggering mechanism for differential antibody production.
101Major depressive disorders accompanying autoimmune diseases - Response to treatment.PubMed
Katarzyna Bialek, Piotr Czarny, Justyna Strycharz, et al.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Dec 20;95:109678. doi: 10.1016/j.pnpbp.2019.109678. Epub 2019 Jun 22.
MDDs (major depressive disorders) belong to the most frequently diagnosed mental diseases and affect approximately 350 million people all over the world. A growing body of evidence suggests that inflammatory processes may play a significant role in the pathophysiology and progression of the disease. The comorbidity of MDDs with many other medical conditions, for example autoimmune diseases (ADs) caused by inflammation, has been observed on numerous occasions. In both cases, increased levels of pro-inflammatory cytokines, chemokines and other inflammatory agents are observed. Furthermore, higher rates of inflammatory markers are associated with a poorer response to antidepressant treatment. Additionally, the presence of any AD is associated with higher prevalence of depression and may reduce the chance of effective therapy. Interestingly, the administration of several anti-inflammatory agents used in AD treatment is positively correlated with a reduction of depressive symptoms. In conclusion, the factors contributing to the coexistence of depression as well as affecting antidepressant treatment effectiveness may lead to an alteration of the cytokine profiles in many autoimmune diseases.
102Factors regulating the differences in frequency of infiltration of Th17 and Treg of the blood-brain barrier.PubMed
Norwin Kubick, Marzena Lazarczyk, Nina Strzałkowska, et al.
Immunogenetics. 2023 Oct;75(5):417-423. doi: 10.1007/s00251-023-01310-y. Epub 2023 Jul 11.
Controlling CD4 immune cell infiltration of the brain is a leading aim in designing therapeutic strategies for a range of neuropathological disorders such as multiple sclerosis, Alzheimer's disease, and depression. CD4 T cells are a highly heterogeneous and reprogrammable family, which includes various distinctive cell types such as Th17, Th1, and Treg cells. Interestingly Th17 and Treg cells share a related transcriptomic profile, where the TGFβ-SMADS pathway plays a fundamental role in regulating the differentiation of both of these cell types. However, Th17 could be highly pathogenic and was shown to promote inflammation in various neuropathological disorders. Conversely, Treg is anti-inflammatory and is known to inhibit Th17. It could be noticed that Th17 frequencies of infiltration of the blood-brain barrier in various neurological disorders are significantly upregulated. However, Treg infiltration numbers are significantly low. The reasons behind these contradicting observations are still unknown. In this perspective, we propose that the difference in the T-cell receptor repertoire diversity, diapedesis pathways, chemokine expression, and mechanical properties of these two cell types could be contributing to answering this intriguing question.
103Temporal relationships between systemic lupus erythematosus and comorbidities.PubMed
Chang-Fu Kuo, I-Jun Chou, Frances Rees, et al.
Rheumatology (Oxford). 2019 May 1;58(5):840-848. doi: 10.1093/rheumatology/key335.
OBJECTIVE: To examine the burden of comorbidities prior to and after the diagnosis of SLE and its impact on mortality. METHODS: We identified 1605 incident cases of SLE and 6284 matched controls from the UK primary care. The risks of comorbidities before (prevalence; odds ratios) and after SLE diagnosis (incidence; hazard ratios) and the impact of comorbidities at diagnosis on all-cause mortality were estimated. RESULTS: At diagnosis, SLE was associated with adjusted odds ratios (95% CI) of 2.25 (1.97-2.56), 3.37 (2.49-4.57) and 3.54 (1.89-6.63) for a Charlson comorbidity index of 1-2, 3-4 and ≥5, respectively. Following diagnosis, SLE also associated with increased risk of developing any comorbidity with an adjusted hazard ratio (95% CI) of 1.30 (95% CI, 1.13-1.49). At diagnosis, SLE was associated with a greater risk of cancer, cardiovascular, renal, liver, rheumatological and neurological diseases as well as depression, anaemia and psoriasis. Risks of developing incident comorbidity in the categories of neoplasm, cardiovascular, genitourinary, metabolic/endocrine, gastrointestinal and hepatic diseases, chronic pulmonary diseases, musculoskeletal/connective tissue and neurological diseases were higher in SLE patients. People with SLE had higher mortality risk compared with controls, with adjusted hazard ratio of 1.91 (95% CI, 1.62-2.26); after further adjusting for comorbidities this reduced to 1.64 (1.37-1.97). Comorbidities at SLE diagnosis accounted for 27.6% of the apparent difference in mortality between SLE patients and matched controls. CONCLUSION: People with SLE have increased risks of multiple comorbidities both prior to and after diagnosis and this contributes significantly to all-cause mortality.
104Omega-3 fatty acids in inflammation and autoimmune diseases.PubMed
Artemis P Simopoulos
J Am Coll Nutr. 2002 Dec;21(6):495-505. doi: 10.1080/07315724.2002.10719248.
Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)--are more biologically potent than alpha-linolenic acid (ALA). Some of the effects of omega-3 PUFA are brought about by modulation of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohn's disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB(4) produced by omega-6 fatty acids. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.
105Prospective associations between major depressive disorder, generalized anxiety disorder, fibromyalgia, and myalgic encephalomyelitis/chronic fatigue syndrome.PubMed
Nathaniel Stembridge Thomas, Michael C Neale, Kenneth S Kendler, et al.
Psychol Med. 2025 Aug 11;55:e232. doi: 10.1017/S0033291725100603.
BACKGROUND: Functional disorders (FDs) are associated with internalizing disorders (IDs). Studies investigating the nature of these associations over time are limited. We tested the direction of causation between measures of IDs (major depressive disorder [MDD], generalized anxiety disorder [GAD]) and FDs (fibromyalgia [FM] and myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) measured across two waves of longitudinal data ( = 108,034 and = 73,590). METHODS: The Lifelines Cohort Study is a large prospective population-based cohort study in the northeast of the Netherlands. We tested competing causal models for the longitudinal association between IDs and FDs and, to follow-up results from the model with all IDs and FDs, tested the direction of causation between MDD and FM. RESULTS: FDs were more stable over time than IDs. Initial model comparisons support a bidirectional relationship between most IDs and FDs. Follow-up analyses support a unidirectional model where FM predicts MDD over time ( = 0.14, 95% confidence interval = [0.11, 0.18]), but not vice versa. CONCLUSIONS: The cross-time associations between ME/CFS, MDD, and GAD appear bidirectional (causal in both directions). Our results are consistent with, but not demonstrative of, a causal relationship from FM to MDD. The consequences of specific FDs vary, underscoring the value of studying these conditions as distinct constructs.
106TNFAIP3, a negative regulator of the TLR signaling pathway, is a potential predictive biomarker of response to antidepressant treatment in major depressive disorder.PubMed
Yi-Yung Hung, Chin-Chuen Lin, Hong-Yo Kang, et al.
Brain Behav Immun. 2017 Jan;59:265-272. doi: 10.1016/j.bbi.2016.09.014. Epub 2016 Sep 15.
Inflammation and abnormalities in Toll-like receptor (TLR) expression and activation have been linked to major depressive disorder (MDD). However, negative regulators of TLR pathways have not been previously investigated in this context. Here, we sought to investigate the association of depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17), with mRNA expression levels of negative regulators of the TLR pathway, including SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2 and TNFAIP3, in peripheral blood mononuclear cells (PBMCs) from 100 patients with MDD and 53 healthy controls, before and after treatment with antidepressants. Positive regulators of the TLR4 pathway, including Pellino 1, TRAF6 and IRAK1, were also investigated. Among all patients, MyD88s, and TNFAIP3 mRNAs were expressed at lower levels in PBMCs from patients with MDD. Multiple linear regression analyses revealed that TNFAIP3 mRNA expression before treatment was inversely correlated with severity of depression and effectively predicted improvement in HAMD-17 scores. Among 79 treatment-completers, only TNFAIP3 mRNA was significantly increased by treatment with antidepressants for 4 weeks. Treatment of human monocytes (THP-1) and mouse microglia (SIM-A9) cell lines with fluoxetine significantly increased TNFAIP3 mRNA expression and suppressed IL-6 levels. The suppressive effect of fluoxetine on IL-6 was attenuated by knockdown of TNFAIP3 expression. These findings suggest that both dysfunction of the negative regulatory system in patients with MDD and antidepressant treatment exert anti-inflammatory effects, at least in part through increased expression of the TNFAIP3 gene. They also indicate that modulating expression of the TNFAIP3 gene to rebalance TLR-mediated inflammatory signaling may be potential therapeutic strategy for treating MDD.
107The Influence of Antidepressants on the Immune System.PubMed
Łukasz P Szałach, Katarzyna A Lisowska, Wiesław J Cubała
Arch Immunol Ther Exp (Warsz). 2019 Jun;67(3):143-151. doi: 10.1007/s00005-019-00543-8. Epub 2019 Apr 29.
Depression is one of the most frequently diagnosed condition in psychiatry. Despite the availability of many preparations, over 30% of treated patients do not achieve remission. Recently the emphasis is put on the contribution of the body's inflammatory response as one of the causes of depression. The interactions between nervous and immune systems are the main issue addressed by psychoneuroimmunology. In patients suffering from depression changes in the plasma concentrations of cytokines and in the number and level of activation of immune cells has been found. Attention is paid to the high levels of pro-inflammatory cytokines, the prevalence of Th1 responses to Th2, weakening of NK cell cytotoxicity and changes in lymphocyte proliferation and apoptosis. A number of studies focus on influence of antidepressants and non-standard methods of depression treatment, such as ketamine infusion, on patients' immunology. Many of them seem to regulate the immune responses. The study results encourage to look for new ways to treat depression with immunomodulatory drugs. In this article authors present the current knowledge about immune system changes accompanying depression as well as the study results showing the influence of drugs on the immune system, especially in the context of reducing the symptoms of depression.
108Cetirizine does not influence the immune response.PubMed
G W Canonica, G Pesce, S Ruffoni, et al.
Ann Allergy. 1992 Mar;68(3):251-4.
Antihistamines are frequently employed in the treatment of allergic rhinitis and urticaria-angioedema syndrome. We analyzed the in vitro effects of cetirizine on the immune response. To this end the proliferation of peripheral mononuclear cells induced by mitogen and by -CD3, -CD2, or -CD28 monoclonal antibodies has been studied. Since the plasma peak of cetirizine following ingestion of 10 mg is about 1 microgram/mL, the drug was tested in the cultures at the concentration of 0.1, 1, or 10 micrograms/mL. No influence of cetirizine on T cell proliferation was detected. We also evaluated the effect of cetirizine on the expression of the following markers expressed by T cells upon activation: lymphocyte markers ICAM-1, HLA-DR, and CD25 surface expression, alpha-1-acid glycoprotein has been also studied. There was no effect of cetirizine on the investigated immunologic parameters; these data acquire clinical relevance when related to previous reports showing a depression of the immunologic response exerted by other compounds such as ketotifen and theophylline and when related to the recent data about the modulation of ICAM-1 expression on eosinophils by cetirizine. Cetirizine does not affect ICAM-1 expression of lymphocyte membrane.
109The brain-gut-microbiota interplay in depression: A key to design innovative therapeutic approaches.PubMed
Angelica Varesi, Lucrezia Irene Maria Campagnoli, Salvatore Chirumbolo, et al.
Pharmacol Res. 2023 Jun;192:106799. doi: 10.1016/j.phrs.2023.106799. Epub 2023 May 19.
Depression is the most prevalent mental disorder in the world associated with huge socio-economic consequences. While depressive-related symptoms are well known, the molecular mechanisms underlying disease pathophysiology and progression remain largely unknown. The gut microbiota (GM) is emerging as a key regulator of the central nervous system homeostasis by exerting fundamental immune and metabolic functions. In turn, the brain influences the intestinal microbial composition through neuroendocrine signals, within the so-called gut microbiota-brain axis. The balance of this bidirectional crosstalk is important to ensure neurogenesis, preserve the integrity of the blood-brain barrier and avoid neuroinflammation. Conversely, dysbiosis and gut permeability negatively affect brain development, behavior, and cognition. Furthermore, although not fully defined yet, changes in the GM composition in depressed patients are reported to influence the pharmacokinetics of common antidepressants by affecting their absorption, metabolism, and activity. Similarly, neuropsychiatric drugs may shape in turn the GM with an impact on the efficacy and toxicity of the pharmacological intervention itself. Consequently, strategies aimed at re-establishing the correct homeostatic gut balance (i.e., prebiotics, probiotics, fecal microbiota transplantation, and dietary interventions) represent an innovative approach to improve the pharmacotherapy of depression. Among these, probiotics and the Mediterranean diet, alone or in combination with the standard of care, hold promise for clinical application. Therefore, the disclosure of the intricate network between GM and depression will give precious insights for innovative diagnostic and therapeutic approaches towards depression, with profound implications for drug development and clinical practice.
110Potential role of gut microbiota in major depressive disorder: A review.PubMed
Mansoor Khaledi, Fatemeh Sameni, Abolfazl Gholipour, et al.
Heliyon. 2024 Jun 15;10(12):e33157. doi: 10.1016/j.heliyon.2024.e33157. eCollection 2024 Jun 30.
Interactions between the gut microbiota and host immunity are sophisticated, dynamic, and host-dependent. Scientists have recently conducted research showing that disturbances in the gut bacterial community can lead to a decrease in some metabolites and, consequently, to behaviors such as depression. Exposure to stressors dropped the relative abundance of bacteria in the genus while soaring the relative abundance of bacteria in the genus , , , and Oscillibacter, were also reduced in people with depression. Microbiota and innate immunity are in a bilateral relationship. The gut microbiota has been shown to induce the synthesis of antimicrobial proteins such as catalysidins, type C lectins, and defensins. Probiotic bacteria can modulate depressive behavior through GABA signaling. The gut microbiome produces essential metabolites such as neurotransmitters, tryptophan metabolites, and short-chain fatty acids (SCFAs) that can act on the CNS. In the case of dysbiosis, due to mucin changes, the ratio of intestinal-derived molecules may change and contribute to depression. Psychotropics, including NCC3001, CBM588, and have mental health benefits, and can have a positive effect on the host-brain relationship, and have antidepressant effects. This article reviews current studies on the association between gut microbiota dysbiosis and depression. Comprehensively, these findings could potentially lead to novel approaches to improving depressive symptoms via gut microbiota alterations, including probiotics, prebiotics, and fecal microbiota transplantation.
111Gut-brain axis: altered microbiome and depression - review.PubMed
Anmol Mohan, Swathi Godugu, Saumya S Joshi, et al.
Ann Med Surg (Lond). 2023 Apr 13;85(5):1784-1789. doi: 10.1097/MS9.0000000000000573. eCollection 2023 May.
The concept of a 'gut-brain axis' was recently developed when the complex communications between the brain and the gut became evident. The interaction may affect emotions, motivation, mood, and higher cognitive functions as well as gut homeostasis. Human microbe symbiosis's merits are now acknowledged to transcend human mental health. Research has recently indicated that the gut-brain axis plays a vital role in brain health maintenance. The term 'gut-brain axis' can only partially capture the intricacy of these interactions. Dysbiosis of the gut commensals has been seen in patients with psychiatric diseases, such as depression. Major depressive disorder is caused by complicated interactions between the individual gene and the environment. In a forced swimming test, P. Zheng discovered that germ-free mice with no gut microbiota had a shorter immobility duration than healthy mice. More radical effects were expressed on the use of probiotics rather than prebiotics and postbiotics in reducing the symptoms of depression in patients with major depressive disorder. One of prime importance can be given to exploring more microbiota to investigate the better therapeutic effects of probiotics, prebiotics, and postbiotics.
112Modulating Gut Microbiota with Dietary Components: A Novel Strategy for Cancer-Depression Comorbidity Management.PubMed
Haochen Dai, Haiyi Yang, Rui Wang, et al.
Nutrients. 2025 Apr 29;17(9):1505. doi: 10.3390/nu17091505.
BACKGROUND: Gut microbiota play a critical role in mediating the bidirectional association between cancer and depression. Emerging evidence indicates that adjusting the dietary component intake can significantly alter gut microbiota composition, thereby influencing the host's metabolism and immune function. Changes in gut microbiota and their metabolites may represent key factors in preventing cancer-depression comorbidity. METHODS: English publications were searched in databases including the Web of Science, Scopus, and PubMed using a series of keywords: "cancer", "depression", "gut microbiota", "dietary components", and related terms, individually or in combination. The search focused on preclinical and clinical studies describing the regulatory effects of dietary component interventions. RESULTS: This narrative review summarizes the associations among gut microbiota, cancer, and depression, and synthesizes current evidence on the modulatory effects and mechanisms of specific dietary component interventions, including dietary patterns, probiotics, prebiotics, and diet-derived phytochemicals, on gut microbiota. On the one hand, these interventions inhibit abnormal proliferation signals in the tumor microenvironment and enhance anticancer immune responses; on the other hand, they modulate neurotransmitter homeostasis, suppress neuroinflammation, and improve mood behaviors through the gut-brain axis interactions mediated by microbial metabolites. CONCLUSIONS: The complex associations among cancer, depression, and gut microbiota require further clarification. Modulating gut microbiota composition through dietary components represents a novel therapeutic strategy for improving cancer-depression comorbidity. Regulated gut microbiota enhance immune homeostasis and intestinal barrier function, while their metabolites bidirectionally modulate one another via systemic circulation and the gut-brain axis, thereby improving both the tumor microenvironment and depressive-like behaviors in cancer patients while reducing the adverse effects of cancer.
113DM8504 Alleviates Autistic-Like Behaviors in Valproic Acid-Exposed Rats Through Gut Microbiota Modulation and SCFA Restoration.PubMed
Hui Liu, Gaojie Liu, Yuxuan Zhang, et al.
Neuropsychiatr Dis Treat. 2025 Nov 7;21:2449-2463. doi: 10.2147/NDT.S547997. eCollection 2025.
OBJECTIVE: Compelling evidence has confirmed that gut microbiota dysbiosis is involved in the development of autism spectrum disorder (ASD). Microbial-based therapies, including probiotics, may provide novel options for ASD management. This study aimed to investigate the alleviative effect of a probiotic strain, () DM8504, on autistic-like behaviors in rats exposed to valproic acid (VPA). METHODS: Male offspring of VPA-exposed pregnant Sprague-Dawley rats treated with DM8504 were subjected to behavioral tests. Fecal short-chain fatty acids (SCFAs) and microbiota composition were determined by targeted metabolomics and 16S rRNA gene sequencing, respectively. Microbial functional profiles were analyzed using the KEGG and COG pathway analyses. RESULTS: DM8504 alleviated autistic-like behaviors in VPA-exposed rats, as evidenced by enhanced locomotor activity, exploratory behavior, sociability, spatial working memory, and depression relief. DM8504 treatment significantly enhanced the fecal levels of acetic acid, butyric acid, isobutyric acid, propionic acid, and hexanoic acid, and restored the diversity of gut microbiota composition in VPA-exposed rats. Specifically, DM8504 increased the abundance of gut bacterial species capable of producing SCFAs in VPA-exposed rats, including , and group. In addition, microbial functional profile analysis showed that DM8504 administration reversed the alterations in COG and KEGG pathways induced by VPA exposure. CONCLUSION: These findings reveal that DM8504 alleviates autistic-like behaviors in VPA-exposed rats through restoration of SCFA levels and enrichment of SCFA-producing bacteria, which indicate that well-defined strains may have potential for the management of children with ASD in the future.
114Identification of characteristic microbes and metabolites in confined environments population.PubMed
Xiangru Feng, Jiaqian Zhong, Jiaming Wang, et al.
Brain Behav Immun. 2025 Nov;130:106114. doi: 10.1016/j.bbi.2025.106114. Epub 2025 Sep 19.
Chronic stress in confined environments can disrupt the microbiota-gut-brain axis. However, the characteristic microbial and metabolic alterations in socially and radically basic activity-restricted people in confined environments (SRBARC) remain unclear. This study integrated assessments of emotional states, gut microbiota, and metabolomic profiles to investigate theirinterrelationships in SRBARC, aiming to identify characteristic microbes and metabolites. The results suggested that the SRBARC tend to exhibit depressive/anxiety-like behaviors, accompanied by hypothalamic-pituitary-adrenal (HPA) axis activation, suppressed testosterone, and elevated pro-inflammatory cytokines. Full-length 16S rDNA sequencing analysis indicated lower Shannon and Chao1 indices in the gut microbiota of the SRBARC. Random forest analysis combined with dual-cohort verification suggested that Blautia massiliensis, Blautia wexlerae, Coprococcus comes, Faecalibacterium prausnitzii, and Lachnospiraceae bacterium may serve as characteristic microbes with diagnostic value (discovery cohort AUC = 0.836, validation cohort AUC = 0.840). Metabolomic analysis of feces, serum and urine revealed alterations in amino acid metabolism and disruptions in tetrahydrobiopterin (BH4) synthesis in the SRBARC, which affected serotonin (5-HT) and dopamine (DA) pathways. Four metabolites, including 5-methoxytryptophol, were identified as potentially metabolites associated with emotional states. These characteristic microorganisms and metabolic features were associated with neuroinflammation and immunity, and their interactions may play a key role in regulating emotional states in SRBARC. In summary, this study suggested a potential interplay among gut microbiota, neurotransmitter metabolism, and emotional states in the SRBARC, identifying potential key microbial signatures and metabolites that may provide a theoretical foundation for developing gut microbiota-based intervention strategies.
115Supplementation with NS8 alleviated behavioral, neural, endocrine, and microbiota abnormalities in an endogenous rat model of depression.PubMed
Husile Alatan, Shan Liang, Yosuke Shimodaira, et al.
Front Immunol. 2024 Sep 13;15:1407620. doi: 10.3389/fimmu.2024.1407620. eCollection 2024.
INTRODUCTION: Major depressive disorder is a condition involving microbiota-gut-brain axis dysfunction. Increasing research aims to improve depression through gut microbiota regulation, including interventions such as probiotics, prebiotics, and fecal microbiota transplants. However, most research focuses on exogenous depression induced by chronic stress or drugs, with less attention given to endogenous depression. Additionally, research on gut mycobiota in depression is significantly less than that on gut bacteria. METHODS: In the present study, Wistar-Kyoto rats were used as an endogenous depression and treatment-resistant depression model, while Wistar rats served as controls. Differences between the two rat strains in behavior, gut bacteria, gut mycobiota, nervous system, endocrine system, immune system, and gut barrier were evaluated. Additionally, the effects of NS8 supplementation were investigated. RESULTS: Wistar-Kyoto rats demonstrated increased depressive-like behaviors in the forced swimming test, reduced sucrose preference in the sucrose preference test, and decreased locomotor activity in the open field test. They also exhibited abnormal gut bacteria and mycobiota, characterized by higher bacterial α-diversity but lower fungal α-diversity, along with increased butyrate, L-tyrosine, and L-phenylalanine biosynthesis from bacteria. Furthermore, these rats showed dysfunction in the microbiota-gut-brain axis, evidenced by a hypo-serotonergic system, hyper-noradrenergic system, defective hypothalamic-pituitary-adrenal axis, compromised gut barrier integrity, heightened serum inflammation, and diminished gut immunity. A 1-month NS8 intervention increased the fecal abundance of ; reduced the abundance of and Debaryomycetaceae; decreased immobility time but increased climbing time in the forced swimming test; reduced hippocampal corticotropin-releasing hormone levels; decreased hypothalamic norepinephrine levels; increased hippocampal glucocorticoid receptor, brain-derived neurotrophic factor dopamine, and 5-hydroxyindoleacetic acid content; and improved the gut microbiota, serotonergic, and noradrenergic system. CONCLUSION: The depressive phenotype of Wistar-Kyoto rats is not only attributed to their genetic context but also closely related to their gut microbiota. Abnormal gut microbiota and a dysfunctional microbiota-gut-brain axis play important roles in endogenous depression, just as they do in exogenous depression. Supplementing with probiotics such as NS8 is likely a promising approach to improve endogenous depression and treatment-resistant depression.
116Dysbiosis and fecal microbiota transplant: Contemplating progress in health, neurodegeneration and longevity.PubMed
Somayeh Ahmadi, Alka Hasani, Aytak Khabbaz, et al.
Biogerontology. 2024 Nov;25(6):957-983. doi: 10.1007/s10522-024-10136-4. Epub 2024 Sep 24.
The gut-brain axis plays an important role in mental health. The intestinal epithelial surface is colonized by billions of commensal and transitory bacteria, known as the Gut Microbiota (GM). However, potential pathogens continuously stimulate intestinal immunity when they find the place. The last two decades have witnessed several studies revealing intestinal bacteria as a key factor in the health-disease balance of the gut, as well as disease-emergent in other parts of the body. Various neurological processes, such as cognition, learning, and memory, could be affected by dysbiosis in GM. Additionally, the aging process and longevity are related to systemic inflammation caused by dysbiosis. Commensal GM affects brain development, behavior, and healthy aging suggesting that building changes in GM might be a potential therapeutic method. The innovation in GM dysbiosis is intervention by Fecal Microbiota Transplantation (FMT), which has been confirmed as a therapy for recurrent Clostridium difficile infections and is promising for other clinical disorders, such as Parkinson's disease, Multiple Sclerosis (MS), Alzheimer's disease, and depression. Additionally, FMT may be possible to promote healthy aging, and extend longevity. This review aims to connect dysbiosis, neurological disorders, and aging and the potential of FMT as a therapeutic strategy to treat these disorders, and to enhance the quality of life in the elderly.
117Nutritional and therapeutic approaches for protecting human gut microbiota from psychotropic treatments.PubMed
Yasmina Ait Chait, Walid Mottawea, Thomas A Tompkins, et al.
Prog Neuropsychopharmacol Biol Psychiatry. 2021 Jun 8;108:110182. doi: 10.1016/j.pnpbp.2020.110182. Epub 2020 Nov 21.
Emerging evidence highlighted the essential role played by the microbiota-gut-brain axis in maintaining human homeostasis, including nutrition, immunity, and metabolism. Much recent work has linked the gut microbiota to many psychiatric and neurodegenerative disorders such as depression, schizophrenia, and Alzheimer's disease. Shared gut microbiota alterations or dysbiotic microbiota have been identified in these separate disorders relative to controls. Much attention has focused on the bidirectional interplay between the gut microbiota and the brain, establishing gut dysbiotic status as a critical factor in psychiatric disorders. Still, the antibiotic-like effect of psychotropic drugs, medications used for the treatment of these disorders, on gut microbiota is largely neglected. In this review, we summarize the current findings on the impact of psychotropics on gut microbiota and how their antimicrobial potency can trigger dysbiosis. We also discuss the potential therapeutic strategies, including probiotics, prebiotics, and fecal transplantation, to attenuate the dysbiosis related to psychotropics intake.
118A comprehensive analysis of the differential expression in the hippocampus of depression induced by gut microbiota compared to traditional stress.PubMed
Xueyi Chen, Xiaolong Mo, Yangdong Zhang, et al.
Gene. 2024 Nov 15;927:148633. doi: 10.1016/j.gene.2024.148633. Epub 2024 Jun 3.
Depression, which is a disease of heterogeneous etiology, is characterized by high disability and mortality rates. Gut microbiota are associated with the development of depression. To further explore any differences in the mechanisms of depression induced by gut microbiota and traditional stresses, as well as facilitate the development of microbiota-based interventions, a fecal microbiota transplantation (FMT) depression model was made. This was achieved by transplanting feces from major depressive disorder (MDD) patients into germ-free mice. Second, the mechanisms of the depression induced by gut microbiota were analyzed in comparison with those of the depression caused by different forms of stress. It turned out that mice exhibited depressive-like behavior after FMT. Then, PCR array analysis was performed on the hippocampus of the depressed mice to identify differentially expressed genes (DEGs). The KEGG analysis revealed that the pathways of depression induced by gut microbes are closely associated with immuno-inflammation. To determine the pathogenic pathways of physiological stress and psychological stress-induced depression, raw data was extracted from several databases and KEGG analysis was performed. The results from the analysis revealed that the mechanisms of depression induced by physiological and psychological stress are closely related to the regulation of neurotransmitters and energy metabolism. Interestingly, the immunoinflammatory response was distinct across different etiologies that induced depression. The findings showed that gut microbiota dysbiosis-induced depression was mainly associated with adaptive immunity, while physiological stress-induced depression was more linked to innate immunity. This study compared the pathogenesis of depression caused by gut microbiota dysbiosis, and physiological and psychological stress. We explored new intervention methods for depression and laid the foundation for precise treatment.
119Cognitive behavioral therapy, mindfulness, and cortisol habituation: A randomized controlled trial.PubMed
Andrew W Manigault, Ryan C Shorey, Katrina Hamilton, et al.
Psychoneuroendocrinology. 2019 Jun;104:276-285. doi: 10.1016/j.psyneuen.2019.03.009. Epub 2019 Mar 18.
BACKGROUND: Hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation is associated with disease and may be indexed by poor cortisol habituation (i.e., a failure to show decreased responding with repeated stressor exposure). Thus, stress management training that can enhance HPA axis habituation may benefit health. To date, the effects of Mindfulness Based Stress Reduction (MBSR) and Cognitive Behavioral Therapy (CBT) interventions on HPA axis habituation remain untested. To test the effects of MBSR and CBT on HPA axis habituation, the present study used a parallel arm randomized controlled trial. METHODS: Healthy adults reporting moderate-to-high stress (n = 138) were randomly assigned to a 6-week MBSR intervention, a 6-week CBT intervention, or Waitlist control group. Post-intervention, participants completed a social-evaluative performance stressor during each of two laboratory visits scheduled 48-h apart. Salivary cortisol was collected pre-stressor, and 25, 35, and 60 min post-stressor onset during each visit. Final analyses included 86 participants who completed procedures up to the first laboratory visit. RESULTS: Relative to the control condition, both MBSR and CBT groups showed greater cortisol habituation. The MBSR group exhibited marginally greater habituation than the Waitlist group in cortisol samples corresponding to the recovery time points (35 and 60 min post-stressor onset). In contrast, the CBT group showed greater habituation than the Waitlist across all sampling timepoints collected (pre-stressor, 25, 35, and 60 min post-stressor onset). Yet, the CBT group also demonstrated elevated pre-stressor cortisol during the first visit. CONCLUSIONS: Results suggest that MBSR and CBT interventions promote greater HPA axis habituation relative to no training, but do not reduce overall cortisol output (i.e., across both visits). Observed differences between CBT and MBSR training in relation to cortisol habituation are discussed.
120The effect of proinflammatory cytokines in Cognitive Behavioral Therapy.PubMed
Fernanda Pedrotti Moreira, Taiane de Azevedo Cardoso, Thaíse Campos Mondin, et al.
J Neuroimmunol. 2015 Aug 15;285:143-6. doi: 10.1016/j.jneuroim.2015.06.004. Epub 2015 Jun 16.
Major depressive disorder (MDD) is a debilitating disorder and its pathophysiology is associated with deregulation of the immune system. We investigated the changes in circulating levels of proinflammatory cytokines (specifically IL-6 and TNF-α) measured by the ELISA kit in two psychotherapeutic interventions for MDD: Narrative Cognitive Therapy (NCT) and Cognitive Behavioral Therapy (CBT). This is a randomized clinical trial including 97 individuals (18 to 29years-old) with MDD. In CBT there was a significant difference in serum levels of IL-6 and TNF-α, therefore indicating that CBT was more effective than NCT on serum levels proinflammatory cytokines.
121Meta-analysis of cognitive-behavioral interventions on HIV-positive persons' mental health and immune functioning.PubMed
Nicole Crepaz, Warren F Passin, Jeffrey H Herbst, et al.
Health Psychol. 2008 Jan;27(1):4-14. doi: 10.1037/0278-6133.27.1.4.
OBJECTIVE: To evaluate the efficacy of cognitive-behavioral interventions (CBIs) for improving the mental health and immune functioning of people living with HIV (PLWH). DESIGN: Comprehensive searches of electronic databases from 1988 to 2005, hand searches of journals, reference lists of articles, and contacts with researchers. Meta-analytic approaches were used in synthesizing findings. MAIN OUTCOME MEASURES: Intervention effects on symptoms of depression, anxiety, and anger, stress, and CD4 cell counts were assessed. RESULTS: Data from 15 controlled trials were analyzed. Significant intervention effects were observed for improving symptoms of depression (d = 0.33), anxiety (d = 0.30), anger (d = 1.00), and stress (d = 0.43). There is limited evidence suggesting intervention effects on CD4 cell counts (d = 0.08). The aggregated effect size estimates for depression and anxiety were statistically significant in trials that provided stress management skills training and had more than 10 intervention sessions. CONCLUSION: CBIs are efficacious in improving various psychological states of PLWH. Future research should examine the relationship among interventions, psychological states, medication adherence, and immune functions, and identify other relevant factors associated with intervention effects.
122Psychosocial-immune relationships in HIV disease.PubMed
D G Cruess, J Leserman, J M Petitto, et al.
Semin Clin Neuropsychiatry. 2001 Oct;6(4):241-51. doi: 10.1053/scnp.2001.26996.
Human immunodeficiency virus (HIV) is now commonly viewed as a chronic disease, which often consists of a wide array of recurrent and sometimes severe psychosocial stressors. An individual's response to these multiple challenges over time may impact their health. In this article, we review research examining the relationship of psychologic factors (eg, depression, stressful life events, coping, social support) with immune system function and disease course. We also explore some of the potential physiologic pathways that may underlie these types of psychosocial-immune relationships, as well as the effects of psychologic interventions, particularly cognitive-behavioral stress management (CBSM), on the psychosocial, neuroendocrine, and immune functioning of people living with HIV. We conclude by suggesting some areas for future research, particularly the study of HIV-positive women.
123The role of stress in the mosaic of autoimmunity: An overlooked association.PubMed
Kassem Sharif, Abdulla Watad, Louis Coplan, et al.
Autoimmun Rev. 2018 Oct;17(10):967-983. doi: 10.1016/j.autrev.2018.04.005. Epub 2018 Aug 14.
Stress is defined as the pscyophysiological reaction in which the steady state is disturbed or threatened. Stress is not always perceived as a negative response. Stress results when environmental demands exceed an individuals' adaptive capacities. Autoimmune diseases are heterogeneous group of chronic diseases which occur secondary to loss of self antigen tolerance. The etiopathogenesis of autoimmune disease is uncertain. Genetic factors as well as environmental factors appear to interplay, leading to a cascade of events resulting in disease onset. Stress has been postulated to play a role in disease onset in the genetically susceptible patients. During the stress response, catecholamines and glucocorticoids are released from locus coeruleus and adrenal gland. These biomolecules exert control over various immune cells in the innate and adaptive arms of the immune system, thereby altering the cytokine profile released. The increase of IL-4 promotes T-helper 2 (T2) cell differentiation, while the decrease in IL-12 and the increased IL-10 production reduce the number of T-helper 1 (T1) cells. The relationship between stress and autoimmune diseases is intricate. Stress has been shown to be associated with disease onset, and disease exacerbations in rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, Graves' disease as well as other autoimmune conditions. In certain conditions such as psoriasis, stress has been implicated in delaying lesion clearance upon the application of standard treatment regimes. Finally, psychological therapy and cognitive behavioral therapy aimed to reduce stress levels was shown to be effective in influencing better outcomes in many autoimmune diseases. The purpose of this paper is to closer inspect the clinical evidence regarding the role of stress on influencing the various aspects of disease entities.
124Evidence for anti-inflammatory effects of exercise in CKD.PubMed
João L Viana, George C Kosmadakis, Emma L Watson, et al.
J Am Soc Nephrol. 2014 Sep;25(9):2121-30. doi: 10.1681/ASN.2013070702. Epub 2014 Apr 3.
CKD is associated with a complex state of immune dysfunction characterized by immune depression, predisposing patients to infections, and immune activation, resulting in inflammation that associates with higher risk of cardiovascular disease. Physical exercise may enhance immune function and exert anti-inflammatory effects, but such effects are unclear in CKD. We investigated the separate effects of acute and regular moderate-intensity aerobic exercise on neutrophil degranulation (elastase release), activation of T lymphocytes (CD69 expression) and monocytes (CD86 and HLA-DR expression), and plasma inflammatory markers (IL-6, IL-10, soluble TNF-receptors, and C-reactive protein) in patients with predialysis CKD. A single 30-minute (acute) bout of walking induced a normal pattern of leukocyte mobilization and had no effect on T-lymphocyte and monocyte activation but improved neutrophil responsiveness to a bacterial challenge in the postexercise period. Furthermore, acute exercise induced a systemic anti-inflammatory environment, evidenced by a marked increase in plasma IL-10 levels (peaked at 1 hour postexercise), that was most likely mediated by increased plasma IL-6 levels (peaked immediately postexercise). Six months of regular walking exercise (30 min/d for 5 times/wk) exerted anti-inflammatory effects (reduction in the ratio of plasma IL-6 to IL-10 levels) and a downregulation of T-lymphocyte and monocyte activation, but it had no effect on circulating immune cell numbers or neutrophil degranulation responses. Renal function, proteinuria, and BP were also unaffected. These findings provide compelling evidence that walking exercise is safe with regard to immune and inflammatory responses and has the potential to be an effective anti-inflammatory therapy in predialysis CKD.
125Tai Chi research review.PubMed
Tiffany Field
Complement Ther Clin Pract. 2011 Aug;17(3):141-6. doi: 10.1016/j.ctcp.2010.10.002. Epub 2010 Oct 24.
This review briefly summarizes recent Tai Chi research on physical benefits including balance and muscle strength and psychological benefits including attentiveness, sleep and anxiety. Cardiovascular changes following Tai Chi include decreased heart rate and blood pressure, increased vagal activity and decreased cholesterol. Pain syndromes that have been affected include fibromyalgia, osteoarthritis and rheumatoid arthritis. Autoimmune and immune conditions recently researched and reviewed here include osteoporosis, diabetes and HIV. Methodological problems with this research include the variability in forms (series of postures) used across studies as well as the intensity of the Tai Chi schedule. Further, most of the studies are based on within group changes rather than attention control group comparisons. Nonetheless, significant clinical improvements have been noted.
126Utilization of Mind-Body Intervention for Integrative Health Care of COVID-19 Patients and Survivors.PubMed
Hyun-Jeong Yang, Noriko Setou, Eugene Koh
Int J Environ Res Public Health. 2022 May 29;19(11):6618. doi: 10.3390/ijerph19116618.
Recent findings suggest a correlation between COVID-19 and diabetes, although the underlying causes are still little understood. COVID-19 infection tends to induce severe symptoms in patients with underlying diabetes, increasing their mortality rate. Moreover, COVID-19 itself appears to be a diabetogenic factor. In addition, mental health conditions, such as depression due to lockdown and anxiety about infection, were found to affect glycemic control and immunity, highlighting the importance of mental health care during the pandemic. Mind-Body Intervention (MBI), which includes meditation, yoga, and qigong, has emerged as a tool for mental health management due to its effects on stress reduction and the promotion of mental and physical well-being. Here, we review the latest randomized controlled trials to determine the effects of MBI on glycemic control and the immune system and discuss the underlying mechanisms by which MBI facilitates the virtuous cycle of stress management, glycemic control, and immune modulation. Furthermore, we examine the actual utilization of MBI during the COVID-19 pandemic era through recent studies. With proper online education, non-pharmacological MBI may be more widely used as an important tool for self-health care that complements the usual treatment of COVID-19 patients and survivors.
127Alterations in brain and immune function produced by mindfulness meditation.PubMed
Richard J Davidson, Jon Kabat-Zinn, Jessica Schumacher, et al.
Psychosom Med. 2003 Jul-Aug;65(4):564-70. doi: 10.1097/01.psy.0000077505.67574.e3.
OBJECTIVE: The underlying changes in biological processes that are associated with reported changes in mental and physical health in response to meditation have not been systematically explored. We performed a randomized, controlled study on the effects on brain and immune function of a well-known and widely used 8-week clinical training program in mindfulness meditation applied in a work environment with healthy employees. METHODS: We measured brain electrical activity before and immediately after, and then 4 months after an 8-week training program in mindfulness meditation. Twenty-five subjects were tested in the meditation group. A wait-list control group (N = 16) was tested at the same points in time as the meditators. At the end of the 8-week period, subjects in both groups were vaccinated with influenza vaccine. RESULTS: We report for the first time significant increases in left-sided anterior activation, a pattern previously associated with positive affect, in the meditators compared with the nonmeditators. We also found significant increases in antibody titers to influenza vaccine among subjects in the meditation compared with those in the wait-list control group. Finally, the magnitude of increase in left-sided activation predicted the magnitude of antibody titer rise to the vaccine. CONCLUSIONS: These findings demonstrate that a short program in mindfulness meditation produces demonstrable effects on brain and immune function. These findings suggest that meditation may change brain and immune function in positive ways and underscore the need for additional research.
128Stress, Meditation, and Alzheimer's Disease Prevention: Where The Evidence Stands.PubMed
Dharma Singh Khalsa
J Alzheimers Dis. 2015;48(1):1-12. doi: 10.3233/JAD-142766.
Although meditation is believed to be over five thousand years old, scientific research on it is in its infancy. Mitigating the extensive negative biochemical effects of stress is a superficially discussed target of Alzheimer's disease (AD) prevention, yet may be critically important. This paper reviews lifestyle and stress as possible factors contributing to AD and meditation's effects on cognition and well-being for reduction of neurodegeneration and prevention of AD. This review highlights Kirtan Kriya (KK), an easy, cost effective meditation technique requiring only 12 minutes a day, which has been successfully employed to improve memory in studies of people with subjective cognitive decline, mild cognitive impairment, and highly stressed caregivers, all of whom are at increased risk for subsequent development of AD. KK has also been shown to improve sleep, decrease depression, reduce anxiety, down regulate inflammatory genes, upregulate immune system genes, improve insulin and glucose regulatory genes, and increase telomerase by 43%; the largest ever recorded. KK also improves psycho-spiritual well-being or spiritual fitness, important for maintenance of cognitive function and prevention of AD. KK is easy to learn and practice by aging individuals. It is the premise of this review that meditation in general, and KK specifically, along with other modalities such as dietary modification, physical exercise, mental stimulation, and socialization, may be beneficial as part of an AD prevention program.
129The Multiple Uses of Guided Imagery.PubMed
Stephen D Krau
Nurs Clin North Am. 2020 Dec;55(4):467-474. doi: 10.1016/j.cnur.2020.06.013. Epub 2020 Oct 14.
Guided imagery is a therapeutic approach that has been used for centuries. Through the use of mental imagery, the mind-body connection is activated to enhance an individual's sense of well-being, reduced stress, and reduced anxiety, and it has the ability to enhance the individual's immune system. There are research and data to support the use of guided imagery for these patient outcomes.