1. 胃作为情绪器官的神经生物学基础
1.1 肠脑轴的双向调控机制
胃作为情绪器官的核心在于其与中枢神经系统（CNS）之间复杂的双向交流系统，即肠脑轴（Gut-Brain Axis, GBA）1。这一轴线不仅涉及神经通路，还包括内分泌、免疫和微生物通路等多种介导方式，共同调控胃的功能并影响情绪状态2。
具体而言，肠脑轴的神经通路主要通过迷走神经（Vagus Nerve）和脊髓传入神经实现3。迷走神经是副交感神经系统的主要组成部分，扮演着连接内脏与大脑的关键角色，将胃肠道的感觉信息传递至中枢神经系统45。胃黏膜的感觉信号，例如胃的扩张、化学刺激（如营养物质或毒素）以及机械刺激，能够被胃肠道内的感受器捕获，并通过迷走神经的传入纤维迅速传导至脑干的孤束核（Nucleus Tractus Solitarius, NTS）67。NTS是胃肠道传入信号进入中枢神经系统的初级整合中心，它进一步将这些信号传递至更高级的脑区，如丘脑、杏仁核、下丘脑和前额叶皮层，从而影响情绪、食欲和行为58。例如，迷走神经能够调节食欲和营养偏好，对饱腹感和食物摄入具有重要影响4。
除了迷走神经，脊髓传入神经也参与胃黏膜感觉信号向脑的传递，尤其是在疼痛和不适感方面。这些传入神经通常与交感神经系统相关，在应激状态下对胃肠道功能的影响更为显著。
大脑对胃运动和分泌功能的反馈调节同样重要。中枢神经系统通过迷走神经传出纤维和交感神经系统，对胃的蠕动、胃酸分泌、胃黏膜血流以及胃肠激素的释放进行精细调控9。例如，在进食时，大脑会通过迷走神经刺激胃酸和消化酶的分泌，并促进胃蠕动以消化食物810。相反，应激和负面情绪（如焦虑、抑郁）可以通过下行神经通路影响胃功能，导致胃动力异常、胃酸分泌紊乱甚至胃黏膜损伤9。研究表明，胃的电生理节律与大脑的多个脑区（包括感觉区）之间存在相位同步，这表明胃与大脑之间存在持续的功能性连接，影响着从摄食行为到功能性胃肠疾病的广泛生理过程11。这种双向调控机制的失衡是许多胃肠道疾病和情绪障碍共病现象的神经生物学基础12。
1.2 胃黏膜的神经内分泌细胞功能
胃黏膜中存在一类特殊的神经内分泌细胞，其中肠嗜铬细胞（Enterochromaffin cells, EC细胞）扮演着将胃内环境信号转化为情绪相关神经信号的关键角色。EC细胞是胃肠道中合成、储存和释放5-羟色胺（5-HT，即血清素）的主要细胞类型 13。5-HT是一种重要的神经递质，在调节胃肠蠕动、内脏感觉以及情绪状态方面发挥着核心作用 1314。
EC细胞能够检测并传递有害刺激，将胃内环境信息传递至中枢神经系统 1415。这种“胃-脑”通路使得胃能够将其内部状态（例如饱胀、不适、疼痛）编码为神经信号，并影响大脑对情绪的感知和调节。例如，化疗药物引起的恶心呕吐就与细胞毒性作用导致肠嗜铬细胞释放大量5-HT有关 16。胆霍乱毒素也能诱导EC细胞释放5-HT，从而引起液体分泌增加 17。
值得注意的是，EC细胞的功能及其对情绪相关神经信号的转化存在显著的性差异。研究表明，女性在内脏痛觉和焦虑样行为方面表现出更高的敏感性，这与EC细胞-黏膜传入神经回路的持续活跃有关 141819。例如，在肠易激综合征（IBS）患者中，女性的EC细胞增生和肠道5-HT生物利用度增加更为常见，这可能导致更严重的内脏高敏感和焦虑症状 131418。此外，雌激素等性激素能够通过多种机制调节肠道5-HT的合成、释放和转运，从而影响肠脑轴的功能，进一步解释了胃肠道疾病和情绪障碍在两性之间发病率和表现上的差异 1819。这种性差异不仅体现在基础生理功能上，也影响了机体对压力的反应。例如，微生物群对急性应激的肠道5-HT反应存在性别依赖性影响，雄性小鼠结肠5-HT应激后升高在无菌小鼠中消失，但定殖后恢复正常 20。母体色氨酸补充剂通过调节肠脑轴，也以性别特异性方式改变后代肠道微生物群和行为，表现为雌性后代焦虑样行为增强，而雄性后代重复行为增加 21。
因此，EC细胞及其释放的5-HT不仅是胃肠功能调节的关键，也是连接胃肠道与情绪状态的重要桥梁，并且在这一过程中，性差异发挥着不可忽视的调节作用。对EC细胞功能失调的研究为理解胃肠道疾病伴随的情绪障碍提供了新的治疗靶点，例如通过调节EC细胞增生、5-HT合成或受体活性来干预相关疾病的进展 1314。
2. 情绪状态对胃功能的影响路径
2.1 应激与焦虑的神经内分泌调控
情绪状态，特别是应激和焦虑，通过复杂的神经内分泌通路对胃功能产生深远影响。其中，下丘脑-垂体-肾上腺（HPA）轴的激活是关键介导机制。当机体面临应激时，下丘脑释放促肾上腺皮质激素释放因子（CRF），刺激垂体前叶分泌促肾上腺皮质激素（ACTH），进而促使肾上腺皮质释放皮质醇等糖皮质激素。皮质醇水平的升高对胃肠道生理功能具有多方面的影响。
皮质醇可影响胃黏膜屏障功能，使其完整性受损，增加胃黏膜对胃酸和其他刺激物的易感性，从而增加溃疡和炎症的风险。同时，应激可通过增加胃酸分泌并改变胃动力来诱发或加重胃食管反流病（GERD）2223。在GERD的病理生理学中，胃食管交界处的抗反流屏障功能受损、食管清除能力下降以及胃排空延迟等因素均可导致胃内容物反流至食管，而应激导致的胃酸分泌增加和胃动力异常则进一步加剧了这一过程 2223。例如，高皮质醇水平可影响胃肠道功能。一项随机对照试验发现，与商业碳水化合物饮料相比，蜂蜜溶液虽然可能导致更高的皮质醇水平，但却显著改善了胃动力，这提示了胃功能与皮质醇水平之间复杂而有时非线性的关联，但总体而言，慢性高皮质醇水平不利于胃的正常生理功能 24。
此外，应激和焦虑也是功能性消化不良（FD）的重要风险因素 252627。FD是一种常见的胃肠道功能紊乱性疾病，其特征为上腹部疼痛、餐后饱胀感和早饱等症状，但缺乏器质性病变。应激可通过影响胃的容受性、胃排空速度以及内脏感觉敏感性来促进FD的发生发展 2526。例如，中枢性CRF的施用已被证明可以抑制胃的周期性移行性复合运动（MMC），而不影响空肠，这表明CRF在胃动力的中枢控制中发挥作用，并且可能通过影响ACTH和皮质醇的释放来进一步调节胃动力 28。
长期或慢性应激不仅影响胃的生理功能，还可导致肠道菌群失调，并触发免疫系统反应，进一步加剧胃肠道炎症和功能障碍 293031。慢性应激能够通过扰乱肠道菌群，增加促炎细菌的丰度，并激活IL-6/STAT3信号通路，从而促进结肠炎的发生 29。这种应激诱导的肠道菌群失调和免疫反应失衡，反过来又可能影响胃的正常功能，形成恶性循环。因此，应激和焦虑通过HPA轴激活及其后续效应，对胃黏膜屏障、胃酸分泌、胃动力以及肠道微生态平衡产生广泛影响，是胃食管反流和功能性消化不良等胃部疾病的重要病理生理机制。
2.2 负面情绪与胃功能异常的关联
除了急性应激和焦虑，抑郁、社交压力等负面情绪也对胃功能产生显著影响，主要通过下行神经通路介导。中枢促肾上腺皮质激素释放因子（CRH）在负面情绪对胃功能的影响中扮演着关键角色。CRH是HPA轴的关键调节因子，其在中枢神经系统中的释放与应激反应和情绪调节密切相关。CRH在胃肠道局部也发挥作用，CRH受体2型（CRHR2）的激活被发现能促进肠道黏膜的修复反应，尤其是在结肠炎后 32。然而，持续的负面情绪或慢性应激可能导致CRH信号通路失调，从而影响胃黏膜的完整性和修复能力。例如，慢性应激与胃黏膜的过度角化和溃疡形成显著相关 33。
此外，糖皮质激素诱导因子TSC22D3 (TSC22 domain family member 3) 也在负面情绪与胃功能异常的关联中发挥作用。研究表明，心理压力会导致小鼠血浆皮质酮水平升高，并上调TSC22D3的表达，进而抑制I型干扰素（IFN）反应和T细胞活化，从而削弱抗肿瘤免疫反应 34。尽管TSC22D3在胃肠道功能中的直接作用尚需进一步阐明，但其在糖皮质激素信号通路中的地位提示它可能参与介导负面情绪（通过皮质醇升高）对胃黏膜稳态的负面影响。例如，在胃癌中，TSC22D3作为铁死亡（ferroptosis）相关ceRNA网络的一部分，其表达变化与胃癌患者的生存率相关 35。这意味着长期负面情绪诱导的TSC22D3上调可能不仅影响免疫系统，还可能通过影响胃黏膜细胞的存活和修复机制，间接加剧胃部疾病的进展。
负面情绪，特别是社交压力，还可能加剧内脏高敏感（visceral hypersensitivity），使个体对胃部刺激（如胃酸、胀气）的感知阈值降低，从而更容易出现不适或疼痛。动物实验表明，社会隔离会增加胃黏膜对溃疡源性刺激（如吲哚美辛）的脆弱性，导致胃糜烂增加，而环境丰富化则能有效逆转这种促溃疡作用 36。这提示社交环境和心理状态对胃部健康有直接影响。
现代生活方式，特别是社交媒体的广泛使用，也对胃-情绪交互产生干扰。社交媒体的过度使用可能导致儿童和青少年出现一系列负面影响，包括取代睡眠、体育活动和人际互动的时间、网络欺凌、不健康的社会比较、错误信息、错失恐惧症（FOMO）以及继发性获益等 37。这些因素都可能加剧精神健康问题，进而影响胃肠道功能。例如，社交媒体使用可能增加焦虑和抑郁的风险，而这些情绪问题本身就是胃肠道功能紊乱（如肠-脑互动障碍，DGBI）的重要诱因。有研究认为，肠-脑互动障碍发病率的上升可能与社交媒体使用的增加有部分关联 37。因此，社交媒体在加剧负面情绪方面的作用，也间接影响了胃作为情绪器官的生理功能和病理生理学表现。
3. 胃功能异常与情绪障碍的双向共病现象
3.1 功能性胃肠病中的情绪共病
功能性胃肠病（Functional Gastrointestinal Disorders, FGIDs）是一组常见的胃肠道疾病，其特征是持续的胃肠道症状，但缺乏可识别的器质性病变。这类疾病与情绪障碍之间存在显著的双向共病现象，即胃肠道症状可以影响情绪，而情绪问题又可以加剧胃肠道症状。肠易激综合征（Irritable Bowel Syndrome, IBS）是FGIDs中最常见的类型之一，为理解这种共病现象提供了典型范例 383940。高达约50%的IBS患者同时伴有肠外症状，其中最常见的是躯体疼痛、疲劳和睡眠障碍，而这些症状与心理困扰密切相关 41。超过三分之二的FGIDs患者存在不同程度的心理健康问题，提示抑郁症状、睡眠障碍和躯体症状之间存在连锁中介效应，共同影响FGIDs的发生发展 42。
IBS患者普遍存在内脏高敏感（visceral hypersensitivity），即对肠道内刺激（如扩张、气体、化学物质）的感知阈值降低，即使是正常生理范围内的刺激也会引起不适或疼痛 383943。这种内脏高敏感是IBS核心症状（如腹痛和腹部不适）的重要病理生理学基础 40。肠道菌群失调在IBS内脏高敏感的发生中扮演关键角色。微生物群组成的改变不仅可以影响肠道屏障功能和局部炎症反应，还可以通过产生神经活性代谢产物直接或间接影响肠道神经系统，从而调节内脏敏感性 384445。例如，乳酸菌片可以通过调节肠道菌群失调和减轻肠道炎症来改善IBS大鼠的内脏敏感性，缓解焦虑和抑郁行为 45。
焦虑和抑郁症状在IBS患者中极为常见，且与疾病的严重程度、生活质量下降以及治疗反应密切相关 39434647。一项研究显示，IBS患者与健康对照组相比，在疲劳、焦虑、抑郁和睡眠障碍等心理困扰指标上得分显著更高，其中精神和躯体疲劳以及焦虑是预测IBS诊断的最强因素 48。这种情绪共病并非简单地是胃肠症状的心理反应，而是肠脑轴功能紊乱的双向体现 444649。肠道菌群失调、肠道炎症以及内脏高敏感性都可以通过肠脑轴影响中枢神经系统，进而诱发或加剧焦虑和抑郁 444650。反之，焦虑和抑郁等负面情绪也可通过下行神经通路影响肠道功能，例如改变肠道运动、分泌和敏感性，形成恶性循环 43。
在这一复杂网络中，EC细胞-黏膜神经信号在持续性疼痛与情绪异常中发挥着核心作用 14。EC细胞作为胃肠道内源性传感器，能够检测肠腔内的各种刺激，并通过释放5-羟色胺（5-HT）激活附近的黏膜传入神经末梢，将信息传递至中枢神经系统 14。在IBS患者中，EC细胞功能异常和5-HT信号通路紊乱是常见的病理特征 14。例如，一项研究指出，增强或抑制EC细胞功能足以引起肠道扩张的超敏感性，并且EC细胞的活化可以导致持续性内脏高敏感，即使在炎症消退后也是如此 14。此外，扰乱EC细胞的活性还可促进焦虑样行为的发生，且这种行为在阻断5-HT信号后恢复正常 14。特别是在女性IBS患者中，EC细胞-黏膜传入神经回路可能更活跃，这可能解释了IBS及相关情绪障碍在女性中更高的发病率和更严重的症状 1451。因此，EC细胞的功能失调不仅直接导致IBS患者的内脏疼痛，也通过5-HT信号途径间接促成了焦虑和抑郁等情绪障碍，从而构成了胃功能异常与情绪障碍双向共病的核心机制。
3.2 胃器质性疾病的情绪影响
除了功能性胃肠病，胃的器质性疾病也与情绪障碍存在密切关联，尤其是在胃癌和胃溃疡患者中，抑郁和焦虑的发生率显著升高。这种共病现象是疾病本身生理影响与心理应激共同作用的结果，涉及到胃激素水平变化和神经可塑性改变。
胃癌患者是抑郁/焦虑的高发群体。研究显示，胃癌患者中抑郁症的患病率高达57%，尤其是在疾病晚期和接受积极治疗期间 52。心理社会因素，如生存焦虑、对未来的不确定性、身体形象改变以及社会支持的缺乏，都极大地加剧了患者的心理负担。例如，一项针对胃癌幸存者的研究发现，34.7%的患者存在自杀意念（suicide ideation），而腹泻、脱发、生存福祉感（existential well-being）和疲劳是自杀意念的重要危险因素 53。另一项研究则指出，44%的胃癌幸存者患有抑郁症，其中女性抑郁评分更高，低收入、术前护理问题、身体形象改变以及疲劳、呼吸困难或失眠等症状均与抑郁症相关 54。此外，胃癌患者中创伤后应激障碍（PTSD）症状与抑郁症状之间存在高度共病性，患有临床水平PTSD的胃癌患者出现临床水平抑郁症的可能性是正常人群的15倍 55。对老年胃癌患者的术前衰弱研究也表明，焦虑是衰弱的独立危险因素之一，并与总并发症、住院时间延长和90天内再入院风险增加相关 56。这些研究强调了胃癌对患者精神健康的深远影响。
胃溃疡也与焦虑障碍密切相关。尽管幽门螺杆菌感染是消化性溃疡的主要病因之一，但情绪因素在此类疾病的发生发展中仍扮演重要角色 57。一项基于德国普通人群的调查发现，任何焦虑障碍（OR=2.6）、惊恐障碍（OR=5.2）、惊恐发作（OR=3.8）和社交恐惧症（OR=3.3）均与医生诊断的溃疡风险增加相关 58。这表明心理应激和负面情绪可以通过多种途径影响胃黏膜的防御机制，从而增加溃疡的风险或延缓其愈合。
疾病本身对情绪的影响体现在多个层面：
- 营养吸收障碍和手术创伤：胃部疾病，特别是胃癌及相关手术（如胃切除术），可能导致消化吸收功能障碍、营养不良，进而影响大脑神经递质的合成，诱发情绪问题。手术创伤和术后恢复过程中的疼痛、不适也构成持续的生理应激源。
- 胃激素变化：胃作为重要的内分泌器官，分泌多种调节食欲和情绪的肽类激素。例如，胃饥饿素（ghrelin）是一种由胃主要分泌的食欲刺激激素。功能性消化不良患者血浆酰基ghrelin水平降低，尤其是在男性患者中，且与饥饿感降低有关 5960。Nesfatin-1是另一种由胃分泌的肽，与饱腹感和焦虑密切相关。有研究指出nesfatin-1可以抑制食物摄入，其水平在神经性厌食症患者中降低，而在肥胖患者中升高，表明它在摄食行为障碍中发挥作用 61。此外，一项动物实验表明，应激诱导的焦虑样胃高敏感性模型中，海马体、血浆和胃底的nesfatin-1含量均显著增加 62。胃器质性疾病可能通过影响这些胃源性激素的正常分泌，从而干扰情绪调节。
- 神经可塑性改变：慢性疾病和持续的心理应激可导致中枢神经系统，特别是边缘系统（如杏仁核、海马体）的结构和功能发生适应性改变，即神经可塑性改变。这些变化可能影响情绪处理、应激反应和疼痛感知，从而使患者更容易出现焦虑和抑郁。长期的疼痛和炎症信号传入大脑，也可能导致中枢敏化，使个体对各种刺激变得更加敏感，包括情感刺激。
综上所述，胃的器质性疾病不仅带来生理上的痛苦，更通过复杂的神经内分泌和心理社会机制，显著影响患者的情绪健康。因此，在对这些疾病进行治疗时，必须将情绪管理纳入多学科综合治疗方案中。
4. 胃-情绪交互的分子与微生物学基础
4.1 胃源性激素的情绪调节作用
胃作为重要的内分泌器官，能够分泌多种肽类激素，这些胃源性激素不仅在消化和能量代谢中发挥核心作用，还通过肠脑轴直接或间接参与情绪调节，揭示了胃在维持情绪稳态中的分子机制。其中，胃饥饿素（ghrelin）和Nesfatin-1是研究较为深入的代表性分子。
胃饥饿素（Ghrelin） 是一种由胃主要分泌的28个氨基酸肽，被称为“饥饿激素”，主要功能是刺激食欲和促进生长激素释放。然而，越来越多的证据表明，ghrelin在情绪调节和神经可塑性方面也具有重要作用。研究发现，ghrelin能够调节成人海马神经发生，并改善记忆功能 63。海马体是与学习、记忆和情绪（特别是焦虑和抑郁）密切相关的脑区。这种神经发生对于维持认知功能、应对压力以及调节情绪至关重要。因此，ghrelin水平的改变，例如在饥饿或能量限制状态下ghrelin升高，可能不仅仅是为了刺激进食，更是为了在资源匮乏的环境下优化脑功能，增强生存适应能力 63。此外，ghrelin与情绪状态之间存在复杂关联。例如，在慢性应激模型中，ghrelin可以通过调节下丘脑-垂体-肾上腺（HPA）轴的活性，对焦虑和抑郁样行为产生影响。脱酰基ghrelin（desacyl ghrelin）是ghrelin的非活性形式，但研究表明其也能抑制酰基ghrelin诱导的摄食行为，并通过激活nesfatin-1免疫阳性神经元来影响神经活动 64。
Nesfatin-1 是另一种由核结合蛋白2（NUCB2）前体裂解而来的神经肽，广泛存在于中枢神经系统和外周组织中，尤其是在下丘脑、杏仁核和胃等区域 6165。Nesfatin-1最初被发现具有抑制食物摄入的厌食作用，与ghrelin作用相反 616566。然而，其功能远不止于此，它在焦虑、抑郁、应激反应和糖代谢调节中也扮演着重要角色 6566。
Nesfatin-1与焦虑等情绪状态密切相关 61。在动物模型中，脑室内注射Nesfatin-1可以抑制食物摄入，而注射Nesfatin-1中和抗体则能刺激食欲 61。同时，Nesfatin-1在情绪通路的调节中发挥作用，其与焦虑相关的性别特异性调节也受到关注 67。应激反应会导致Nesfatin-1神经元的激活和其浓度的改变，并进而影响行为 65。研究发现，Nesfatin-1与凤凰素（phoenixin）之间存在相互作用，两者可能在应激反应中发挥平衡作用 6869。
Nesfatin-1也参与到摄食-焦虑关联中的肽能信号作用。通过抑制食欲和影响情绪，Nesfatin-1在摄食障碍的病理生理学中具有潜在作用。例如，神经性厌食症患者血清Nesfatin-1水平通常低于正常体重对照组，而肥胖患者血清Nesfatin-1水平则相对较高 61。在肥胖女性患者中，NUCB2/nesfatin-1血浆水平与进食障碍症状（EDI-2总分）呈正相关 67。这些发现表明，胃源性激素如ghrelin和Nesfatin-1不仅仅是代谢调节因子，更是胃与情绪之间复杂信号通路的关键介质。它们通过影响脑区的神经发生、信号转导以及与焦虑相关的行为反应，揭示了胃作为内分泌器官在情绪稳态维持中的重要分子机制。内源性大麻素系统和这些神经肽（包括nesfatin-1和phoenixin）之间也存在神经化学和功能上的相互作用，尤其是在下丘脑区域，这种相互作用在抑郁和焦虑障碍的病理机制及药理治疗中具有重要意义 70。
4.2 肠道菌群-胃-脑轴的调节作用
肠道菌群是胃-情绪交互作用中不可或缺的组成部分，其通过复杂的肠道菌群-胃-脑轴（microbiota-gut-brain axis）对胃黏膜功能、EC细胞活性及中枢神经系统（CNS）的神经递质水平产生深远影响 7172。肠道微生物产生多种代谢产物，这些产物是介导菌群与宿主相互作用的关键分子 73。
肠道菌群代谢产物对胃黏膜屏障和EC细胞功能的调控：
短链脂肪酸（SCFAs）：肠道菌群通过发酵膳食纤维产生乙酸、丙酸和丁酸等SCFAs 74。这些SCFAs对肠道屏障功能的维护至关重要，它们能作为肠上皮细胞的主要能量来源，促进黏膜修复，并增强紧密连接蛋白的表达，从而减少“肠漏”（leaky gut）现象 75。丁酸（Butyrate）尤其被发现能影响血管内皮细胞的完整性，并能特异性地影响VE-cadherin的磷酸化 76。虽然这些研究主要集中在肠道，但肠道屏障功能的维护对于整个胃肠道的稳态都具有积极影响。SCFAs还可以与肠道内的G蛋白偶联受体（如GPR41、GPR43）结合，影响肠道激素的释放和肠道蠕动 77。此外，肠道菌群失调和由此产生的SCFA代谢产物变化被认为是导致阿尔茨海默病（AD）肠道屏障受损和神经炎症的关键因素之一 78。
神经活性物质：肠道菌群可以直接或间接产生多种神经递质和神经活性物质，如γ-氨基丁酸（GABA）、血清素（5-HT）、多巴胺（DA）、去甲肾上腺素（NE）和组胺等 7980。
- GABA：作为哺乳动物主要的抑制性神经递质，GABA不仅影响中枢神经系统，也作用于肠道。许多益生菌菌株，特别是乳酸杆菌属（Lactobacillus）和双歧杆菌属（Bifidobacterium），能够产生GABA 8182。微生物来源的GABA已被证明通过调节肠道黏蛋白和紧密连接蛋白来影响肠道完整性，并可能参与迷走神经信号的抑制 82。一项研究发现，发酵乳中富含GABA，能够调节小鼠肠道菌群和血清神经递质，显著增加血清l-谷氨酰胺、l-色氨酸和血清素水平，表明其在改善情绪和缓解压力方面的潜力 83。
- 5-HT（血清素）：90%的5-HT在肠道中产生，其中EC细胞是主要的合成和释放源。肠道菌群可以通过调节色氨酸代谢来影响5-HT的合成。例如，某些细菌可以增加肠道中游离色氨酸的利用，从而促进5-HT的生物合成 79。血清素的失衡与多种胃肠道疾病（如IBS）和情绪障碍（如抑郁、焦虑）密切相关。
肠道菌群影响脑内神经递质水平的路径：
肠道菌群通过多种途径与大脑进行双向交流，从而影响脑内的神经递质水平和情绪 7184：
- 迷走神经通路：迷走神经是连接肠道与大脑的主要通路之一，能够直接将肠道信号（包括微生物代谢产物、EC细胞释放的神经递质等）传递至中枢神经系统 727479。微生物代谢产物可以直接刺激迷走神经传入纤维，或通过激活肠道内的内分泌细胞间接调控神经活动。
- 循环系统通路：肠道菌群产生的代谢产物（如SCFAs、某些神经递质前体、胆汁酸、脂多糖LPS等）可以进入血液循环，并通过血脑屏障，直接影响大脑功能 8485。例如，LPS作为一种细菌内毒素，当肠道屏障受损时进入循环系统，可诱导全身炎症，进而影响中枢神经系统，导致神经炎症和情绪改变 75。
- 免疫系统通路：肠道菌群及其代谢产物与宿主免疫系统密切互动。菌群失调可引起慢性低度炎症反应，释放促炎细胞因子，这些细胞因子可以穿过血脑屏障，或通过迷走神经信号传递至大脑，影响神经递质的合成和释放，进而影响情绪和认知功能 72。
- 内分泌系统通路：肠道菌群可以影响宿主内分泌系统，例如通过调节HPA轴的活性，进而影响皮质醇等应激激素的水平，而这些激素又反过来影响神经递质的平衡。
总之，肠道菌群及其代谢产物在肠道黏膜屏障维护、EC细胞功能调控以及中枢神经递质平衡中发挥关键作用，从而构成了胃-情绪交互作用中不可或缺的分子与微生物学基础。通过靶向肠道菌群进行干预，例如使用益生菌、益生元或粪菌移植，有望为改善胃功能异常伴随的情绪障碍提供新的治疗策略 8687。
5. 基于胃-情绪关联的干预策略与临床应用
5.1 神经与心理干预技术
鉴于胃功能异常与情绪障碍之间的密切关联，基于肠脑轴理论的神经与心理干预技术为改善这类共病症状提供了新的途径。这些干预方法旨在通过调节神经通路、改变认知行为模式或利用传统医学手段来恢复胃肠功能和情绪稳态。
迷走神经刺激（Vagus Nerve Stimulation, VNS） 是一种通过电刺激迷走神经来调节中枢神经系统活性的技术。迷走神经是肠脑轴中关键的双向通讯通路，其传入纤维能将胃肠道信息传递至大脑，而传出纤维则调控胃肠道功能 88。因此，通过刺激迷走神经，可以直接影响大脑中与情绪、疼痛和食欲相关的脑区，同时也能调节胃肠道的运动和分泌。VNS最初被批准用于治疗难治性癫痫和抑郁症，但其在功能性胃肠道疾病中的应用也日益受到关注。通过调节迷走神经的活性，VNS可能有助于改善胃动力异常（如胃排空延迟）、减轻内脏高敏感性，并缓解与胃肠道疾病相关的焦虑和抑郁症状。例如，对迷走神经功能的调节有助于改善食欲、情绪障碍和炎症反应 88。
认知行为疗法（Cognitive Behavioral Therapy, CBT） 是一种已被广泛证实有效的心理干预技术，旨在帮助患者识别并改变导致情绪困扰和功能障碍的非适应性思维模式和行为。CBT在治疗功能性消化不良（FD）和肠易激综合征（IBS）等胃肠道疾病中表现出显著疗效。多项系统评价和荟萃分析表明，CBT能够显著减轻功能性消化不良患者的胃肠道症状以及伴随的抑郁和焦虑症状 89909192。对于胃十二指肠的肠脑互动障碍（DGBIs），CBT类干预措施能有效改善胃肠道症状和心理结果，其效果在中等到大型效应量之间，且能维持长达一年 90。CBT通过教授患者应对策略（如放松训练、压力管理、症状再解读）来打破胃肠症状与负面情绪之间的恶性循环。除了传统的CBT，基于正念的认知疗法（MBCT）也显示出治疗功能性消化不良的潜力，一项小型随机试验发现MBCT组患者的消化不良症状（SF-NDI）和压力、焦虑、抑郁评分（DASS-21）有显著改善趋势 93。
针灸 作为一种传统中医治疗方法，在调节胃肠功能和改善情绪方面也展现出独特的优势。特定穴位（如足三里ST36）的针刺刺激可以激活大脑中与疼痛、情绪和内脏感觉处理相关的区域。功能磁共振成像（fMRI）研究显示，针刺足三里（ST36）可以激活包括扣带回、前额叶皮层等在内的多个脑区，这些区域与情绪调节、认知控制和内脏感知密切相关。这种对中枢神经系统的调节作用有助于改善胃动力障碍、减轻疼痛和焦虑。例如，一项研究表明针刺对胃肠道肿瘤患者的化疗引起的恶心呕吐有显著疗效，并且可以改善患者的生活质量和情绪状态。虽然针灸的神经机制复杂，但其通过调节神经递质释放、改善局部血流以及影响肠脑轴功能，在协调胃-情绪交互方面发挥着重要作用。
5.2 药物与营养干预方案
在胃-情绪交互作用的背景下，药物和营养干预方案在改善胃功能异常及伴随情绪障碍方面扮演着重要角色。这些策略不仅针对胃肠道症状，也兼顾情绪调节，旨在实现更全面的治疗效果。
药物干预
- 5-HT受体调节剂：5-羟色胺（5-HT）在胃肠道功能和情绪调节中均发挥关键作用 94。因此，靶向5-HT受体的药物被广泛应用于胃肠道和精神疾病的治疗。例如，一些药物通过调节肠道5-HT的活性来改善肠易激综合征（IBS）的症状，如5-HT3受体拮抗剂可用于缓解IBS-D（腹泻型IBS）患者的腹泻和腹痛，而5-HT4受体激动剂则可用于治疗IBS-C（便秘型IBS）。这些药物通过影响肠道蠕动和内脏敏感性，间接改善患者的舒适度，进而对情绪产生积极影响。
- SSRI类药物：选择性5-羟色胺再摄取抑制剂（SSRIs）是目前最常用的一线抗抑郁药物，通过增加突触间隙中5-HT的浓度发挥作用。SSRIs对肠脑轴具有双重影响：一方面，它们通过改善中枢神经系统的5-HT信号传导来缓解抑郁和焦虑症状；另一方面，由于胃肠道是5-HT的重要来源和作用部位，SSRIs也会对胃肠道功能产生直接影响。肠道上皮的5-HT转运体（SERT）是SSRIs的作用靶点之一，其功能受损或改变可能与胃肠道功能紊乱（DGBI）的发展有关 95。在治疗伴有情绪障碍的功能性胃肠病时，SSRIs常被使用。例如，在功能性消化不良患者中，三环类抗抑郁药（TCAs）和SSRIs被发现能够改善症状，尤其对于那些伴有疼痛或内脏高敏感的患者 96。
然而，SSRIs的胃肠道副作用不容忽视。常见的副作用包括恶心、呕吐、腹泻或便秘 97。一项对FDA不良事件报告系统（FAERS）数据的分析显示，五种SNRI（5-羟色胺和去甲肾上腺素再摄取抑制剂，作用机制类似SSRIs）药物的胃肠道不良事件发生率很高，其中便秘、口干、口腔感觉迟钝、恶心和呕吐是显著风险 98。此外，SSRIs还可能增加胃肠道和颅内出血的风险，特别是与抗凝剂或抗血小板药物（如华法林、氯吡格格雷、阿司匹林）联合使用时，风险会显著升高，这可能与SSRIs增加胃酸分泌和抑制血小板对5-HT的摄取有关 99100。有报道指出，一些H2受体拮抗剂（如雷尼替丁）与抑郁症状的出现有关 101，这提示在选择药物时需要全面评估其对胃肠道和精神状态的潜在影响。
营养干预方案
- 益生菌（Probiotics）：益生菌是活的微生物，当摄入足够量时，对宿主健康有益。它们可以通过多种机制调节肠道菌群-胃-脑轴，从而改善胃肠道功能和情绪。益生菌能够：
- 调节肠道菌群组成：恢复肠道微生态平衡，抑制有害菌生长，促进有益菌增殖，从而减少肠道炎症，维护肠道屏障功能。
- 影响肠道代谢产物：例如，一些益生菌可以产生短链脂肪酸（SCFAs），这些SCFAs对肠上皮细胞的健康至关重要，并可以通过肠道神经系统和循环系统影响中枢神经系统功能。
- 调节神经递质前体和活性物质：某些益生菌菌株可以直接产生神经递质（如GABA）或其前体，影响肠道和大脑中的神经递质水平。例如，有研究发现特定的益生菌株能增加血清素前体色氨酸的水平。
- 改善胃黏膜修复：通过减少炎症和增强屏障功能，益生菌有助于胃黏膜的修复。
这些效应协同作用，有助于缓解胃肠道症状，并减轻相关的焦虑和抑郁情绪。
- ω-3脂肪酸：ω-3多不饱和脂肪酸（PUFA），特别是鱼油中的二十碳五烯酸（EPA）和二十二碳六烯酸（DHA），被认为具有强大的免疫调节和抗炎作用 102。炎症是许多胃肠道疾病和情绪障碍的共同病理基础。ω-3脂肪酸可以通过：
5.3 胃术后患者的情绪管理
胃切除术，特别是针对胃癌患者的全胃切除术，虽然是挽救生命的必要手段，但术后患者常常面临一系列复杂的生理和心理挑战，这些挑战对患者的情绪健康和生活质量产生深远影响。因此，对胃术后患者进行系统的情绪管理至关重要，需要整合生理、心理和社会的全面考量 103。
生理挑战与情绪关联
- 营养吸收障碍与营养不良：胃切除术后，胃的消化和吸收功能受到严重影响，导致多种营养素缺乏，如维生素B12、铁、钙和脂溶性维生素 104105。例如，全胃切除术后患者体重平均下降15%，且存在严重的脂肪吸收不良和身体脂肪缺乏 104。长期营养不良不仅影响身体健康，还可能导致疲劳、虚弱，进而诱发或加重抑郁和焦虑情绪。一些研究也指出，胃饥饿素（ghrelin）水平在全胃切除术后显著下降，远低于术前水平，而胃饥饿素在刺激食欲、改善情绪和抗炎方面具有重要作用，其缺乏可能加剧术后患者的厌食和情绪低落 106。
- 呼吸系统风险：胃切除术是内脏外科手术中要求较高的操作之一，术后并发症风险较高 107。呼吸系统并发症是胃切除术后常见且严重的并发症之一，可能导致患者出现呼吸困难、感染，甚至呼吸衰竭。这些生理上的不适和威胁会显著增加患者的恐惧、焦虑和无助感。
- 其他术后并发症：除了营养障碍和呼吸风险，胃切除术后还可能出现倾倒综合征、吻合口瘘、术后出血、感染、胰腺炎等并发症 103107。这些并发症的发生会延长住院时间，增加治疗负担，并严重影响患者的心理状态，导致焦虑、抑郁情绪的加重。
心理社会挑战与情绪健康
胃癌本身及胃切除术给患者带来巨大的心理应激。患者可能面临：
- 生存焦虑：对疾病复发、治疗效果及生存预后的担忧。
- 身体形象改变：特别是全胃切除术后，患者可能因进食习惯改变、体重骤降而产生身体形象困扰。
- 社会角色与生活质量下降：疾病和手术可能限制患者的社交活动和工作能力，导致社会隔离感和价值感降低。
- 创伤后应激障碍（PTSD）：胃癌患者，特别是经历过创伤性治疗过程的患者，PTSD的患病率较高，且常与抑郁症共病 103。
多学科联合干预模式
鉴于胃术后患者问题的复杂性，单一学科的治疗往往不足以应对，因此，多学科（Multi-Disciplinary Team, MDT）联合干预模式被认为是最佳实践 103108。MDT通常由外科医生、肿瘤科医生、营养师、心理医生/精神科医生、疼痛管理专家、康复师和社会工作者组成。
- 外科医生：负责手术本身和术后生理并发症的初步管理。
- 营养师：制定个性化的营养支持方案，包括口服营养补充剂（ONS）、肠内营养（EN）或肠外营养（PN），并指导患者进行饮食调整以适应术后消化功能 109110。有效的营养管理能够改善患者的体力状态，减轻身体不适，从而间接改善情绪。
- 心理医生/精神科医生：评估和管理患者的抑郁、焦虑、PTSD等情绪问题。提供认知行为疗法（CBT）、支持性心理治疗、放松训练等，帮助患者应对疾病和治疗带来的心理压力。
- 疼痛管理专家：有效控制术后疼痛，减少疼痛对情绪的负面影响。
- 康复师：指导患者进行适当的身体锻炼，促进身体功能恢复，提高生活自理能力。
社会支持与生活方式调整
除了专业的医疗和心理干预，社会支持和生活方式调整在改善胃术后患者生存质量方面也发挥着关键作用：
- 家庭和社会支持：鼓励家人和朋友提供情感支持，帮助患者重塑社会连接。参与支持小组，与其他有相似经历的患者交流，可以减轻孤独感，提供实用建议和情感慰藉。
- 生活方式调整：
通过多学科团队的紧密合作，辅以充分的社会支持和积极的生活方式调整，胃切除术后患者的生理和心理困境可以得到有效缓解，从而显著提升其长期生存质量。
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参考文献
1The Molecular Gut-Brain Axis in Early Brain Development.PubMed
Fahim Muhammad, Bufang Fan, Ruoxi Wang, et al.
Int J Mol Sci. 2022 Dec 6;23(23):15389. doi: 10.3390/ijms232315389.
Millions of nerves, immune factors, and hormones in the circulatory system connect the gut and the brain. In bidirectional communication, the gut microbiota play a crucial role in the gut-brain axis (GBA), wherein microbial metabolites of the gut microbiota regulate intestinal homeostasis, thereby influencing brain activity. Dynamic changes are observed in gut microbiota as well as during brain development. Altering the gut microbiota could serve as a therapeutic target for treating abnormalities associated with brain development. Neurophysiological development and immune regulatory disorders are affected by changes that occur in gut microbiota composition and function. The molecular aspects relevant to the GBA could help develop targeted therapies for neurodevelopmental diseases. Herein, we review the findings of recent studies on the role of the GBA in its underlying molecular mechanisms in the early stages of brain development. Furthermore, we discuss the bidirectional regulation of gut microbiota from mother to infant and the potential signaling pathways and roles of posttranscriptional modifications in brain functions. Our review summarizes the role of molecular GBA in early brain development and related disorders, providing cues for novel therapeutic targets.
2Bidirectional 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."
3Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders.PubMed
Sigrid Breit, Aleksandra Kupferberg, Gerhard Rogler, et al.
Front Psychiatry. 2018 Mar 13;9:44. doi: 10.3389/fpsyt.2018.00044. eCollection 2018.
The vagus nerve represents the main component of the parasympathetic nervous system, which oversees a vast array of crucial bodily functions, including control of mood, immune response, digestion, and heart rate. It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain afferent fibers. In this review article, we discuss various functions of the vagus nerve which make it an attractive target in treating psychiatric and gastrointestinal disorders. There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders. In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms.
4Microbiota-gut-brain axis: relationships among the vagus nerve, gut microbiota, obesity, and diabetes.PubMed
Susanna Longo, Stefano Rizza, Massimo Federici
Acta Diabetol. 2023 Aug;60(8):1007-1017. doi: 10.1007/s00592-023-02088-x. Epub 2023 Apr 14.
AIMS: The purpose of this review is to explore the interconnected pathways of the microbiota-gut-brain axis (MGBA), focusing on the roles of the vagus nerve and glucagon like peptide-1 in appetite control, and in the development of obesity and diabetes. METHODS: Type 2 diabetes mellitus (T2DM) and obesity are metabolic disorders whose prevalence has significantly increased in recent decades and is expected to increase every year, to pandemic proportions. These two pathologies often coexist and have substantial public health implications. The term "diabesity" defines the pathophysiological connection between overweight and T2DM. The gut microbiota affects many aspects of the host. Beyond the regulation of intestinal functions and the activation of immune responses, the gut microbiota plays a role in central nervous system functions (i.e., mood, and psychiatric conditions associated with stress and memory) and is a central regulator of metabolism and appetite. RESULTS: The MGBA involves pathways such as the autonomic and enteric nervous systems, the hypothalamic- pituitary-adrenal axis, the immune system, enteroendocrine cells, and microbial metabolites. Notably, the vagus nerve plays an essential role in eating behavior by modulating appetite and learning nutritional preferences. CONCLUSIONS: Because of its enteroendocrine cell-mediated interaction with the gut microbiota, the vagus nerve may provide a potential pathway through which gut microorganisms influence host feeding behavior and metabolic control of physiological and pathological conditions.
5The gut-brain axis and cognitive control: A role for the vagus nerve.PubMed
Léa Décarie-Spain, Anna M R Hayes, Logan Tierno Lauer, et al.
Semin Cell Dev Biol. 2024 Mar 15;156:201-209. doi: 10.1016/j.semcdb.2023.02.004. Epub 2023 Feb 16.
Survival requires the integration of external information and interoceptive cues to effectively guide advantageous behaviors, particularly foraging and other behaviors that promote energy acquisition and consumption. The vagus nerve acts as a critical relay between the abdominal viscera and the brain to convey metabolic signals. This review synthesizes recent findings from rodent models and humans revealing the impact of vagus nerve signaling from the gut on the control of higher-order neurocognitive domains, including anxiety, depression, reward motivation, and learning and memory. We propose a framework where meal consumption engages gastrointestinal tract-originating vagal afferent signaling that functions to alleviate anxiety and depressive-like states, while also promoting motivational and memory functions. These concurrent processes serve to favor the encoding of meal-relevant information into memory storage, thus facilitating future foraging behaviors. Modulation of these neurocognitive domains by vagal tone is also discussed in the context of pathological conditions, including the use of transcutaneous vagus nerve stimulation for the treatment of anxiety disorders, major depressive disorder, and dementia-associated memory impairments. Collectively, these findings highlight the contributions of gastrointestinal vagus nerve signaling to the regulation of neurocognitive processes that shape various adaptive behavioral responses.
6A gut-brain neural circuit for nutrient sensory transduction.PubMed
Melanie Maya Kaelberer, Kelly L Buchanan, Marguerita E Klein, et al.
Science. 2018 Sep 21;361(6408). doi: 10.1126/science.aat5236.
The brain is thought to sense gut stimuli only via the passive release of hormones. This is because no connection has been described between the vagus and the putative gut epithelial sensor cell-the enteroendocrine cell. However, these electrically excitable cells contain several features of epithelial transducers. Using a mouse model, we found that enteroendocrine cells synapse with vagal neurons to transduce gut luminal signals in milliseconds by using glutamate as a neurotransmitter. These synaptically connected enteroendocrine cells are referred to henceforth as neuropod cells. The neuroepithelial circuit they form connects the intestinal lumen to the brainstem in one synapse, opening a physical conduit for the brain to sense gut stimuli with the temporal precision and topographical resolution of a synapse.
7A vagus nerve dominant tetra-synaptic ascending pathway for gastric pain processing.PubMed
Fu-Chao Zhang, Rui-Xia Weng, Di Li, et al.
Nat Commun. 2024 Nov 13;15(1):9824. doi: 10.1038/s41467-024-54056-w.
Gastric pain has limited treatment options and the mechanisms within the central circuitry remain largely unclear. This study investigates the central circuitry in gastric pain induced by noxious gastric distension (GD) in mice. Here, we identified that the nucleus tractus solitarius (NTS) serves as the first-level center of gastric pain, primarily via the vagus nerve. The prelimbic cortex (PL) is engaged in the perception of gastric pain. The lateral parabrachial nucleus (LPB) and the paraventricular thalamic nucleus (PVT) are crucial regions for synaptic transmission from the NTS to the PL. The glutamatergic tetra-synaptic NTS-LPB-PVT-PL circuitry is necessary and sufficient for the processing of gastric pain. Overall, our finding reveals a glutamatergic tetra-synaptic NTS-LPB-PVT-PL circuitry that transmits gastric nociceptive signaling by the vagus nerve in mice. It provides an insight into the gastric pain ascending pathway and offers potential therapeutic targets for relieving visceral pain.
8The stomach-brain axis.PubMed
Gerald Holtmann, Nicholas J Talley
Best Pract Res Clin Gastroenterol. 2014 Dec;28(6):967-79. doi: 10.1016/j.bpg.2014.10.001. Epub 2014 Oct 8.
The stomach has distinct functions in relation to the ingestion and handling of solids and liquids. These functions include storage of the food before it is gradually emptied into the duodenum, mechanical crushing of larger food particles to increase the surface area, secretion of an acidic enzyme rich gastric juice and mixing the ingested food with the gastric juice. In addition, the stomach 'senses' the composition of the gastric content and this information is passed via the vagal nerve to the lateral hypothalamus and the limbic system, most likely as palatability signals that influence eating behaviour. Other sensory qualities related to the stimulation of gastric tension receptors are satiety and fullness. Receptors that respond to macronutrient content or gastric wall tension influence appetite and meal related hormone responses. The ingestion of food - in contrast to an infusion of nutrients into the stomach - has distinct effects on the activation of specific brain regions. Brain areas such as thalamus, amygdala, putamen and praecuneus are activated by the ingestion of food. Gastric nutrient infusion evokes greater activation in the hippocampus and anterior cingulate. The brain integrates these interrelated neural and hormonal signals arising from the stomach as well as visual, olfactory and anticipatory stimuli that ultimately influence eating and other behavioural patterns. Furthermore, there is now good evidence from experimental studies that gastric afferents influence mood, and animal studies point towards the possibility that gastric dysfunction may be a risk factor for mood disorders such as anxiety and depression. The stomach is also not only colonised by Helicobacter pylori but a large array of bacteria. While there is sufficient evidence to suggest that H. pylori may alter caloric intake and mood, the role of other gastric microbiome for the brain function is unknown. To address this appropriate targeted gastric microbiome studies would be required instead of widely utilised opportunistic stool microbiome studies. In summary, it is now well established that there are important links between the brain and the stomach that have significant effects on gastric function. However, the stomach also influences the brain. Disturbances in the crosstalk between the stomach and the brain may manifest as functional GI disorders while disturbances in the stomach-brain communication may also result in an altered regulation of satiety and as a consequence may affect eating behaviour and mood. These observations may enable the identification of novel therapies targeted at the gastroduodenum that positively alter brain function and treat or prevent conditions such as obesity or functional gastrointestinal disorders.
9The psyche and gastric functions.PubMed
Gerardo Nardone, Debora Compare
Dig Dis. 2014;32(3):206-12. doi: 10.1159/000357851. Epub 2014 Apr 10.
Although the idea that gastric problems are in some way related to mental activity dates back to the beginning of the last century, until now it has received scant attention by physiologists, general practitioners and gastroenterologists. The major breakthrough in understanding the interactions between the central nervous system and the gut was the discovery of the enteric nervous system (ENS) in the 19th century. ENS (also called 'little brain') plays a crucial role in the regulation of the physiological gut functions. Furthermore, the identification of corticotropin-releasing factor (CRF) and the development of specific CRF receptor antagonists have permitted to characterize the neurochemical basis of the stress response. The neurobiological response to stress in mammals involves three key mechanisms: (1) stress is perceived and processed by higher brain centers; (2) the brain mounts a neuroendocrine response by way of the hypothalamic-pituitary-adrenal axis (HPA) and the autonomic nervous system (ANS), and (3) the brain triggers feedback mechanisms by HPA and ANS stimulation to restore homeostasis. Various stressors such as anger, fear, painful stimuli, as well as life or social learning experiences affect both the individual's physiologic and gastric function, revealing a two-way interaction between brain and stomach. There is overwhelming experimental and clinical evidence that stress influences gastric function, thereby outlining the pathogenesis of gastric diseases such as functional dyspepsia, gastroesophageal reflux disease and peptic ulcer disease. A better understanding of the role of pathological stressors in the modulation of disease activity may have important pathogenetic and therapeutic implications.
10Neurobiologic and psychobiologic mechanisms in gastric function and ulceration.PubMed
H Weiner, D Novin, C V Grijalva, et al.
West J Med. 1985 Aug;143(2):207-22.
The initiation and termination of feeding behavior are not fully understood. The stomach has been implicated as one source of signals regulating food intake. The sight and smell of food are potent stimuli to gastric acid secretion and contraction. The mouth, upper gastrointestinal tract and liver contain receptors regulating food intake; afferent information passes into the brain stem and into the brain areas. Lateral hypothalamic lesions abolish feeding, raise the body temperature and basal gastric acid secretion and produce gastric erosions. Vagotomy and administering propantheline bromide abolish the increased acid secretion after such lesions; they also alter the mucosal barrier permitting diffusion of protons into mucosal cells. Several of the neuropeptides via the central nervous system stimulate or inhibit gastric acid secretion through modulation of the autonomic nervous system. Most animal models of gastric erosions are associated with a reduced body temperature. Unknown is whether or not this association is the result of increased levels of thyrotropin-releasing hormone-a potent stimulus to gastric acid secretion and erosion formation when injected intracisternally.
11Reliability and validity of brain-gastric phase synchronization.PubMed
Gidon Levakov, Shira Ganor, Galia Avidan
Hum Brain Mapp. 2023 Oct 1;44(14):4956-4966. doi: 10.1002/hbm.26436. Epub 2023 Aug 1.
Recent studies have reported that various brain regions, mainly sensory, unimodal regions, display phase synchronization with the stomach's slow (0.05 Hz) myoelectrical rhythm. These gastric-brain interactions have broad implications, from feeding behavior to functional gastrointestinal disorders. However, in contrast to other interoceptive signals (e.g., heart rate) and their relation to the brain, little is known about the reliability of these gastric-brain interactions, their robustness to artifacts such as motion, and whether they can be generalized to new samples. Here we examined these aspects in 43 subjects that had undergone multiple runs of concurrent electrogastrography (EGG), brain fMRI, and pulse oximetry. We also repeated all analyses in an open dataset of a highly sampled individual. We found a set of brain regions that were coupled with the EGG signal after controlling for non-grey matter (GM) signals, head motion, and cardiac artifacts. These regions exhibited significant overlap with previous work. However, we also showed that prior to confound regression, the spatial extent of the gastric network was largely overestimated. Finally, we found substantial test-retest reliability in both the brain and the gastric signals when estimated alone, but not for measures of gastric-brain synchrony. Together, these results provide methodological scaffolding for future research into brain-stomach interactions and for a better understanding of the role of the gastric network.
12Underneath the Gut-Brain Axis in IBD-Evidence of the Non-Obvious.PubMed
Lidiya V Boldyreva, Anna A Evtushenko, Maria N Lvova, et al.
Int J Mol Sci. 2024 Nov 12;25(22):12125. doi: 10.3390/ijms252212125.
The gut-brain axis (GBA) plays a pivotal role in human health and wellness by orchestrating complex bidirectional regulation and influencing numerous critical processes within the body. Over the past decade, research has increasingly focused on the GBA in the context of inflammatory bowel disease (IBD). Beyond its well-documented effects on the GBA-enteric nervous system and vagus nerve dysregulation, and gut microbiota misbalance-IBD also leads to impairments in the metabolic and cellular functions: metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton dysregulation. These systemic effects are currently underexplored in relation to the GBA; however, they are crucial for the nervous system cells' functioning. This review summarizes the studies on the particular mechanisms of metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton impairments in IBD. Understanding the involvement of these processes in the GBA may help find new therapeutic targets and develop systemic approaches to improve the quality of life in IBD patients.
13Enterochromaffin cell hyperplasia in the gut: Factors, mechanism and therapeutic clues.PubMed
Hong-Yan Qin, Hoi Leong Xavier Wong, Kai-Hong Zang, et al.
Life Sci. 2019 Dec 15;239:116886. doi: 10.1016/j.lfs.2019.116886. Epub 2019 Oct 31.
Enterochromaffin (EC) cell is the main cell type that responsible for 5-hydroxytryptamine (5-HT) synthesis, storage and release of the gut. Intestinal 5-HT play a key role in visceral sensation, intestinal motility and permeability, EC cell hyperplasia and increased 5-HT bioavailability in the gut have been found to be involved in the symptoms generation of irritable bowel syndrome and inflammatory bowel disease. EC cells originate from intestinal stem cells, the interaction between proliferation and differentiation signals on intestinal stem cells enable EC cell number to be regulated in a normal level. This review focuses on the impact factors, pathogenesis mechanisms, and therapeutic clues for intestinal EC cells hyperplasia, and showed that EC cell hyperplasia was observed under the condition of physiological stress, intestinal infection or intestinal inflammation, the disordered proliferation and/or differentiation of intestinal stem cells as well as their progenitor cells all contribute to the pathogenesis of intestinal EC cell hyperplasia. The altered intestinal niche, i.e. increased corticotrophin releasing factor (CRF) signal, elevated nerve growth factor (NGF) signal, and Th2-dominant cytokines production, has been found to have close correlation with intestinal EC cell hyperplasia. Currently, CRF receptor antagonist, nuclear factor-κB inhibitor, and NGF receptor neutralizing antibody have been proved useful to attenuate intestinal EC cell hyperplasia, which may provide a promising clue for the therapeutic strategy in EC cell hyperplasia related diseases.
14Gut 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.
15Microbiota-neuroepithelial signalling across the gut-brain axis.PubMed
Takahiro E Ohara, Elaine Y Hsiao
Nat Rev Microbiol. 2025 Jun;23(6):371-384. doi: 10.1038/s41579-024-01136-9. Epub 2025 Jan 2.
Research over the past two decades has established a remarkable ability of the gut microbiota to modulate brain activity and behaviour. Conversely, signals from the brain can influence the composition and function of the gut microbiota. This bidirectional communication across the gut microbiota-brain axis, involving multiple biochemical and cellular mediators, is recognized as a major brain-body network that integrates cues from the environment and the body's internal state. Central to this network is the gut sensory system, formed by intimate connections between chemosensory epithelial cells and sensory nerve fibres, that conveys interoceptive signals to the central nervous system. In this Review, we provide a broad overview of the pathways that connect the gut and the brain, and explore the complex dialogue between microorganisms and neurons at this emerging intestinal neuroepithelial interface. We highlight relevant microbial factors, endocrine cells and neural mechanisms that govern gut microbiota-brain interactions and their implications for gastrointestinal and neuropsychiatric health.
16Mechanisms by which cancer chemotherapeutic drugs induce emesis.PubMed
L X Cubeddu
Semin Oncol. 1992 Dec;19(6 Suppl 15):2-13.
Because the area postrema seems essential for chemotherapy-induced vomiting, both circulating and/or neurally mediated stimuli in this area could trigger the emetic response. In our laboratories results of cross-circulation and direct intracerebroventricular infusion experiments in dogs do not support a role for circulating substances. The large increases in serum vasopressin induced by cisplatin were not blocked by inhibitors of the angiotensin-converting enzyme. In the ferret inhibition of serotonin synthesis with p-chloro-phenylalanine, administration of selective antagonists of 5-hydroxy-tryptamine3 (5-HT3) receptors, or visceral deafferentation inhibited the emetic response evoked by cisplatin or high-dose cyclophosphamide. The results suggest that serotonin plays an important role and that peripheral neural mechanisms are involved in the emetic response. The strong antiemetic efficacy of selective 5-HT3 antagonists also has been confirmed in humans. In cancer patients high-dose cisplatin increased the plasma and urinary levels of 5-hydroxy-indoleacetic acid (5-HIAA), but did not affect platelet and free plasma serotonin. The changes in 5-HIAA levels paralleled the onset and development of vomiting. No evidence of serotonin depletion has been obtained after high-dose cisplatin. Dacarbazine, another strongly emetogenic agent, increased urinary 5-HIAA; however, only small increases in 5-HIAA were produced with low-dose cisplatin or cyclophosphamide-containing regimens. Thus, emetogenicity appears to be directly related to the ability of the cytotoxic agent to release serotonin. In humans, antiemetics such as ondansetron, metoclopramide, and dexamethasone did not effect high-dose cisplatin-induced increases in serotonin metabolism. Therefore, these antiemetics seem not to affect the amount of serotonin released. The mechanism by which chemotherapeutic drugs induce serotonin release is unknown; however, release may occur by direct cytotoxicity on the gastrointestinal mucosa, including the enterochromaffin cells. Delayed emesis appears to be mediated by 5-HT3-independent mechanisms. It is proposed that emesis that develops despite high-dose ondansetron (residual emesis) should be considered delayed emesis. Residual and delayed episodes of emesis have similar time courses, are characterized by very mild emetic episodes and poor response to 5-HT3 antagonists, and are not associated with increases in serotonin metabolism.
17Molecular mediators formed in the small intestine in response to cholera toxin.PubMed
J W Peterson, J Cantu, S Duncan, et al.
J Diarrhoeal Dis Res. 1993 Dec;11(4):227-34.
The molecular mechanism of experimental cholera, leading to increased water and electrolyte secretion, was evaluated with the rabbit intestinal loop model. The levels of cyclic adenosine monophosphate (cAMP), prostaglandin E2 (PGE2), and 5-hydroxytryptamine (5-HT) were measured in mucosal tissue or luminal fluids from intestinal segments exposed to cholera toxin (CT). Each mediator increased in a dose-dependent manner coinciding with the amount of fluid accumulating in the CT-treated loops within the 16 h observation period. Interestingly, a substantial amount of the cAMP in the CT loops was released into the intestinal lumen, along with the fluid. Fluid accumulation was evoked by instillation of PGE2 and CT into the intestinal segments, but not by 5-HT. Large doses of dibutyryl cAMP at 50 mg/ml, but not at 25 mg/ml, also evoked fluid accumulation when injected into the intestine. Further, CT evoked the release of 5-HT from the mucosa, although the high doses of cAMP caused a massive release of 5-HT. PGE2 injection was without effect on 5-HT release. Although CT increased the amount of PGE2 into the luminal fluid, no effect on PGE2 levels was observed by injecting any dose of dibutyryl cAMP or 5-HT into the intestinal lumen. Our interpretation of these data is that CT stimulates the independent synthesis and release of both cAMP and PGE2. The cAMP appears to cause the release of 5-HT from the enterochromaffin cells. Since dibutyryl cAMP did not evoke a PGE2 response, it was concluded that cAMP could elicit secretion of fluid without the participation of PGE2; however, the cAMP doses were not physiological.(ABSTRACT TRUNCATED AT 250 WORDS)
18Sex as a biological variable in irritable bowel syndrome.PubMed
Michael Camilleri
Neurogastroenterol Motil. 2020 Jul;32(7):e13802. doi: 10.1111/nmo.13802. Epub 2020 Jan 13.
BACKGROUND: The pathophysiology and mechanisms of irritable bowel syndrome (IBS) involve both central and peripheral mechanisms that result in altered perception, as well as changes in bowel functions. These dysfunctions are associated with motor, sensory, immune, barrier, and intraluminal perturbations, including the microbiota, and their products and endogenous molecules with bioactive properties. There is evidence that these mechanisms are altered in both females and males. However, there is also increasing evidence that sex is a biological variable that impacts a number of aspects of the mechanisms, epidemiology, and manifestations of IBS. PURPOSE: The objective of this article is to review the evidence of the differences among genders of the following factors in IBS: the brain-gut axis and sex hormones, epidemiology, diagnostic criteria and prognosis, pain perception, colonic transit, abdominal distension, overlap with urogynecological conditions, psychologic issues, anorexia, fibromyalgia, serotonin, and responsiveness to treatment of IBS. It is important to consider the variations attributable to sex in order to enhance the management of patients with IBS and the research of mechanisms involved in IBS.
19Sex hormones in the modulation of irritable bowel syndrome.PubMed
Agata Mulak, Yvette Taché, Muriel Larauche
World J Gastroenterol. 2014 Mar 14;20(10):2433-48. doi: 10.3748/wjg.v20.i10.2433.
Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of "microgenderome" related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.
20Gut-brain axis serotonergic responses to acute stress exposure are microbiome-dependent.PubMed
Joshua M Lyte, Cassandra E Gheorghe, Michael S Goodson, et al.
Neurogastroenterol Motil. 2020 Nov;32(11):e13881. doi: 10.1111/nmo.13881. Epub 2020 May 11.
BACKGROUND: Understanding the mechanisms underpinning the response to acute stress is critical for determining how this can be modulated in both health and disease and across sexes. Stress can markedly alter the microbiome and gut-brain axis signaling with the serotonergic system being particularly sensitive to acute stress. As the impact of acute stress on regional serotonergic dynamics in the gut-brain axis and the contribution of the microbiome to this are poorly appreciated, we used microbiota-deficient mice to assess whether the serotonergic response to acute stress exposure is microbiome dependent. METHODS: Adult male and female conventional, germ-free, and colonized germ-free mice underwent a single acute stressor and samples were harvested immediately or 45 minutes following stress. Serotonin and related metabolites and serotonergic gene expression were determined. KEY RESULTS: Our data clearly show the microbiota influenced gastrointestinal serotonergic response to acute stress in a sex- and region-dependent manner. Male-specific poststress increases in colonic serotonin were absent in germ-free mice but normalized following colonization. mRNA serotonergic gene expression was differentially expressed in colon and ileum of germ-free mice on a sex-dependent basis. Within the frontal cortex, absence of the microbiome altered basal serotonin, its main metabolite 5-hydroxyindoleacetic acid, and prevented stress-induced increases in serotonin turnover. CONCLUSIONS AND INFERENCES: The gut microbiome influences the set points of the brain and gastrointestinal serotonergic systems and affected their response to acute stress in a sex- and region-dependent manner.
21Maternal Tryptophan Supplementation Alters Offspring Gut-Brain Axis and Behavior in a Sex-Specific Manner.PubMed
Maria Carolina Fortunato, João Neves, Mariana Lapo Pais, et al.
J Neurochem. 2025 Jul;169(7):e70161. doi: 10.1111/jnc.70161.
The maternal diet is a key determinant of offspring neurodevelopment, influencing gut microbiota composition and the gut-brain axis. These interactions are critical in shaping sex-specific vulnerabilities to neuropsychiatric disorders. Tryptophan, an essential amino acid and precursor to serotonin, plays a pivotal role in neurodevelopment and immune function. However, the impact of maternal tryptophan supplementation on healthy offspring's neurochemical and behavioral outcomes remains unclear. This study investigated the effects of a tryptophan-enriched maternal diet on offspring gut microbiota, metabolism, neurochemical pathways, and behavior. We analyzed microbial composition, metabolic activity, brain, and plasma levels of tryptophan and serotonin, and behavioral outcomes in male and female mice offspring. Maternal tryptophan supplementation led to sex-specific changes. Female offspring exhibited disrupted microbiota diversity, reduced brain tryptophan and serotonin levels, and heightened anxiety-like behaviors. In contrast, male offspring displayed increased metabolic activity, elevated brain tryptophan levels, and repetitive behaviors. These findings suggest that maternal tryptophan supplementation influences offspring neurodevelopment and behavior by modulating gut-brain axis components in a sex-dependent manner. This work underscores the importance of further research into prenatal dietary interventions targeting gut microbiota and neurochemical pathways to support healthy neurodevelopment and potentially inform sex-specific preventive strategies. These findings contribute to a growing understanding of how maternal nutrition influences offspring neurodevelopment and may guide the development of preventive strategies to improve long-term mental health outcomes..
22Pathophysiology of Gastroesophageal Reflux Disease.PubMed
Jan Tack, John E Pandolfino
Gastroenterology. 2018 Jan;154(2):277-288. doi: 10.1053/j.gastro.2017.09.047. Epub 2017 Oct 14.
The pathogenesis of gastroesophageal reflux disease (GERD) is complex and involves changes in reflux exposure, epithelial resistance, and visceral sensitivity. The gastric refluxate is a noxious material that injures the esophagus and elicits symptoms. Esophageal exposure to gastric refluxate is the primary determinant of disease severity. This exposure arises via compromise of the anti-reflux barrier and reduced ability of the esophagus to clear and buffer the refluxate, leading to reflux disease. However, complications and symptoms also occur in the context of normal reflux burden, when there is either poor epithelial resistance or increased visceral sensitivity. Reflux therefore develops via alterations in the balance of aggressive and defensive forces.
23Overview of pathophysiological features of GERD.PubMed
Paolo Usai Satta, Francesco Oppia, Francesco Cabras
Minerva Gastroenterol Dietol. 2017 Sep;63(3):184-197. doi: 10.23736/S1121-421X.17.02390-X. Epub 2017 Mar 1.
Gastroesophageal reflux disease (GERD) is a very prevalent condition and has a high impact on the quality of life. Nevertheless, pathophysiology is complex and multi-factorial. Several mechanisms have been proposed: decreased salivation, decreased lower esophageal sphincter pressure resting tone, presence of hiatal hernia, increased number of transient lower esophageal sphincter relaxations, increased acid, and pepsin secretion, duodeno-gastro-esophageal reflux of bile acids and trypsin. Other factors contributing to the pathophysiology of GERD include poor esophageal clearance, delayed gastric emptying and impaired mucosal defensive factors. Esophageal mucosa integrity is impaired both in patients with erosive esophagitis also in regions macroscopically normal and in NERD patients. Patients with functional heartburn have instead a normal mucosal integrity. The mechanisms underlying extra-esophageal GERD are instead more controversial. Reflux symptoms could be caused by esophageal hypersensitivity as a result of visceral neural pathway dysfunction. Multiple mechanisms influence the perception of GERD symptoms, such as the acidity of the refluxate, its proximal extent, the presence of gas in the refluxate, duodeno-gastro-esophageal reflux, mucosal integrity, and peripheral and central sensitization. Furthermore several risk factors can influence the onset of GERD and its complications such as life style, obesity, genetics, pregnancy, and stress. In particular obesity is associated with complications related to longstanding reflux such as erosive esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Understanding the pathophysiology of gastro-esophageal reflux is important for future targets for therapy. Further research is necessary to improve the current knowledge of the contributing factors leading to GERD.
24The effects of honey solution on postoperative stress, gastric motility, and patient comfort: a randomized controlled trial.PubMed
Janja Tarčuković, Lucia Klarica, Mario Dugonjić, et al.
Croat Med J. 2025 Jul 5;66(3):204-212. doi: 10.3325/cmj.2025.66.204.
AIM: To compare the effects of an in-house prepared honey solution (HS) and a commercial carbohydrate beverage (CCB) on postoperative stress response, gastric motility, and self-reported comfort in patients undergoing laparoscopic cholecystectomy. METHODS: This randomized controlled trial enrolled 55 adult patients (the American Society of Anesthesiologists physical status I-II) undergoing laparoscopic cholecystectomy at the University Hospital Center Rijeka from January 1, 2022, to December 31, 2022. Participants were randomly assigned to receive either HS (n=20), prepared from diluted chestnut honey, or CCB (n=35). Both solutions were administered in the volumes of 800 mL the evening before surgery and 400 mL two hours before anesthesia. Stress response and inflammation were assessed by measuring cortisol and interleukin 6 levels at six standardized time points. Gastric motility was evaluated with a paracetamol absorption test, and patient-reported outcomes were recorded postoperatively using a visual analogue scale. RESULTS: The HS group exhibited higher cortisol and interleukin 6 levels at multiple perioperative time points compared with the CCB group (P<0.05). However, they had significantly improved gastric motility, with higher paracetamol concentrations 15 to 180 minutes post-ingestion (P=0.028-0.001). Additionally, HS group reported reduced thirst, nausea, and pain, but had lower appetite and well-being scores. CONCLUSION: While HS represents a potential natural and cost-effective alternative to CCB, further studies are needed to determine its role within preoperative nutrition strategies for enhanced recovery after surgery.
25United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia.PubMed
Lucas Wauters, Ram Dickman, Vasile Drug, et al.
United European Gastroenterol J. 2021 Apr;9(3):307-331. doi: 10.1002/ueg2.12061.
BACKGROUND: Functional dyspepsia (FD) is one of the most common conditions in clinical practice. In spite of its prevalence, FD is associated with major uncertainties in terms of its definition, underlying pathophysiology, diagnosis, treatment, and prognosis. METHODS: A Delphi consensus was initiated with 41 experts from 22 European countries who conducted a literature summary and voting process on 87 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus (defined as >80% agreement) was reached for 36 statements. RESULTS: The panel agreed with the definition in terms of its cardinal symptoms (early satiation, postprandial fullness, epigastric pain, and epigastric burning), its subdivision into epigastric pain syndrome and postprandial distress syndrome, and the presence of accessory symptoms (upper abdominal bloating, nausea, belching), and overlapping conditions. Also, well accepted are the female predominance of FD, its impact on quality of life and health costs, and acute gastrointestinal infections, and anxiety as risk factors. In terms of pathophysiological mechanisms, the consensus supports a role for impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention, Helicobacter pylori infection, and altered central processing of signals from the gastroduodenal region. There is consensus that endoscopy is mandatory for establishing a firm diagnosis of FD, but that in primary care, patients without alarm symptoms or risk factors can be managed without endoscopy. There is consensus that H. pylori status should be determined in every patient with dyspeptic symptoms and H. pylori positive patients should receive eradication therapy. Also, proton pump inhibitor therapy is considered an effective therapy for FD, but no other treatment approach reached a consensus. The long-term prognosis and life expectancy are favorable. CONCLUSIONS AND INFERENCES: A multinational group of European experts summarized the current state of consensus on the definition, diagnosis and management of FD.
26United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia.PubMed
Lucas Wauters, Ram Dickman, Vasile Drug, et al.
Neurogastroenterol Motil. 2021 Sep;33(9):e14238. doi: 10.1111/nmo.14238.
BACKGROUND: Functional dyspepsia (FD) is one of the most common conditions in clinical practice. In spite of its prevalence, FD is associated with major uncertainties in terms of its definition, underlying pathophysiology, diagnosis, treatment, and prognosis. METHODS: A Delphi consensus was initiated with 41 experts from 22 European countries who conducted a literature summary and voting process on 87 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus (defined as >80% agreement) was reached for 36 statements. RESULTS: The panel agreed with the definition in terms of its cardinal symptoms (early satiation, postprandial fullness, epigastric pain, and epigastric burning), its subdivision into epigastric pain syndrome and postprandial distress syndrome, and the presence of accessory symptoms (upper abdominal bloating, nausea, belching), and overlapping conditions. Also, well accepted are the female predominance of FD, its impact on quality of life and health costs, and acute gastrointestinal infections, and anxiety as risk factors. In terms of pathophysiological mechanisms, the consensus supports a role for impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention, Helicobacter pylori infection, and altered central processing of signals from the gastroduodenal region. There is consensus that endoscopy is mandatory for establishing a firm diagnosis of FD, but that in primary care, patients without alarm symptoms or risk factors can be managed without endoscopy. There is consensus that H. pylori status should be determined in every patient with dyspeptic symptoms and H. pylori positive patients should receive eradication therapy. Also, proton pump inhibitor therapy is considered an effective therapy for FD, but no other treatment approach reached a consensus. The long-term prognosis and life expectancy are favorable. CONCLUSIONS AND INFERENCES: A multinational group of European experts summarized the current state of consensus on the definition, diagnosis and management of FD.
27The Association between Functional Dyspepsia and Metabolic Syndrome-The State of the Art.PubMed
Mile Volarić, Dunja Šojat, Ljiljana Trtica Majnarić, et al.
Int J Environ Res Public Health. 2024 Feb 18;21(2):237. doi: 10.3390/ijerph21020237.
Functional dyspepsia is a common functional disorder of the gastrointestinal tract that is responsible for many primary care visits. No organic changes have been found to explain its symptoms. We hypothesize that modern lifestyles and environmental factors, especially psychological stress, play a crucial role in the high prevalence of functional dyspepsia and metabolic syndrome. While gastrointestinal tract diseases are rarely linked to metabolic disorders, chronic stress, obesity-related metabolic syndrome, chronic inflammation, intestinal dysbiosis, and functional dyspepsia have significant pathophysiological associations. Functional dyspepsia, often associated with anxiety and chronic psychological stress, can activate the neuroendocrine stress axis and immune system, leading to unhealthy habits that contribute to obesity. Additionally, intestinal dysbiosis, which is commonly present in functional dyspepsia, can exacerbate systemic inflammation and obesity, further promoting metabolic syndrome-related disorders. It is worth noting that the reverse is also true: obesity-related metabolic syndrome can worsen functional dyspepsia and its associated symptoms by triggering systemic inflammation and intestinal dysbiosis, as well as negative emotions (depression) through the brain-gut axis. To understand the pathophysiology and deliver an effective treatment strategy for these two difficult-to-cure disorders, which are challenging for both caregivers and patients, a psychosocial paradigm is essential.
28Effects of corticotropin-releasing factor, corticotropin and cortisol on gastrointestinal motility in dogs.PubMed
L Bueno, J Fioramonti
Peptides. 1986 Jan-Feb;7(1):73-7. doi: 10.1016/0196-9781(86)90064-1.
Gastrointestinal motor activity following intracerebroventricular (ICV) and intravenous (IV) administration of corticotropin releasing factor (CRF), corticotropin (ACTH) and cortisol was investigated in fasted dogs with strain-gauge transducers chronically implanted on the antrum and proximal jejunum. ICV but not IV administration of CRF (20 to 100 ng/kg) suppressed the gastric cyclic migrating motor complex (MMC) for 3 to 6 hours without affecting the jejunum. Similar disruptive effects on the gastric MMC were observed after ICV administration of ACTH (0.5 U/kg) or cortisol (0.1 micrograms/kg) but not after IV administration of 10 times higher doses. These results suggest that in dog CRF may be involved in the central control of the interdigestive gastric motility, these effects were not probably due to the release of ACTH and cortisol the other hormones of the pituitary adrenocortical system change the gastric motility when centrally administered through a possible feed-back mechanism affecting brain CRF level.
29Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response.PubMed
Xinghua Gao, Qiuhua Cao, Yan Cheng, et al.
Proc Natl Acad Sci U S A. 2018 Mar 27;115(13):E2960-E2969. doi: 10.1073/pnas.1720696115. Epub 2018 Mar 12.
Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium (DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6C macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6 mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis.
30Inflammation and Impaired Gut Physiology in Post-operative Ileus: Mechanisms and the Treatment Options.PubMed
Zahid Hussain, Hyojin Park
J Neurogastroenterol Motil. 2022 Oct 30;28(4):517-530. doi: 10.5056/jnm22100.
Post-operative ileus (POI) is the transient cessation of coordinated gastrointestinal motility after abdominal surgical intervention. It decreases quality of life, prolongs length of hospital stay, and increases socioeconomic costs. The mechanism of POI is complex and multifactorial, and has been broadly categorized into neurogenic and inflammatory phase. Neurogenic phase mediated release of corticotropin-releasing factor (CRF) plays a central role in neuroinflammation, and affects both central autonomic response as well hypothalamic-pituitary-adrenal (HPA) axis. HPA-stress axis associated cortisol release adversely affects gut microbiota and permeability. Peripheral CRF (CRF) is a key player in stress induced gastric emptying and colonic transit. It functions as a local effector and interacts with the CRF receptors on the mast cell to release chemical mediators of inflammation. Mast cells proteases disrupt epithelial barrier via protease activated receptor-2 (PAR-2). PAR-2 facilitates cytoskeleton contraction to reorient tight junction proteins such as occludin, claudins, junctional adhesion molecule, and zonula occludens-1 to open epithelial barrier junctions. Barrier opening affects the selectivity, and hence permeation of luminal antigens and solutes in the gastrointestinal tract. Translocation of luminal antigens perturbs mucosal immune system to further exacerbate inflammation. Stress induced dysbiosis and decrease in production of short chain fatty acids add to the inflammatory response and barrier disintegration. This review discusses potential mechanisms and factors involved in the pathophysiology of POI with special reference to inflammation and interlinked events such as epithelial barrier dysfunction and dysbiosis. Based on this review, we recommend CRF, mast cells, macrophages, and microbiota could be targeted concurrently for efficient POI management.
31Gut microbiota, dysbiosis and colon lavage.PubMed
Lorenzo Drago, Casini Valentina, Pace Fabio
Dig Liver Dis. 2019 Sep;51(9):1209-1213. doi: 10.1016/j.dld.2019.06.012. Epub 2019 Jul 27.
Gut microbial dysbiosis is considered an alteration of diversity and abundance of intestinal microbes, which contributes to the onset of many disorders. Several factors cause dysbiosis, depending on life-style (nutrition, stress, environment, smoking, physical activity) or particular diseases (inflammatory, autoimmune, chronic diseases). Drugs (i.e. antibiotics, anticancer drugs), as well as medical and surgical procedures, can often cause dysbiosis. Mechanical bowel preparations (MBP) and the so called "bowel cleansing" have an immediate impact on intestinal microbial composition. Whether these "acute" changes may lead to any clinical consequences is still unknown. It is tempting to speculate that such dysbiosis fostering events, at least in patients already presenting abdominal complaints, such as irritable bowel syndrome (IBS), or inflammatory bowel disease (IBD) patients, may drive additional or more severe symptoms. Recently, the possibility of using probiotic supplementation has been addressed in the literature, with the purpose to counteract intestinal dysfunctional changes observed in relation to a dysbiotic state. Whereas probiotics are recognized to be effective and safe in restoring gut microbiota dysbiosis, preliminary evidence suggest that this approach may prove helpful even in case of transient dysbiotic states related to colonoscopy bowel preparation.
32Corticotropin-Releasing Hormone Receptor 2 Signaling Promotes Mucosal Repair Responses after Colitis.PubMed
Jill M Hoffman, Stavroula Baritaki, Jonathan J Ruiz, et al.
Am J Pathol. 2016 Jan;186(1):134-44. doi: 10.1016/j.ajpath.2015.09.013. Epub 2015 Nov 18.
The corticotropin-releasing hormone family mediates functional responses in many organs, including the intestine. Activation of corticotropin-releasing hormone receptor 2 (CRHR2) in the colonic mucosa promotes inflammation during acute colitis but inhibits inflammation during chronic colitis. We hypothesized that specific modulation of CRHR2 signaling in the colonic mucosa can promote restoration of the epithelium through stimulation of cell proliferative, migratory, and wound healing responses. Mucosal repair was assessed after dextran sodium sulfate (DSS)-induced colitis in mice receiving intracolonic injections of a CRHR2 antagonist or vehicle and in Crhr2(-/-) mice. Histologic damage, cytokine expression, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and Ki-67 immunoreactivity were evaluated. Cell viability, proliferation, and migration were compared between parental and CRHR2-overexpressing colonic epithelial cells. Protein lysates were processed for phosphoprotein assays and a wound healing assay performed in vitro. Administration of a CRHR2 antagonist after DSS-induced colitis increased disease activity, delayed healing, and decreased epithelial cell proliferation in vivo. Colons from these mice also showed increased apoptosis and proinflammatory cytokine expression. Compared with controls, Crhr2(-/-) mice showed increased mortality in the DSS healing protocol. CRHR2-overexpressing cells had increased proliferation and migration compared with parental cells. Wound healing and signal transducer and activator of transcription 3 activity were elevated in CRHR2-overexpressing cells after urocortin 2 and IL-6 treatment, suggesting advanced healing progression. Our results suggest that selective CRHR2 activation may provide a targeted approach to enhance mucosal repair pathways after colitis.
33Chronic intermittent stress exposure and access to grass silage interact differently in their effect on behaviour, gastric health and stress physiology of entire or castrated male growing-finishing pigs.PubMed
Mirjam Holinger, Barbara Früh, Peter Stoll, et al.
Physiol Behav. 2018 Oct 15;195:58-68. doi: 10.1016/j.physbeh.2018.07.019. Epub 2018 Jul 24.
Entire male pigs display more aggressive and sexual behaviour. This might cause a condition of chronic stress and impair their welfare. In order to assess chronic stress in entire and castrated male pigs, as well as effects of providing grass silage as occupational and feed material on behaviour and health, we carried out a 2 × 2 × 2-factorial experiment with 147 growing-finishing pigs. Factors investigated were castration (entire/castrated), chronic intermittent social stress exposure (yes/no) and access to grass silage (yes/no), as well as their interactions. The stress exposure treatment consisted of repeated short-term confrontations and separations. We recorded different behavioural variables, circadian rhythm of salivary cortisol, response to an ACTH (adrenocorticotropic hormone) challenge test, pathological changes in the gastric mucosa and morphology of the intestinal epithelium. Stress exposure caused a decrease in posture changes and head knocks/bites in the home pen. Reference indicators affected by stress exposure did not differ between entire and castrated male pigs, indicating that there is no permanently increased baseline level of stress in entire male pigs. However, entire males responded more pronouncedly to the stress exposure compared to castrated males in terms of posture changes and play behaviour. Pigs provided with grass silage showed more play behaviour and less manipulative behaviours than pigs not receiving grass silage. Stress treated pigs had more hyperkeratosis in the gastric mucosa and gastric ulcers, while offering grass silage reduced such changes. In conclusion, our results indicate that the increased behavioural stress response of entire male pigs might require some adaptations in housing and management of entire male pigs. Gastric ulceration scoring turned out to be a potential post mortem indicator for chronic stress. Finally, providing roughages like grass silage could be a means to positively affect behaviour and gastric health in pigs.
34Stress-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.
35Identification of a key ceRNA network associated with ferroptosis in gastric cancer.PubMed
Wen Jin, Jianli Liu, Jie Yang, et al.
Sci Rep. 2022 Nov 22;12(1):20088. doi: 10.1038/s41598-022-24402-3.
Ferroptosis, a newly discovered irondependent form of regulated cell death caused by excessive accumulation of lipid peroxides, is linked to the development and treatment response of various types of cancer, including gastric cancer (GC). Noncoding RNAs (ncRNAs), as key regulators in cancer, have both oncogenic and tumor suppressive roles. However, studies on ferroptosis-related ncRNA networks in GC are still lacking. Here, we first identified 61 differentially expressed genes associated with ferroptosis in GC by computing and analyzing gene expression profile of tumor and normal tissues for GC. Then, upstream lncRNAs and miRNAs interacting with them were found through miRNet and miRBase databases, and hub lncRNAs and miRNAs were obtained through topological analysis. Finally, the ceRNA regulatory network linked to ferroptosis in GC was established, which includes two ferroptosis marker genes (TXNIP and TSC22D3), one driver gene (GABARAPL1), and one suppressor gene (CAV1). Kaplan-Meier survival analysis showed that changes in the expression of these genes were associated with the survival of GC patients. Furthermore, our study revealed that this ceRNA network may influence the progression of GC by regulating ferroptosis process. These results will help experimental researchers to design an experiment study to further explore the roles of this regulatory network in GC ferroptosis.
36Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and positively influences pain sensitivity and work capacity.PubMed
Ludmila P Filaretova, Olga P Komkova, Olga Yu Morozova, et al.
Inflammopharmacology. 2024 Apr;32(2):909-915. doi: 10.1007/s10787-024-01451-w. Epub 2024 Mar 16.
The aim of the study was to investigate the effects of rat housing conditions-standard conditions, social isolation, environmental enrichment-and the subsequent reversal of these conditions on the vulnerability of the gastric mucosa to ulcerogenic stimuli, somatic pain sensitivity, and treadmill work capacity. Rats, aged 30 days, were placed in standard conditions (SC), social isolation (Is), and environmental enrichment (EE) for 4 weeks. Then half of each group underwent a reversal of housing conditions: SC rats were moved to Is, Is rats were placed in EE, EE rats were moved to Is, for 2 weeks. The other half served as a control with no change in their initial housing. Two weeks after the reversal, vulnerability of the gastric mucosa to ulcerogenic action of indomethacin (IM, 35 mg/kg, sc), somatic pain sensitivity (hot plate test), and work capacity (measured by the running distance on a treadmill) were assessed in control and reversed groups. Social isolation induced a proulcerogenic effect, increasing IM-induced gastric erosions, which was effectively reversed when rats were transferred to an environmental enrichment. Conversely, transferring rats from an environmental enrichment to social isolation exacerbated ulcerogenic action of IM. Somatic pain sensitivity and treadmill work capacity were also influenced by housing conditions, with environmental enrichment showing positive effects. The present findings show that social isolation of rats induces a proulcerogenic effect. Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and increases resilience to pain stimuli and treadmill work capacity.
37Social Media and Children with Disorders of Gut-Brain Interaction.PubMed
Carlo Di Lorenzo
Gastroenterol Clin North Am. 2025 Sep;54(3):627-638. doi: 10.1016/j.gtc.2025.04.002. Epub 2025 May 24.
It is undeniable that internet use and access to social media (SM) have a profound impact on children and adolescents. Clinicians need to be aware of the several detrimental impacts that the excessive use of SM may have on their patients' health. Displacement of other activities (sleep, physical activity, and personal interactions), cyberbullying, unhealthy social comparisons, misinformation, fear of missing out, and secondary gains are only some of the potential negative effects of SM on children's mental health. The current increase in disorders of gut-brain interaction may be at least partially explained by the increase in use of SM.
38Irritable Bowel Syndrome, Depression, and Neurodegeneration: A Bidirectional Communication from Gut to Brain.PubMed
Muhammad Nazirul Mubin Aziz, Jaya Kumar, Khairul Najmi Muhammad Nawawi, et al.
Nutrients. 2021 Aug 31;13(9):3061. doi: 10.3390/nu13093061.
Patients with irritable bowel syndrome (IBS) are increasingly presenting with a wide range of neuropsychiatric symptoms, such as deterioration in gastroenteric physiology, including visceral hypersensitivity, altered intestinal membrane permeability, and gastrointestinal motor dysfunction. Functional imaging of IBS patients has revealed several abnormalities in various brain regions, such as significant activation of amygdala, thinning of insular and anterior cingulate cortex, and increase in hypothalamic gray matter, which results in poor psychiatric and cognitive outcomes. Interrelations between the enteric and central events in IBS-related gastrointestinal, neurological, and psychiatric pathologies have compelled researchers to study the gut-brain axis-a bidirectional communication that maintains the homeostasis of the gastrointestinal and central nervous system with gut microbiota as the protagonist. Thus, it can be disrupted by any alteration owing to the gut dysbiosis or loss of diversity in microbial composition. Available evidence indicates that the use of probiotics as a part of a balanced diet is effective in the management of IBS and IBS-associated neurodegenerative and psychiatric comorbidities. In this review, we delineate the pathogenesis and complications of IBS from gastrointestinal and neuropsychiatric standpoints while also discussing the neurodegenerative events in enteric and central nervous systems of IBS patients and the therapeutic potential of gut microbiota-based therapy established on clinical and preclinical data.
39All in my head or all in my gut? An update on irritable bowel syndrome.PubMed
Amy T Woods, Alexander C Ford, Christopher J Black
Curr Opin Gastroenterol. 2026 Jan 1;42(1):52-58. doi: 10.1097/MOG.0000000000001141. Epub 2025 Oct 22.
PURPOSE OF REVIEW: Irritable bowel syndrome (IBS) has a considerable impact on patients and healthcare systems. IBS is a disorder of brain-gut interaction with numerous biopsychosocial factors involved, including early life experiences, previous gastrointestinal infections, and coexisting mood disorders. An understanding of the role of the gut-brain axis in symptom generation is vital to enable delivery of holistic care. RECENT FINDINGS: We explore psychological mechanisms, such as coexisting anxiety and depression, adverse life experiences, and somatisation and how these impact symptom severity. There is evidence for psychological therapies, such as cognitive behavioural therapy or gut-directed hypnotherapy, in IBS. We go on to summarise gut-based mechanisms, such as abnormal motility, visceral hypersensitivity, inflammation, and dysbiosis. Efficacious treatments targeting these include antidiarrhoeals, laxatives, antispasmodics, drugs acting on ion channels or serotonin, gut-brain neuromodulators, and treatments targeting the microbiota or inflammation. Finally, we consider emerging evidence from models describing distinct IBS phenotypes and their potential to facilitate a more integrated approach to identify best treatment options. SUMMARY: For many patients with IBS, both brain and gut mechanisms must be considered within the context of the biopsychosocial model to enable effective delivery of holistic and personalised care.
40Irritable bowel syndrome: an integrated explanatory model for clinical practice.PubMed
A P S Hungin, A Becher, B Cayley, et al.
Neurogastroenterol Motil. 2015 Jun;27(6):750-63. doi: 10.1111/nmo.12524. Epub 2015 Feb 20.
BACKGROUND: Although irritable bowel syndrome (IBS) is a symptom-based diagnosis, clinicians' management of and communication about the disorder is often hampered by an unclear conceptual understanding of the nature of the problem. We aimed to elucidate an integrated explanatory model (EM) for IBS from the existing literature for pragmatic use in the clinical setting. METHODS: Systematic and exploratory literature searches were performed in PubMed to identify publications on IBS and EMs. KEY RESULTS: The searches did not identify a single, integrated EM for IBS. However, three main hypotheses were elucidated that could provide components with which to develop an IBS EM: (i) altered peripheral regulation of gut function (including sensory and secretory mechanisms); (ii) altered brain-gut signaling (including visceral hypersensitivity); and (iii) psychological distress. Genetic polymorphisms and epigenetic changes may, to some degree, underlie the etiology and pathophysiology of IBS and could increase the susceptibility to developing the disorder. The three model components also fit into one integrated explanation for abdominal symptoms and changes in stool habit. Additionally, IBS may share a common pathophysiological mechanism with other associated functional syndromes. CONCLUSIONS & INFERENCES: It was possible to elucidate an integrated, three-component EM as a basis for clinicians to conceptualize the nature of IBS, with the potential to contribute to better diagnosis and management, and dialog with sufferers.
41Extraintestinal manifestations in irritable bowel syndrome: A systematic review.PubMed
Bodil Ohlsson
Therap Adv Gastroenterol. 2022 Aug 9;15:17562848221114558. doi: 10.1177/17562848221114558. eCollection 2022.
BACKGROUND: Irritable bowel syndrome (IBS) is characterized by abdominal pain and altered bowel habits. Further, IBS patients experience a high degree of extraintestinal symptoms. OBJECTIVES: The aim of this review was to describe the relation between IBS and extraintestinal manifestations and mechanisms and treatments of these extraintestinal manifestations. DESIGN: The study was performed as a systematic review. DATA SOURCES AND METHODS: Search terms including extraintestinal manifestations or somatization and IBS were used to scrutinize for publications in Pubmed. In total, 630 publications were identified and 80 were finally included in this review. RESULTS: About 50% of all IBS patients have extraintestinal manifestations in addition to gastrointestinal symptoms. Somatic pain, fatigue, and sleeping disturbances are most common, and most often described in women. Both extraintestinal manifestations and psychological distress are associated with exaggerated gastrointestinal symptoms, impaired quality of life, and difficulties to treat IBS symptoms. The extraintestinal manifestations render an excess of healthcare costs. Varying etiology and pathophysiology to IBS are discussed, and many patients express a general hypersensitivity. Extraintestinal symptoms are seldom documented at clinical healthcare or included in the assessment of treatment outcomes. A good patient-physician relationship and strengthening of coping mechanisms have rendered less gastrointestinal symptoms, psychological distress, and somatization. Altered lifestyle habits may improve both gastrointestinal and extraintestinal symptoms. Pharmacological treatment, including antidepressant drugs, should be considered when lifestyle advice fails. Teamwork between different specialists and healthcare providers may be of importance in the wide range of symptoms and extraintestinal manifestations. CONCLUSION: Extraintestinal manifestations are common in IBS patients and is associated with worse suffering and difficulties to treat symptoms. Evaluation and treatment of IBS patients should consider also extraintestinal manifestations and their treatment outcome. Establishment of good relationship, strengthening of coping mechanisms, and education in healthier lifestyle habits are crucial in the management of these patients.
42The Relationship Between Depressive Symptoms and Functional Gastrointestinal Disorders (FGIDs): The Chain Mediating Effect of Sleep Disorders and Somatic Symptom.PubMed
Jiana Wang, Nana Meng, Kun Chen, et al.
Depress Anxiety. 2024 Nov 20;2024:5586123. doi: 10.1155/2024/5586123. eCollection 2024.
More than two-thirds of patients with functional gastrointestinal disorders (FGIDs) experience various degrees of mental health issues. Although studies indicate that FGIDs are related to depressive symptoms, sleep disorders, and somatic symptoms, the underlying mechanism between these variables remains unknown. Our objective was to establish a model that outlines the interactions between these psychological dimensions in FGIDs and, thus, provide valuable insights into how to enhance the well-being of affected individuals. This study used the convenient sampling method to enroll patients who visited the digestive internal medicine department. A total of 238 patients were investigated using the Rome IV criteria (irritable bowel syndrome used Rome Ⅲ criteria). A questionnaire including the Hospital Anxiety and Depressive Symptoms Scale, the Pittsburgh Sleep Quality Index, and the Patient Health Questionnaire-12 was used. The chain mediating roles of sleep disorders and somatic symptoms in the relationship between depressive symptoms and FGIDs were examined by the bootstrap method. Correlation analysis revealed that depressive symptoms were positively related to sleep disorders, somatic symptoms, and FGIDs. Sleep disorders were positively related to somatic symptoms and FGIDs. Somatic symptoms were positively related to FGIDs. Chain mediating effect analysis showed that depressive symptoms can not only affect FGIDs but also through three indirect paths, as follows: the mediating role of sleep disorders and somatic symptoms, the chain mediating roles of sleep disorders and somatic symptoms, and the mediating effect size accounted for 7.2%, 7.7%, and 2.5% of the total effect, respectively. This study is conducive to understanding the internal mechanism underlying the relationship between depressive symptoms and FGIDs. It reminds us that when treating FGIDs patients, we should not only provide adequate psychological support to improve but also pay attention to improvements in their sleep quality and somatic symptoms.
43Psychosocial determinants of irritable bowel syndrome.PubMed
Teodora Surdea-Blaga, Adriana Băban, Dan L Dumitrascu
World J Gastroenterol. 2012 Feb 21;18(7):616-26. doi: 10.3748/wjg.v18.i7.616.
From a pure motor disorder of the bowel, in the past few years, irritable bowel syndrome (IBS) has become a multifactorial disease that implies visceral hypersensitivity, alterations at the level of nervous and humoral communications between the enteric nervous system and the central nervous system, alteration of the gut microflora, an increased intestinal permeability and minimum intestinal inflammation. Psychological and social factors can interfere with the communication between the central and enteric nervous systems, and there is proof that they are involved in the onset of IBS and influence the response to treatment and outcome. There is evidence that abuse history and stressful life events are involved in the onset of functional gastrointestinal disorders. In order to explain clustering of IBS in families, genetic factors and social learning mechanisms have been proposed. The psychological features, such as anxiety, depression as well as the comorbid psychiatric disorders, health beliefs and coping of patients with IBS are discussed in relation to the symptoms and outcome.
44The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.PubMed
Marilia Carabotti, Annunziata Scirocco, Maria Antonietta Maselli, et al.
Ann Gastroenterol. 2015 Apr-Jun;28(2):203-209.
The gut-brain axis (GBA) consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent advances in research have described the importance of gut microbiota in influencing these interactions. This interaction between microbiota and GBA appears to be bidirectional, namely through signaling from gut-microbiota to brain and from brain to gut-microbiota by means of neural, endocrine, immune, and humoral links. In this review we summarize the available evidence supporting the existence of these interactions, as well as the possible pathophysiological mechanisms involved. Most of the data have been acquired using technical strategies consisting in germ-free animal models, probiotics, antibiotics, and infection studies. In clinical practice, evidence of microbiota-GBA interactions comes from the association of dysbiosis with central nervous disorders (i.e. autism, anxiety-depressive behaviors) and functional gastrointestinal disorders. In particular, irritable bowel syndrome can be considered an example of the disruption of these complex relationships, and a better understanding of these alterations might provide new targeted therapies.
45Lacidophilin tablets relieve irritable bowel syndrome in rats by regulating gut microbiota dysbiosis and intestinal inflammation.PubMed
Huiqun Fan, Yang Zhan, Xiaoying Cheng, et al.
Sci Rep. 2025 Mar 9;15(1):8151. doi: 10.1038/s41598-025-91883-3.
Irritable bowel syndrome (IBS) is a common clinical functional gastrointestinal disease. It has a complex pathophysiological mechanism, in which the imbalance of gut microbiota might play an important role. Lacidophilin tablets (LH) can regulate gut microbiota, but their effect on IBS is unknown. In this study, the IBS model was established by acetic acid enema combined with the constrained stress method, and rats were fed LH for 2 weeks. LH significantly reduced visceral sensitivity and intestinal propulsion rate and improved IBS-induced anxiety and depressive behavior in IBS rats. LH elevated the expression levels of mucin 2, claudin1, and occludin, and ameliorated IBS-induced structural damage to colonic tissues. The gut microbiota analysis revealed that LH altered the structure and composition of the gut microbiota in IBS rats. In addition, LH reduced the expression levels of inflammatory factor-related genes. These results suggest that LH could significantly improve the visceral sensitivity and intestinal motility disorders of IBS rats, relieve anxiety and depression levels, and alleviate the symptoms of IBS rats by regulating gut microbiota and reducing intestinal inflammation.
46Intestinal microbiome-gut-brain axis and irritable bowel syndrome.PubMed
Gabriele Moser, Camille Fournier, Johannes Peter
Wien Med Wochenschr. 2018 Mar;168(3-4):62-66. doi: 10.1007/s10354-017-0592-0. Epub 2017 Sep 8.
Psychological comorbidity is highly present in irritable bowel syndrome (IBS). Recent research points to a role of intestinal microbiota in visceral hypersensitivity, anxiety, and depression. Increased disease reactivity to psychological stress has been described too. A few clinical studies have attempted to identify features of dysbiosis in IBS. While animal studies revealed strong associations between stress and gut microbiota, studies in humans are rare. This review covers the most important studies on intestinal microbial correlates of psychological and clinical features in IBS, including stress, anxiety, and depression.
47Psychological aspects and psychotherapy of inflammatory bowel diseases and irritable bowel syndrome in children.PubMed
Jan Prasko, Daniela Jelenova, Vladimir Mihal
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010 Dec;154(4):307-14. doi: 10.5507/bp.2010.046.
BACKGROUND: Despite holistic approach to psychosomatic medicine, gastroenterological disorders (GI) tend to be categorized broadly into "functional" and "organic". Major GI illnesses are Inflammatory bowel diseases (IBD) include ulcerative colitis and Crohn's disease. Both are chronic, with remissions and relapses over the years while irritable bowel syndrome (IBS) is a common, often disabling functional gastrointestinal disorder. METHODS: A literature review was performed using the National Library of Medicine PubMed database, including all resources within the period 1991-2008, additional references were found through bibliography reviews of relevant articles. RESULTS: Psychological problems: Higher scores of neuroticism, depression, inhibition, and emotional instability, are typical for many patients with chronic diseases and nonspecific for chronic gastroenterological disorders. Patients with chronic gastrointestinal disorders have impaired health-related quality. Psychological treatments: There have been few adequate psychological treatment trials in IBD. These achieved lower demands for health care rather than a reduction of anxiety or depression. Psychotherapy with chronic gastrointestinal disorders could lead to improve the course of the disease, changing psychological factors such as depression and dysfunctional coping and improving the patient's quality of life. CONCLUSIONS: There seem to be "risk patients" in whom psychosocial components have a bigger influence on the course of disease than in other patients; and those would probably benefit from psychotherapeutic treatment. Psychological treatments help patients manage the psychological distress which worsens bowel symptoms and quality of life.
48Decoding IBS: a machine learning approach to psychological distress and gut-brain interaction.PubMed
Astri J Lundervold, Julie E Billing, Birgitte Berentsen, et al.
BMC Gastroenterol. 2024 Aug 15;24(1):267. doi: 10.1186/s12876-024-03355-z.
PURPOSE: Irritable bowel syndrome (IBS) is a diagnosis defined by gastrointestinal (GI) symptoms like abdominal pain and changes associated with defecation. The condition is classified as a disorder of the gut-brain interaction (DGBI), and patients with IBS commonly experience psychological distress. The present study focuses on this distress, defined from reports of fatigue, anxiety, depression, sleep disturbances, and performance on cognitive tests. The aim was to investigate the joint contribution of these features of psychological distress in predicting IBS versus healthy controls (HCs) and to disentangle clinically meaningful subgroups of IBS patients. METHODS: IBS patients ( ) and HCs ( ) completed the Chalder Fatigue Scale (CFQ), the Hamilton Anxiety and Depression Scale (HADS), and the Bergen Insomnia Scale (BIS), and performed tests of memory function and attention from the Repeatable Battery Assessing Neuropsychological Symptoms (RBANS). An initial exploratory data analysis was followed by supervised (Random Forest) and unsupervised (K-means) classification procedures. RESULTS: The explorative data analysis showed that the group of IBS patients obtained significantly more severe scores than HCs on all included measures, with the strongest pairwise correlation between fatigue and a quality measure of sleep disturbances. The supervised classification model correctly predicted belongings to the IBS group in 80% of the cases in a test set of unseen data. Two methods for calculating feature importance in the test set gave mental and physical fatigue and anxiety the strongest weights. An unsupervised procedure with showed that one cluster contained 24% of the patients and all but two HCs. In the two other clusters, their IBS members were overall more impaired, with the following differences. One of the two clusters showed more severe cognitive problems and anxiety symptoms than the other, which experienced more severe problems related to the quality of sleep and fatigue. The three clusters were not different on a severity measure of IBS and age. CONCLUSION: The results showed that psychological distress is an integral component of IBS symptomatology. The study should inspire future longitudinal studies to further dissect clinical patterns of IBS to improve the assessment and personalized treatment for this and other patient groups defined as disorders of the gut-brain interaction. The project is registered at https://classic. CLINICALTRIALS: gov/ct2/show/NCT04296552 20/05/2019.
49Is there a causal link between psychological disorders and functional gastrointestinal disorders?PubMed
Natasha Koloski, Gerald Holtmann, Nicholas J Talley
Expert Rev Gastroenterol Hepatol. 2020 Nov;14(11):1047-1059. doi: 10.1080/17474124.2020.1801414. Epub 2020 Aug 17.
INTRODUCTION: Psychological distress is associated with functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS) and functional dyspepsia (FD) but only evidence from prospective longitudinal and treatment studies can indicate whether the link between FGIDs and psychological distress is causal. Emerging evidence suggests underlying biological mechanisms may explain the association of psychological distress with FGIDs. AREAS COVERED: This review critically evaluates whether anxiety and/or depression and FGIDs are causally related including evidence for a temporal sequence, strength and specificity of the association, biological gradient, and biological plausibility. EXPERT OPINION: Accumulating evidence suggests that psychological factors are causal for symptoms in a subset of FGID patients and not explained by health care seeking behavior (brain-gut disorder). In other cases, psychological factors may arise secondary to intestinal disease (gut-brain disorder). Prospective population-based studies are needed in FGIDs other than IBS and FD to determine if a similar brain-gut and gut-brain syndrome exists. Treatment studies have not phenotyped FGIDs according to brain-gut versus gut-brain origins which may be important in understanding true treatment efficacy. Future research needs to unravel biological mechanisms that may explain the link between psychological factors and FGIDs but promising data in the area of the brain-gut-immune-microbe axis is emerging.
50What does irritable bowel syndrome share with non-alcoholic fatty liver disease?PubMed
Antonella Scalera, Matteo Nicola Dario Di Minno, Giovanni Tarantino
World J Gastroenterol. 2013 Sep 7;19(33):5402-20. doi: 10.3748/wjg.v19.i33.5402.
Non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS) are two very common diseases in the general population. To date, there are no studies that highlight a direct link between NAFLD and IBS, but some recent reports have found an interesting correlation between obesity and IBS. A systematic PubMed database search was conducted highlighting that common mechanisms are involved in many of the local and systemic manifestations of NAFLD, leading to an increased cardiovascular risk, and IBS, leading to microbial dysbiosis, impaired intestinal barrier and altered intestinal motility. It is not known when considering local and systemic inflammation/immune system activation, which one has greater importance in NAFLD and IBS pathogenesis. Also, the nervous system is implicated. In fact, inflammation participates in the development of mood disorders, such as anxiety and depression, characteristics of obesity and consequently of NAFLD and, on the other hand, in intestinal hypersensitivity and dysmotility.
51A Correlation Between the Pathogenic Processes of Fibromyalgia and Irritable Bowel Syndrome in the Middle-Aged Population: A Systematic Review.PubMed
Carla Valencia, Hameeda Fatima, Ijeoma Nwankwo, et al.
Cureus. 2022 Oct 4;14(10):e29923. doi: 10.7759/cureus.29923. eCollection 2022 Oct.
Irritable bowel syndrome (IBS) is a common pathology in middle-aged patients and a regular consultation in the gastroenterology office. The prevalence is high in females with a ratio of 2:1, and due to its multifactorial etiology, it is difficult to address the symptomatology. On the other hand, fibromyalgia syndrome (FMS) is a chronic widespread pain syndrome also prevalent in the female population, characterized by systemic symptoms. It is proven that 28-59 % of patients with FMS develop IBS at some point in their illness; on the other hand, 32-77% of those with IBS will develop FMS. Our study aims to compile information about the pathogenesis of these diseases and highlight their common processes to target these two illnesses potentially. This systematic review comprises twenty-three studies published between 2017 and 2022, selected by electronic research with keywords and Medical Subject Headings (MESH) strategy. The articles were taken from PubMed, Pubmed Central (PMC), Medline, and Cochrane libraries and met the inclusion and exclusion criteria and the pertinent quality checklists. Of the reviewed studies, 10 were case-control, six were narrative reviews, three were systematic reviews, three were cross-sectional, and one was a cohort study. They investigated the correlation and similitudes in the pathogenic process between FMS and IBS. There are some similar mechanisms in the physiopathologies of IBS and FMS, where the immune system, especially the mast cells (MCs), along with their products, receptors, the inflammatory cells with their intermediaries, hormones, and neurotransmitters such as serotonin, act together pathologically. Also, the role of the microbiota is very important in this pathogenesis since dysbiosis alters the levels of serotonin in the body and can produce hyperstimulation of the autonomic nervous system. There are common associated factors in IBS and FMS, with evident symptoms presented in both syndromes such as fatigue, pain, hypersensitivity, depression, anxiety, and others, that could be correlated in a certain way. After this systematic review, we can conclude that the most accepted theories of the common pathogenesis are the role of serotonin and MCs with their inflammatory biomarkers, which can affect different parts of the body producing the characteristic symptomatology. Moreover, other pathogenic mechanisms such as the involvement of microbiota and dysregulation of the gut-brain axis have shown promising results, and further investigation should be made to support their role.
52Depression in gastric cancer patients: Integrated therapeutic strategies and clinical implications.PubMed
Pei-Yuan Yu, Feng Liu, Yan Jiao, et al.
World J Clin Oncol. 2025 Jun 24;16(6):106229. doi: 10.5306/wjco.v16.i6.106229.
Depression is a common comorbidity in gastric cancer (GC) patients, with prevalence rates reaching up to 57%, particularly in advanced stages and during active treatment. While prior studies have explored the bidirectional relationship between GC and depression, this editorial provides a structured synthesis of therapeutic strategies including pharmacological, psychotherapeutic, integrative, and biomarker-driven interventions, within a multidisciplinary care framework. Depression may exacerbate tumor progression through chronic stress and neurotransmitter dysregulation, such as β2-adrenergic receptor activation, while the cancer burden deepens psychological distress. Antidepressants, especially selective serotonin reuptake inhibitors, have demonstrated efficacy in alleviating depressive symptoms in up to 70% of cases, particularly when used alongside chemotherapy. Psychotherapeutic modalities, including cognitive-behavioral therapy and family-based interventions, help reduce depressive symptoms, improve coping mechanisms, and prevent relapse. Integrative strategies like music therapy, mindfulness, and physical activity further support emotional well-being, particularly in mild-to-moderate depression. Multidisciplinary care that combines nutritional support, pain control, and psychosocial interventions is essential. Notably, the integration of interventional therapies with traditional Chinese medicine has shown potential in stabilizing tumor growth and improving mental health, enabling functional "tumor-bearing survival". Emerging immunotherapies such as cadonilimab may also contribute indirectly to depression alleviation by enhancing treatment efficacy and extending survival. Future research should focus on biomarker-guided approaches, such as targeting β2-adrenergic signaling, and developing personalized psychosocial care models. A holistic approach that integrates both physical and psychological care is vital to improving outcomes and quality of life in GC patients.
53Suicide ideation in stomach cancer survivors and possible risk factors.PubMed
Ye-Ni Choi, Young-Ae Kim, Young Ho Yun, et al.
Support Care Cancer. 2014 Feb;22(2):331-7. doi: 10.1007/s00520-013-1975-4. Epub 2013 Sep 21.
PURPOSE: Although the suicide rate of cancer survivors is higher than that of the general population, few studies have examined the potential risk factors. We assessed suicide ideation (SI) and investigated its correlates among survivors of stomach cancer, which is one of the most prevalent cancers in Korea. METHODS: We surveyed 378 stage I-III stomach cancer survivors who had been disease free for at least 1 year. The survey contained demographic questions and quality of life assessments from the European Organization for Research and Treatment of Cancer QLQ-C30 and its stomach cancer-specific module, the McGill Quality of Life Questionnaire, the Brief Fatigue Inventory, and one question from the Beck Depression Inventory. RESULTS: We found that 131/378 stomach cancer survivors (34.7 %) experienced SI. Univariate analyses showed that SI was significantly associated with income, comorbidity, smoking, and the following quality of life factors: general health status, emotional functioning, fatigue, nausea/vomiting, dyspnea, appetite loss, constipation, diarrhea, financial problems, eating restriction, anxiety, dry mouth, trouble belching, hair loss, body image, existential well-being, and social support. Multivariate logistic regression confirmed that SI was independently associated with diarrhea (adjusted odds ratio (aOR) 2.84; 95 % confidence interval (CI) 1.44-5.62), hair loss (aOR 2.77; 95 % CI 1.04-7.36), existential well-being (aOR 6.18; 95 % CI 2.91-13.1), and usual fatigue (aOR 2.29; 95 % CI 1.30-4.06). CONCLUSION: Our findings reveal a high prevalence of SI among stomach cancer survivors and identify health-related quality of life issues such as diarrhea, hair loss, existential well-being, and fatigue as important risk factors of SI.
54Factors associated with depression in disease-free stomach cancer survivors.PubMed
Kyung Hee Han, In Cheol Hwang, Sung Kim, et al.
J Pain Symptom Manage. 2013 Oct;46(4):511-22. doi: 10.1016/j.jpainsymman.2012.10.234. Epub 2013 Mar 13.
CONTEXT: Depression in cancer survivors affects the rest of their lives in many ways. OBJECTIVES: To estimate the prevalence of depression and identify associated factors in disease-free stomach cancer survivors. METHODS: We enrolled 391 stomach cancer survivors who had been disease-free for at least one year after surgery from the cancer registries of two hospitals in Korea. Stomach cancer survivors were mailed a survey that included the Beck Depression Inventory, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and the associated stomach module, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Stomach Cancer Module 22. RESULTS: Forty-four percent of survivors suffered from depression, and more women (49%) than men (42%) had high depression scores (Beck Depression Inventory >13). In multiple logistic regression analysis, lower income (odds ratio [OR] 2.49; 95% CI 1.64-3.78), problems with care before treatment (OR 1.92; 95% CI 1.23-2.98), body image change (OR 2.23; 95% CI 1.41-3.53), and symptoms of fatigue (OR 3.11; 95% CI 1.49-6.52), dyspnea (OR 2.57; 95% CI 1.48-4.45), or insomnia (OR 4.51; 95% CI 1.88-10.83) were associated with depression. CONCLUSION: The prevalence of depression was high in stomach cancer survivors even after the completion of treatment, especially among those with problems amenable to treatment, and we identified the associated factors. We suggest that stomach cancer survivors should be screened for depression after the end of treatment.
55Comorbidity of posttraumatic stress symptoms and depressive symptoms among gastric cancer patients.PubMed
Yuval Palgi, Amit Shrira, Yeela Haber, et al.
Eur J Oncol Nurs. 2011 Dec;15(5):454-8. doi: 10.1016/j.ejon.2010.11.011. Epub 2011 Jan 8.
PURPOSE: The present study aimed to examine the association between clinical level of posttraumatic stress disorder (PTSD) symptoms and clinical level of depression among gastric cancer patients. The main hypothesis was that most gastric cancer patients with clinical level of PTSD symptoms will suffer from clinical level of depression. METHODS: Participants were 123 consecutive gastric outpatients at stage I-IV recruited from the oncology unit at Tel Aviv Sourasky Medical Center. The patients filled a battery of self-administered questionnaire that assessed demographics, psychiatric symptoms, and data from their medical records. RESULTS: Having an elevated risk for clinical level of PTSD increased the probability to have an elevated risk for clinical level of depression by fifteen times (OR = 15.739; Wald = 11.333; 95% C.I. = 3.163-78.322; p = .001). CONCLUSION: Given the high comorbidity between PTSD symptoms and depressive symptoms among gastric cancer patients, one may suggest that patients, who demonstrate clinical level of PTSD, should be also screened for depression. Psychotherapy with these patients might aim to reduce the double risk of PTSD and depression.
56Adverse outcomes and health-ecological influencing factors of preoperative frailty among elderly patients with gastric cancer.PubMed
Lingyu Ding, Xueyi Miao, Xiaoman Jiang, et al.
J Cancer Res Clin Oncol. 2023 Aug;149(10):7043-7051. doi: 10.1007/s00432-023-04651-z. Epub 2023 Mar 2.
PURPOSE: Frailty is defined as a state of decreased physiologic reserves arising from cumulative deficits in multiple homeostatic systems, which is important in the field of clinical oncology. We aimed to explore the relationship between preoperative frailty and adverse outcomes, and systematically analyze the factors influencing frailty based on the health ecology model among elderly gastric cancer patients. METHODS: A observational study was conducted to select 406 elderly patients who would undergo gastric cancer surgery at a tertiary hospital. The logistic regression model was used to examine the relationship between preoperative frailty and adverse outcomes, including total complications, prolonged length of stay (PLOS), and 90-day hospital readmission. Based on the health ecology model, the factors which may influence frailty were collected from four levels. Univariate and multivariate analysis were utilized to determine the factors influencing preoperative frailty. RESULTS: Preoperative frailty was associated with total complications (odds ratio [OR] 2.776, 95% confidence interval [CI] 1.588-4.852), PLOS (OR 2.338, 95%CI 1.342-4.073), and 90-day hospital readmission (OR 2.640, 95% CI 1.275-5.469). Besides, nutritional risk (OR 4.759, 95% CI 2.409-9.403), anemia (OR 3.160, 95% CI 1.751-5.701), number of comorbidity ≥ 2 (OR 2.318, 95% CI 1.253-4.291), low physical activity level (OR 3.069, 95% CI 1.164-8.092), apathetic attachment (OR 2.656, 95% CI 1.457-4.839), personal monthly income ≤ 1000 yuan (OR 2.033, 95% CI 1.137-3.635) and anxiety (OR 2.574, 95% CI 1.311-5.053) were independent risk factors for frailty. High physical activity level (OR 0.413, 95% CI 0.208-0.820) and improved objective support (OR 0.818, 95% CI 0.683-0.978) were independent protective factors for frailty. CONCLUSIONS: Preoperative frailty was associated with multiple adverse outcomes and could be affected by factors of different dimensions from the health ecology perspective, including nutrition, anemia, comorbidity, physical activity, attachment style, objective support, anxiety, and income, which can guide the formation of a comprehensive prehabilitation for frailty among elderly gastric cancer patients.
57Psychosomatic medicine in the 21st century: understanding mechanisms and barriers to utilization.PubMed
Thomas N Wise, Richard Balon
Adv Psychosom Med. 2015;34:1-9. doi: 10.1159/000369043. Epub 2015 Mar 30.
The psychosomatic approach arose in antiquity as mankind looked for explanations for illness and death. With the rise of modern medicine, the links between emotions and medical conditions, such as cardiac disease and diabetes, were described by astute clinical observers, but the mechanisms for these conditions were based on correlation from observations rather than on experimental design. Psychoanalytic theory was often utilized to explain many common diseases. For example, peptic ulcer disease was blamed upon anger and stress, but scientific methodology discovered Helicobacter pylori to be the significant causal factor of this disease and resulted in the development of more effective treatments. Nevertheless emotional factors are still linked to disease states and morbidity; for example, depression is a risk factor for mortality following myocardial infarction. Advances in neuroscience demonstrate that the reduction of telomere length by anxiety and stress leads to more rapid aging and potential disease vulnerability. Thus, neuroscientific probes may allow for the elucidation of psychosomatic mechanisms. Sadly, clinical barriers, in terms of time pressure upon physicians and the current separation of mental health services from primary care settings, continue the dualistic treatment of many conditions where psychological factors are important. It is not clear whether a mandate for the integration of behavioral health into primary care will remedy this partition and finally maximize a psychosomatic approach to medical care.
58A link between physician-diagnosed ulcer and anxiety disorders among adults.PubMed
Renee D Goodwin, Nicholas J Talley, Matthew Hotopf, et al.
Ann Epidemiol. 2013 Apr;23(4):189-92. doi: 10.1016/j.annepidem.2013.01.003. Epub 2013 Feb 28.
PURPOSE: Previous studies have suggested an association between mood and anxiety disorders and peptic ulcer, yet extant work suffers from methodologic limitations. Centrally, previous epidemiologic studies have relied exclusively on self-report of ulcer. This study aimed to investigate the relationship between DSM-IV depression and anxiety disorders and physician-diagnosed ulcer among adults in the general population. METHODS: Data were drawn from a population-based, representative sample of 4181 adults aged 18 to 79 in the German National Health Interview and Examination Survey. RESULTS: Any anxiety disorder (odds ratio [OR], 2.6), panic disorder (OR, 5.2), panic attacks (OR, 3.8), and social phobia (OR, 3.3) were associated with increased likelihood of physician-diagnosed ulcer, compared with those without ulcer. There was evidence of a dose-response relationship between number of mental disorders and likelihood of current ulcer. CONCLUSIONS: These findings provide initial evidence of a link between anxiety disorders and physician-diagnosed ulcer among adults in the community. Future work, ideally taking into account Helicobacter pylori infection, stress, and mental health problems is needed to improve our understanding of the possible mechanisms that can provide insight into the etiology of peptic ulcers.
59Gender differences in ghrelin, nociception genes, psychological factors and quality of life in functional dyspepsia.PubMed
Yoon Jin Choi, Young Soo Park, Nayoung Kim, et al.
World J Gastroenterol. 2017 Dec 7;23(45):8053-8061. doi: 10.3748/wjg.v23.i45.8053.
AIM: to evaluate gender differences in the aspect of ghrelin, nociception-related genes and psychological aspects and the quality of life (QoL) in Korean functional dyspepsia (FD) patients. METHODS: Total of 191 persons were prospectively enrolled between March 2013 and May 2016 in Seoul National Bundang Hospital, and classified into control and FD group based on ROME III criteria. Questionnaire included assessment for dyspepsia symptoms, QoL and anxiety or depression. Preproghrelin and nociception genes in the gastric mucosa and plasma acyl/des-acyl ghrelin were measured. RESULTS: Lower level of plasma acyl ghrelin in FD patients compared to control was significant only in male (15.9 fmol/mL 10.4 fmol/mL, = 0.017). Significantly higher mRNA expressions of nerve growth factor and transient receptor potential vanilloid receptor 1 were observed in male ( = 0.002 and = 0.014, respectively) than in female. In contrast, female FD patients had a higher anxiety and depression score than male FD ( = 0.029), and anxiety score was correlated with epigastric pain only in female FD patients (female: Spearman rho = 0.420, = 0.037). The impairment of overall QoL was more prominent in female FD patients than male patients (5.4 ± 0.3 6.5 ± 0.3, = 0.020). CONCLUSION: Gender differences of ghrelin and nociception-related genes in male and psychological factors in female underlie FD symptoms. More careful assessment of psychological or emotional status is required particularly for the female FD patients.
60The preproghrelin 3056 TT genotype is associated with the feeling of hunger and low acylated ghrelin levels in Japanese patients with Helicobacter pylori-negative functional dyspepsia.PubMed
Seiji Futagami, Mayumi Shimpuku, Tetsuro Kawagoe, et al.
Intern Med. 2013;52(11):1155-63. doi: 10.2169/internalmedicine.52.8662.
OBJECTIVE: An impairment of gastric motility is strongly associated with the pathophysiology of functional dyspepsia (FD). Plasma ghrelin is one of the key molecules linked to gastric motility. Therefore, this study aimed to evaluate whether ghrelin (GHRL) gene polymorphisms are associated with clinical symptoms, the plasma ghrelin levels and gastric emptying in patients with FD as defined by the Rome III classification. METHODS: We enrolled 74 Helicobacter pylori-negative patients presenting with typical symptoms of FD (epigastric pain syndrome (EPS), n=23; postprandial distress syndrome (PDS), n=51) and 102 healthy volunteers. Gastric motility was evaluated according to the Tmax value and T1/2 using the (13)C-acetate breath test. We used the Rome III criteria to evaluate upper abdominal symptoms and SRQ-D scores to determine the depression status. The Arg51Gln(346G->A), preproghrelin3056T->C, Leu72Met(408C->A) and Gln90Leu(3412T->A) polymorphisms were analyzed in DNA in blood samples obtained from the enrolled subjects. Genotyping was performed using polymerase chain reaction. RESULTS: There was a significant relationship (p=0.048) between the preproghrelin 3056TT genotype and the serum levels of acylated ghrelin in the H. pylori-negative FD patients. The preproghrelin 3056TT genotype was significantly (p=0.047) associated with the feeling of hunger in the H. pylori-negative FD patients. CONCLUSION: The preproghrelin 3056TT genotype is significantly associated with the acylated ghrelin levels and the feeling of hunger in H. pylori-negative FD patients. Further studies are needed to clarify the association between the preproghrelin 3056TT genotype and lower plasma acylated ghrelin levels and the impact of this relationship on the feeling of hunger in H. pylori-negative FD patients.
61"Satiety molecules" - nesfatin-1 and glucagon-like peptide 1 in blood serum in patients with anorexia nervosa and obesity.PubMed
Małgorzata Blaska, Katarzyna Gołąb-Jenerał, Katarzyna Ziora
Endokrynol Pol. 2025;76(2):134-144. doi: 10.5603/ep.104689.
INTRODUCTION: Nesfatin-1 (NESF-1) is a neuropeptide occurring in the central nervous system and peripheral tissues. Strongly associated with anxiety, it regulates glucose levels and is a negative modulator of food intake. Intracerebroventricularly injected nesfatin-1 in experimental animals inhibits food intake, whereas administration of a NESF-1 neutralizing antibody stimulates their appetite. Glucagon-like peptide 1 (GLP-1), a gastrointestinal ormone released ca. 15-30 min. after a meal, demonstrates incretin properties. Peripheral administration of GLP-1 stimulates the secretion of gastric acid, slows down the emptying of the stomach, and reduces the feeling of hunger and the quantity of food ingested by the obese population. MATERIAL AND METHODS: A review of the medical database PubMed was carried out covering the years 1990-2024 in terms of blood concentrations of nesfatin-1 and GLP-1 in patients suffering from anorexia nervosa and simple obesity and the role of these hormones in the etiopathogenesis of the eating disorders referred to above. RESULTS: Based on the review of the available literature, it was noted that concentrations of NESF-1 in blood serum are reduced in the group of adult patients with anorexia nervosa (AN) and higher in the group of obese patients, in comparison to a control group of individuals with normal body weight. Findings of research on blood concentrations of GLP-1 in adult subjects with AN are divergent - they point to higher, reduced, or not significantly different GLP-1 levels as compared to the control group. According to the studies, in obese subjects basal GLP-1 levels in blood do not differ significantly from those of subjects with normal body weight, whereas after a meal or glucose administration they are significantly reduced compared to obese subjects. CONCLUSIONS: Nesfatin-1 and GLP-1 are associated with eating disorders, although their role has not been fully clarified so far. Regulation of concentrations of these peptides is assumed to be important in adaptation processes of an organism to deficient and excessive body weight or to play a role in the etiopathogenesis of anorexia nervosa and obesity.
62Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress.PubMed
Fu-Chun Jing, Jun Zhang, Chen Feng, et al.
World J Gastroenterol. 2017 Nov 14;23(42):7594-7608. doi: 10.3748/wjg.v23.i42.7594.
AIM: To establish a rat model of anxiety-like gastric hypersensitivity (GHS) of functional dyspepsia (FD) induced by novel sequential stress. METHODS: Animal pups were divided into two groups from postnatal day 2: controls and the sequential-stress-treated. The sequential-stress-treated group received maternal separation and acute gastric irritation early in life and restraint stress in adulthood; controls were reared undisturbed with their mothers. Rats in both groups were followed to adulthood (8 wk) at which point the anxiety-like behaviors and visceromotor responses to gastric distention (20-100 mmHg) and gastric emptying were tested. Meanwhile, alterations in several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined. RESULTS: Sequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS in dose-dependent manner compared with the control group. Although rats in both groups consumed similar amount of solid food, the rate of gastric emptying was lower in the sequential-stress-treated rats than in the control group. Sequential stress significantly decreased the levels of 5-HT (51.91 ± 1.88 104.21 ± 2.88, < 0.01), GABA (2.38 ± 0.16 5.01 ± 0.13, < 0.01) and BDNF (304.40 ± 10.16 698.17 ± 27.91, < 0.01) in the hippocampus but increased the content of nesfatin-1 (1961.38 ± 56.89 1007.50 ± 33.05, < 0.01) in the same site; significantly decreased the levels of 5-HT (47.82 ± 2.29 89.45 ± 2.61, < 0.01) and BDNF (257.05 ± 12.89 536.71 ± 20.73, < 0.01) in the plasma but increased the content of nesfatin-1 in it (1391.75 ± 42.77 737.88 ± 33.15, < 0.01); significantly decreased the levels of 5-HT (41.15 ± 1.81 89.17 ± 2.31, < 0.01) and BDNF (226.49 ± 12.10 551.36 ± 16.47, < 0.01) in the gastric fundus but increased the content of nesfatin-1 in the same site (1534.75 ± 38.52 819.63 ± 38.04, < 0.01). The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated measured by IHC (Optical Density value: Hippocampus 15253.50 ± 760.35 21149.75 ± 834.13; gastric fundus 15865.25 ± 521.24 23865.75 ± 1868.60; < 0.05, respectively) and WB (0.38 ± 0.01 0.57 ± 0.03, < 0.01) ( = 8 in each group). CONCLUSION: Sequential stress could induce a potential rat model of anxiety-like GHS of FD, which could be used to research the mechanisms of this intractable disease.
63Ghrelin mediated hippocampal neurogenesis.PubMed
Jeffrey S Davies
Vitam Horm. 2022;118:337-367. doi: 10.1016/bs.vh.2021.12.003. Epub 2022 Jan 27.
The stomach hormone, ghrelin, which is released during food restriction, provides a link between circulating energy state and adaptive brain function. The maintenance of such homeostatic systems is essential for an organism to survive and thrive, and accumulating evidence points to ghrelin being a key regulator of adult hippocampal neurogenesis and memory function. Aberrant neurogenesis is linked to cognitive decline in aging and neurodegeneration. Therefore, identifying endogenous metabolic factors that regulate new adult-born neuron formation is an important objective in understanding the link between nutritional status and CNS function. Here, we review current developments in our understanding of ghrelin's role in regulating neurogenesis and memory function.
64Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats.PubMed
Tobias Inhoff, Hubert Mönnikes, Steffen Noetzel, et al.
Peptides. 2008 Dec;29(12):2159-68. doi: 10.1016/j.peptides.2008.09.014. Epub 2008 Sep 30.
Studies showed that the metabolic unlike the neuroendocrine effects of ghrelin could be abrogated by co-administered unacylated ghrelin. The aim was to investigate the interaction between ghrelin and desacyl ghrelin administered intraperitoneally on food intake and neuronal activity (c-Fos) in the arcuate nucleus in non-fasted rats. Ghrelin (13 microg/kg) significantly increased food intake within the first 30 min post-injection. Desacyl ghrelin at 64 and 127 microg/kg injected simultaneously with ghrelin abolished the stimulatory effect of ghrelin on food intake. Desacyl ghrelin alone at both doses did not alter food intake. Both doses of desacyl ghrelin injected separately in the light phase had no effects on food intake when rats were fasted for 12h. Ghrelin and desacyl ghrelin (64 microg/kg) injected alone increased the number of Fos positive neurons in the arcuate nucleus compared to vehicle. The effect on neuronal activity induced by ghrelin was significantly reduced when injected simultaneously with desacyl ghrelin. Double labeling revealed that nesfatin-1 immunoreactive neurons in the arcuate nucleus are activated by simultaneous injection of ghrelin and desacyl ghrelin. These results suggest that desacyl ghrelin suppresses ghrelin-induced food intake by curbing ghrelin-induced increased neuronal activity in the arcuate nucleus and recruiting nesfatin-1 immunopositive neurons.
65NUCB2/nesfatin-1: Expression and functions in the regulation of emotion and stress.PubMed
Yanyan Wei, Jiangbo Li, Huiling Wang, et al.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:221-227. doi: 10.1016/j.pnpbp.2017.09.024. Epub 2017 Sep 27.
Nesfatin-1, a food-intake inhibiting factor processed from nucleobindin 2 (NUCB2), was originally identified by the Oh-I research group. The initial functional studies on NUCB2/nesfatin-1 were mainly focused on its properties of appetite regulation. As is well known, emotional state has an interactional relationship with food intake, and difficulties in regulating emotion and stress have a great influence on appetite and body weight. Some anorexigenic or orexigenic neurotransmitters also play a role in the adjustment of emotion and stress responses in addition to their actions on the homeostatic regulation of food intake, including neuropeptide Y (NPY), melanocyte stimulating hormone (MSH), corticotropin-releasing factor (CRF), and ghrelin. Furthermore, NUCB2/nesfatin-1 immunoreactive neurons were detected extensively in brain areas involved in emotion and stress regulation, such as the hippocampus, hypothalamus, amygdala, and prefrontal cortex (PFC). These data suggest that NUCB2/nesfatin-1 might also have effects on affective states; therefore, many studies were carried out researching the functions of NUCB2/nesfatin-1 in emotion regulation. An increasing body of evidence has been published to elucidate the stress-related activation of NUCB2/nesfatin-1 neurons and alteration of NUCB2/nesfatin-1 concentrations, as well as the behavioral changes induced by the administration of NUCB2/nesfatin-1. In the present review, we summarized current data focusing on the association between NUCB2/nesfatin-1, stress, and psychiatric disorders to elucidate the functions of NUCB2/nesfatin-1 in emotion regulation.
66Role of nesfatin-1 in anxiety, depression and the response to stress.PubMed
Elena Weibert, Tobias Hofmann, Andreas Stengel
Psychoneuroendocrinology. 2019 Feb;100:58-66. doi: 10.1016/j.psyneuen.2018.09.037. Epub 2018 Sep 29.
Nesfatin-1 has been discovered a decade ago and since then drawn a lot of attention. The initially proposed anorexigenic effect was followed by the description of several other involvements such as a role in gastrointestinal motility, glucose homeostasis, cardiovascular functions and thermoregulation giving rise to a pleiotropic action of this peptide. The recent years witnessed mounting evidence on the involvement of nesfatin-1 in emotional processes as well. The present review will describe the peptide's relations to anxiety, depressiveness and stress in animal models and humans and also discuss existing gaps in knowledge in order to stimulate further research.
67NUCB2/nesfatin-1 is associated with severity of eating disorder symptoms in female patients with obesity.PubMed
Elena Weibert, Tobias Hofmann, Ulf Elbelt, et al.
Psychoneuroendocrinology. 2022 Sep;143:105842. doi: 10.1016/j.psyneuen.2022.105842. Epub 2022 Jun 17.
BACKGROUND: Nesfatin-1 has been described as an anorexigenic peptide. Comprehensive evidence also points towards an involvement of nesfatin-1 in the modulation of emotional pathways with a sex-specific regulation of nesfatin-1 in association with anxiety. Although the implication of nesfatin-1 in the regulation of food intake is well-established in animals, data in humans are lacking. Therefore, we investigated a possible association of circulating NUCB2/nesfatin-1 with eating disorder symptoms in female and male patients displaying a wide range of body weight. METHODS: We enrolled 243 inpatients (177 female, 66 male) hospitalized due to anorexia nervosa (n = 66) or obesity (n = 144) or with normal weight and suffering from somatoform, adjustment, depressive or anxiety disorders (n = 33). Plasma samples (NUCB2/nesfatin-1 levels measured by ELISA) and measures of eating disorder symptoms (by EDI-2, range 0-100) were obtained within three days after admission. RESULTS: The study population displayed a distinct prevalence of eating disorder symptoms with female patients with anorexia nervosa (+ 77.0%, p < 0.001) and obesity (+ 87.9%, p < 0.001) reported significantly higher EDI-2 scores than normal weight patients of the same sex. Accordingly, males with anorexia nervosa (+ 39.7%, p < 0.05) and obesity (+ 51.7%, p < 0.001) had significantly higher EDI-2 scores than males with normal weight. Within the same BMI group, women displayed significantly higher scores than men (+ 21.4%, p < 0.05 in patients with anorexia nervosa, + 18.8%, p < 0.001 in participants with obesity). We observed a positive correlation between NUCB2/nesfatin-1 levels and EDI-2 total scores in female patients with obesity (r = 0.285, p = 0.015), whereas no associations were found in other subgroups. A positive correlation between NUCB2/nesfatin-1 levels and BMI was only observed in the male study population (r = 0.315, p = 0.018). CONCLUSIONS: NUCB2/nesfatin-1 plasma levels were positively associated with EDI-2 total scores in women with obesity, while no association was observable in men. The lacking association of NUCB2/nesfatin-1 and EDI-2 total scores in female patients with anorexia nervosa might be due to already low NUCB2/nesfatin-1 plasma levels. Whether NUCB2/nesfatin-1 is selectively involved in eating behavior in women with obesity will have to be further investigated.
68Regulation and physiological functions of phoenixin.PubMed
Han Liang, Qian Zhao, Shuangyu Lv, et al.
Front Mol Biosci. 2022 Aug 25;9:956500. doi: 10.3389/fmolb.2022.956500. eCollection 2022.
Phoenixin is a newly discovered neuropeptide generated from small integral membrane protein 20. Phoenixin is a ligand for the G protein-coupled receptor 173 (GPR173) and has been detected in central and peripheral tissues of human, rats, mice, bovine, and zebrafish. It was initially involved in regulating reproductive function by stimulating the luteinizing hormone release from pituitary cells by increasing the level of gonadotropin-releasing hormone. Recently, many functions of phoenixin have been generalized, including regulation of food intake, memory, Alzheimer's disease, anxiety, inflammation, neuronal and microglial activity, energy metabolism and body fluid balance, cardiovascular function, and endocrine activity. In addition, the interaction between phoenixin and nesfatin-1 have been revealed. The present article summarized the latest research progress on physiological function of phoenixin, suggesting that it is a potential target for novel drug development and clinical application.
69Role of the Novel Peptide Phoenixin in Stress Response and Possible Interactions with Nesfatin-1.PubMed
Tiemo Friedrich, Andreas Stengel
Int J Mol Sci. 2021 Aug 25;22(17):9156. doi: 10.3390/ijms22179156.
The novel peptide phoenixin was shown to be involved in several physiological processes ranging from reproduction to food intake. Interest in this protein has steadily increased over the last few years and its known implications have become much broader, playing a role in glucose homeostasis, anxiety, nociception, and pruritus. Phoenixin is expressed in a multitude of organs such as the small intestine, pancreas, and in the hypothalamus, as well as several other brain nuclei influencing numerous physiological functions. Its highly conserved amino-acid sequence amongst species leads to the assumption, that phoenixin might be involved in essential physiological functions. Its co-expression and opposing functionality to the extensively studied peptide nesfatin-1 has given rise to the idea of a possible counterbalancing role. Several recent publications focused on phoenixin's role in stress reactions, namely restraint stress and lipopolysaccharide-induced inflammation response, in which also nesfatin-1 is known to be altered. This review provides an overview on the phoenixins and nesfatin-1 properties and putative effects, and especially highlights the recent developments on their role and interaction in the response to response.
70Role of interplay between endocannabinoids and neuropeptides in pathogenesis and therapy of depressive and anxiety disorders.PubMed
Miłosz Gołyszny, Jonasz Dragon, Ewa Obuchowicz
Neuropeptides. 2025 Dec;114:102564. doi: 10.1016/j.npep.2025.102564. Epub 2025 Oct 11.
A growing body of evidence suggests the existence of a neurochemical and functional interplay between endocannabinoids and neuropeptides, which are both relevant for the pathomechanism and effects of pharmacotherapy in depressive and anxiety disorders. Here, we review the available data on how endocannabinoids influence the activity of the neuropeptidergic systems and conversely, how neuropeptides affect the endocannabinoid system. The explicit/implicit interactions in the relationship of endocannabinoids-neuropeptides are presented. Our paper focuses on both well-known neuropeptides, i.e., corticotropin-releasing hormone/factor, CRH/CRF; oxytocin, OT; arginine-vasopressin, AVP; neuropeptide Y, NPY; orexins/hypocretins, OXs/HCRTs) and less investigated neuropeptides, i.e., nesfatin-1, NEFA; phoenixin, PNX; spexin, SPX; neuropeptide S, NPS). Of all of the brain regions that have been studied, the direct and indirect bidirectional interactions between endocannabinoids and the neuropeptides has most clearly been established in the hypothalamus. It has been proven that neuropeptides are modulators of the multifaceted effects of the endocannabinoid system, namely, its influence on neuroendocrine (CRH/CRF) and behavioral stress responsivity (CRH/CRF, OXs), sociability (OT), feelings of pleasure (OXs/HCRTs, NPS), appetite control (NPY, OXs/HCRTs, CRH/CRF, NEFA) and nociception (OT). This latter effect has only the desirable support of positive influence of endocannabinoids on emotional homeostasis to some extent. Nowadays, increasing attention is being paid to the interplay between endocannabinoids and the less explored peptides, especially NEFA and NPS. This trend is both desirable and necessary for gaining a better understanding of the neurochemical aspects and for providing new insights into the potential therapeutic implications in the treatment of affective disorders.
71The Microbiome-Gut-Brain Axis in Health and Disease.PubMed
Timothy G Dinan, John F Cryan
Gastroenterol Clin North Am. 2017 Mar;46(1):77-89. doi: 10.1016/j.gtc.2016.09.007. Epub 2017 Jan 4.
Gut microbes are capable of producing most neurotransmitters found in the human brain. Evidence is accumulating to support the view that gut microbes influence central neurochemistry and behavior. Irritable bowel syndrome is regarded as the prototypic disorder of the brain-gut-microbiota axis that can be responsive to probiotic therapy. Translational studies indicate that certain bacteria may have an impact on stress responses and cognitive functioning. Manipulating the gut microbiota with psychobiotics, prebiotics, or even antibiotics offers a novel approach to altering brain function and treating gut-brain axis disorders, such as depression and autism.
72The emerging role of the gut microbiome in posttraumatic stress disorder.PubMed
Shanlin Ke, Jakob Hartmann, Kerry J Ressler, et al.
Brain Behav Immun. 2023 Nov;114:360-370. doi: 10.1016/j.bbi.2023.09.005. Epub 2023 Sep 7.
Posttraumatic stress disorder (PTSD) occurs in some people following exposure to a terrifying or catastrophic event involving actual/threatened death, serious injury, or sexual violence. PTSD is a common and debilitating mental disorder that imposes a significant burden on individuals, their families, health services, and society. Moreover, PTSD is a risk factor for chronic diseases such as coronary heart disease, stroke, diabetes, as well as premature mortality. Furthermore, PTSD is associated with dysregulated immune function. Despite the high prevalence of PTSD, the mechanisms underlying its etiology and manifestations remain poorly understood. Compelling evidence indicates that the human gut microbiome, a complex community of microorganisms living in the gastrointestinal tract, plays a crucial role in the development and function of the host nervous system, complex behaviors, and brain circuits. The gut microbiome may contribute to PTSD by influencing inflammation, stress responses, and neurotransmitter signaling, while bidirectional communication between the gut and brain involves mechanisms such as microbial metabolites, immune system activation, and the vagus nerve. In this literature review, we summarize recent findings on the role of the gut microbiome in PTSD in both human and animal studies. We discuss the methodological limitations of existing studies and suggest future research directions to further understand the role of the gut microbiome in PTSD.
73Regulation of Intestinal Barrier Function by Microbial Metabolites.PubMed
Sweta Ghosh, Caleb Samuel Whitley, Bodduluri Haribabu, et al.
Cell Mol Gastroenterol Hepatol. 2021;11(5):1463-1482. doi: 10.1016/j.jcmgh.2021.02.007. Epub 2021 Feb 18.
The human gastrointestinal tract (GI) harbors a diverse population of microbial life that continually shapes host pathophysiological responses. Despite readily available abundant metagenomic data, the functional dynamics of gut microbiota remain to be explored in various health and disease conditions. Microbiota generate a variety of metabolites from dietary products that influence host health and pathophysiological functions. Since gut microbial metabolites are produced in close proximity to gut epithelium, presumably they have significant impact on gut barrier function and immune responses. The goal of this review is to discuss recent advances on gut microbial metabolites in the regulation of intestinal barrier function. While the mechanisms of action of these metabolites are only beginning to emerge, they mainly point to a small group of shared pathways that control gut barrier functions. Amidst expanding technology and broadening knowledge, exploitation of beneficial microbiota and their metabolites to restore pathophysiological balance will likely prove to be an extremely useful remedial tool.
74The Role of Short-Chain Fatty Acids in Microbiota-Gut-Brain Cross-Talk with a Focus on Amyotrophic Lateral Sclerosis: A Systematic Review.PubMed
Anca Moțățăianu, Georgiana Șerban, Sebastian Andone
Int J Mol Sci. 2023 Oct 11;24(20):15094. doi: 10.3390/ijms242015094.
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by the gradual loss of motor neurons in the brain and spinal cord, leading to progressive motor function decline. Unfortunately, there is no effective treatment, and its increasing prevalence is linked to an aging population, improved diagnostics, heightened awareness, and changing lifestyles. In the gastrointestinal system, the gut microbiota plays a vital role in producing metabolites, neurotransmitters, and immune molecules. Short-chain fatty acids, of interest for their potential health benefits, are influenced by a fiber- and plant-based diet, promoting a diverse and balanced gut microbiome. These fatty acids impact the body by binding to receptors on enteroendocrine cells, influencing hormones like glucagon-like peptide-1 and peptide YY, which regulate appetite and insulin sensitivity. Furthermore, these fatty acids impact the blood-brain barrier, neurotransmitter levels, and neurotrophic factors, and directly stimulate vagal afferent nerves, affecting gut-brain communication. The vagus nerve is a crucial link between the gut and the brain, transmitting signals related to appetite, inflammation, and various processes. Dysregulation of this pathway can contribute to conditions like obesity and irritable bowel syndrome. Emerging evidence suggests the complex interplay among these fatty acids, the gut microbiota, and environmental factors influences neurodegenerative processes via interconnected pathways, including immune function, anti-inflammation, gut barrier, and energy metabolism. Embracing a balanced, fiber-rich diet may foster a diverse gut microbiome, potentially impacting neurodegenerative disease risk. Comprehensive understanding requires further research into interventions targeting the gut microbiome and fatty acid production and their potential therapeutic role in neurodegeneration.
75Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review.PubMed
Federica Di Vincenzo, Angelo Del Gaudio, Valentina Petito, et al.
Intern Emerg Med. 2024 Mar;19(2):275-293. doi: 10.1007/s11739-023-03374-w. Epub 2023 Jul 28.
The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition of the intestinal microbiome and the activity of intercellular connections, regulated by hormones, dietary components, inflammatory mediators, and the enteric nervous system (ENS). Over the years, it has become increasingly evident that maintaining a stable intestinal barrier is crucial to prevent various potentially harmful substances and pathogens from entering the internal environment. Disruption of the barrier is referred to as 'leaky gut' or leaky gut wall syndrome and seems to be characterized by the release of bacterial metabolites and endotoxins, such as lipopolysaccharide (LPS), into the circulation. This condition, mainly caused by bacterial infections, oxidative stress, high-fat diet, exposure to alcohol or chronic allergens, and dysbiosis, appear to be highly connected with the development and/or progression of several metabolic and autoimmune systemic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), neurodegeneration, cardiovascular disease, inflammatory bowel disease, and type 1 diabetes mellitus (T1D). In this review, starting from a description of the mechanisms that enable barrier homeostasis and analyzing the relationship between this complex ecosystem and various pathological conditions, we explore the role of the gut barrier in driving systemic inflammation, also shedding light on current and future therapeutic interventions.
76The short-chain fatty acid butyrate exerts a specific effect on VE-cadherin phosphorylation and alters the integrity of aortic endothelial cells.PubMed
Jiangang Guo, Inka Terhorst, Paul Stammer, et al.
Front Cell Dev Biol. 2023 Feb 8;11:1076250. doi: 10.3389/fcell.2023.1076250. eCollection 2023.
Short-chain fatty acids (SCFAs) like butyrate (BUT) largely influence vascular integrity and are closely associated with the onset and progression of cardiovascular diseases. However, their impact on vascular endothelial cadherin (VEC), a major vascular adhesion and signaling molecule, is largely unknown. Here, we explored the effect of the SCFA BUT on the phosphorylation of specific tyrosine residues of VEC (Y731, Y685, and Y658), which are reported to be critical for VEC regulation and vascular integrity. Moreover, we shed light on the signaling pathway engaged by BUT to affect the phosphorylation of VEC. Thereby, we used phospho-specific antibodies to evaluate the phosphorylation of VEC in response to the SCFA sodium butyrate in human aortic endothelial cells (HAOECs) and performed dextran assays to analyze the permeability of the EC monolayer. The role of c-Src and SCFA receptors FFAR2 and FFAR3 in the induction of VEC phosphorylation was analyzed using inhibitors and antagonists for c-Src family kinases and FFAR2/3, respectively, as well as by RNAi-mediated knockdown. Localization of VEC in response to BUT was assessed by fluorescence microscopy. BUT treatment of HAOEC resulted in the specific phosphorylation of Y731 at VEC with minor effects on Y685 and Y658. Thereby, BUT engages FFAR3, FFAR2, and c-Src kinase to induce phosphorylation of VEC. VEC phosphorylation correlated with enhanced endothelial permeability and c-Src-dependent remodeling of junctional VEC. Our data suggest that BUT, an SCFA and gut microbiota-derived metabolite, impacts vascular integrity by targeting VEC phosphorylation with potential impact on the pathophysiology and therapy of vascular diseases.
77Gut microbiome and health: mechanistic insights.PubMed
Willem M de Vos, Herbert Tilg, Matthias Van Hul, et al.
Gut. 2022 May;71(5):1020-1032. doi: 10.1136/gutjnl-2021-326789. Epub 2022 Feb 1.
The gut microbiota is now considered as one of the key elements contributing to the regulation of host health. Virtually all our body sites are colonised by microbes suggesting different types of crosstalk with our organs. Because of the development of molecular tools and techniques (ie, metagenomic, metabolomic, lipidomic, metatranscriptomic), the complex interactions occurring between the host and the different microorganisms are progressively being deciphered. Nowadays, gut microbiota deviations are linked with many diseases including obesity, type 2 diabetes, hepatic steatosis, intestinal bowel diseases (IBDs) and several types of cancer. Thus, suggesting that various pathways involved in immunity, energy, lipid and glucose metabolism are affected.In this review, specific attention is given to provide a critical evaluation of the current understanding in this field. Numerous molecular mechanisms explaining how gut bacteria might be causally linked with the protection or the onset of diseases are discussed. We examine well-established metabolites (ie, short-chain fatty acids, bile acids, trimethylamine N-oxide) and extend this to more recently identified molecular actors (ie, endocannabinoids, bioactive lipids, phenolic-derived compounds, advanced glycation end products and enterosynes) and their specific receptors such as peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ), aryl hydrocarbon receptor (AhR), and G protein-coupled receptors (ie, GPR41, GPR43, GPR119, Takeda G protein-coupled receptor 5).Altogether, understanding the complexity and the molecular aspects linking gut microbes to health will help to set the basis for novel therapies that are already being developed.
78The impact of the microbiota-gut-brain axis on Alzheimer's disease pathophysiology.PubMed
Tejaswini Doifode, Vijayasree V Giridharan, Jaqueline S Generoso, et al.
Pharmacol Res. 2021 Feb;164:105314. doi: 10.1016/j.phrs.2020.105314. Epub 2020 Nov 25.
The gut microbiota is a complex ecosystem that comprises of more than 100 trillion symbiotic microbial cells. The microbiota, the gut, and the brain form an association, 'the microbiota-gut-brain axis,' and synchronize the gut with the central nervous system and modify the behavior and brain immune homeostasis. The bidirectional communication between gut and brain occurs via the immune system, the vagus nerve, the enteric nervous system, and microbial metabolites, including short-chain fatty acids (SCFAs), proteins, and tryptophan metabolites. Recent studies have implicated the gut microbiota in many neurodegenerative diseases, including Alzheimer's disease (AD). In this review, we present an overview of gut microbiota, including Firmicutes, Bacteroidetes, SCFA, tryptophan, bacterial composition, besides age-related changes in gut microbiota composition, the microbiota-gut-brain axis pathways, the role of gut metabolites in amyloid-beta clearance, and gut microbiota modulation from experimental and clinical AD models. Understanding the role of the microbiota may provide new targets for treatment to delay the onset, progression, or reverse AD, and may help in reducing the prevalence of AD.
79Neurotransmitter modulation by the gut microbiota.PubMed
Philip Strandwitz
Brain Res. 2018 Aug 15;1693(Pt B):128-133. doi: 10.1016/j.brainres.2018.03.015.
The gut microbiota - the trillions of bacteria that reside within the gastrointestinal tract - has been found to not only be an essential component immune and metabolic health, but also seems to influence development and diseases of the enteric and central nervous system, including motility disorders, behavioral disorders, neurodegenerative disease, cerebrovascular accidents, and neuroimmune-mediated disorders. By leveraging animal models, several different pathways of communication have been identified along the "gut-brain-axis" including those driven by the immune system, the vagus nerve, or by modulation of neuroactive compounds by the microbiota. Of the latter, bacteria have been shown to produce and/or consume a wide range of mammalian neurotransmitters, including dopamine, norepinephrine, serotonin, or gamma-aminobutyric acid (GABA). Accumulating evidence in animals suggests that manipulation of these neurotransmitters by bacteria may have an impact in host physiology, and preliminary human studies are showing that microbiota-based interventions can also alter neurotransmitter levels. Nonetheless, substantially more work is required to determine whether microbiota-mediated manipulation of human neurotransmission has any physiological implications, and if so, how it may be leveraged therapeutically. In this review this exciting route of communication along the gut-brain-axis, and accompanying data, are discussed.
80Gut Bacteria and Neurotransmitters.PubMed
Leon M T Dicks
Microorganisms. 2022 Sep 14;10(9):1838. doi: 10.3390/microorganisms10091838.
Gut bacteria play an important role in the digestion of food, immune activation, and regulation of entero-endocrine signaling pathways, but also communicate with the central nervous system (CNS) through the production of specific metabolic compounds, e.g., bile acids, short-chain fatty acids (SCFAs), glutamate (Glu), γ-aminobutyric acid (GABA), dopamine (DA), norepinephrine (NE), serotonin (5-HT) and histamine. Afferent vagus nerve (VN) fibers that transport signals from the gastro-intestinal tract (GIT) and gut microbiota to the brain are also linked to receptors in the esophagus, liver, and pancreas. In response to these stimuli, the brain sends signals back to entero-epithelial cells via efferent VN fibers. Fibers of the VN are not in direct contact with the gut wall or intestinal microbiota. Instead, signals reach the gut microbiota via 100 to 500 million neurons from the enteric nervous system (ENS) in the submucosa and myenteric plexus of the gut wall. The modulation, development, and renewal of ENS neurons are controlled by gut microbiota, especially those with the ability to produce and metabolize hormones. Signals generated by the hypothalamus reach the pituitary and adrenal glands and communicate with entero-epithelial cells via the hypothalamic pituitary adrenal axis (HPA). SCFAs produced by gut bacteria adhere to free fatty acid receptors (FFARs) on the surface of intestinal epithelial cells (IECs) and interact with neurons or enter the circulatory system. Gut bacteria alter the synthesis and degradation of neurotransmitters. This review focuses on the effect that gut bacteria have on the production of neurotransmitters and vice versa.
81Psychobiotics: a novel class of psychotropic.PubMed
Timothy G Dinan, Catherine Stanton, John F Cryan
Biol Psychiatry. 2013 Nov 15;74(10):720-6. doi: 10.1016/j.biopsych.2013.05.001. Epub 2013 Jun 10.
Here, we define a psychobiotic as a live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness. As a class of probiotic, these bacteria are capable of producing and delivering neuroactive substances such as gamma-aminobutyric acid and serotonin, which act on the brain-gut axis. Preclinical evaluation in rodents suggests that certain psychobiotics possess antidepressant or anxiolytic activity. Effects may be mediated via the vagus nerve, spinal cord, or neuroendocrine systems. So far, psychobiotics have been most extensively studied in a liaison psychiatric setting in patients with irritable bowel syndrome, where positive benefits have been reported for a number of organisms including Bifidobacterium infantis. Evidence is emerging of benefits in alleviating symptoms of depression and in chronic fatigue syndrome. Such benefits may be related to the anti-inflammatory actions of certain psychobiotics and a capacity to reduce hypothalamic-pituitary-adrenal axis activity. Results from large scale placebo-controlled studies are awaited.
82Implications of microbe-derived ɣ-aminobutyric acid (GABA) in gut and brain barrier integrity and GABAergic signaling in Alzheimer's disease.PubMed
Kathryn A Conn, Emily M Borsom, Emily K Cope
Gut Microbes. 2024 Jan-Dec;16(1):2371950. doi: 10.1080/19490976.2024.2371950. Epub 2024 Jul 15.
The gut microbial ecosystem communicates bidirectionally with the brain in what is known as the gut-microbiome-brain axis. Bidirectional signaling occurs through several pathways including signaling via the vagus nerve, circulation of microbial metabolites, and immune activation. Alterations in the gut microbiota are implicated in Alzheimer's disease (AD), a progressive neurodegenerative disease. Perturbations in gut microbial communities may affect pathways within the gut-microbiome-brain axis through altered production of microbial metabolites including ɣ-aminobutyric acid (GABA), the primary inhibitory mammalian neurotransmitter. GABA has been shown to act on gut integrity through modulation of gut mucins and tight junction proteins and may be involved in vagus nerve signal inhibition. The GABAergic signaling pathway has been shown to be dysregulated in AD, and may be responsive to interventions. Gut microbial production of GABA is of recent interest in neurological disorders, including AD. and Lactic Acid Bacteria (LAB), including , are predominant producers of GABA. This review highlights how temporal alterations in gut microbial communities associated with AD may affect the GABAergic signaling pathway, intestinal barrier integrity, and AD-associated inflammation.
83Regulation of gut microbiota and serum neurotransmitters in mice by Streptococcus thermophilus GA8- and Lacticaseibacillus rhamnosus HAO9-fermented milk containing high levels of gamma-aminobutyric acid.PubMed
Mei Han, Yao Dong, Shuo Wang, et al.
J Sci Food Agric. 2024 Oct;104(13):8050-8058. doi: 10.1002/jsfa.13634. Epub 2024 Jun 3.
BACKGROUND: Gamma-aminobutyric acid (GABA) is an important neurotransmitter in the human body, with several negative emotions reported as being associated with GABA dysregulation. This study investigates the safety and modulatory effects of GABA-enriched milk, fermented by Streptococcus thermophilus GA8 and Lacticasebacillus rhamnosus HAO9, on the gut microbiota and neurotransmitter profiles in mice. RESULTS: Through rigorous culturing and fermentation processes, we achieved consistent GABA production in milk, with concentrations reaching 4.6 and 8.5 g L for GA8-fermented and co-fermented milk, respectively, after 48 h. Using SPF male C57BL/6J mice, we administered either mono-culture or combined-culture milk treatments and monitored physiological impacts. The treatments did not affect mouse body weight but induced significant changes in gut microbiota composition. Beta diversity analysis revealed distinct microbial profiles between treatment groups, highlighting fermentation-specific microbial shifts, such as an increase in Verrucomicrobia for the GA8 group and a modulation in Saccharibacteria_genera_incertae_sedis for the GA8 + HAO9 group. Serum neurotransmitter levels were elevated in both treatment groups, with significant increases in l-glutamine, l-tryptophan and, notably, serotonin hydrochloride in the GA8 + HAO9 group. Correlation analysis identified a positive association between specific bacterial genera and neurotransmitter levels, suggesting a probiotic effect on neuroactive substances. CONCLUSION: These findings suggest that fermented milk has potential as a probiotic supplement for mood improvement and stress relief, highlighting its role in modulating the gut-brain axis. © 2024 Society of Chemical Industry.
84Small talk: microbial metabolites involved in the signaling from microbiota to brain.PubMed
Giorgia Caspani, Jonathan Swann
Curr Opin Pharmacol. 2019 Oct;48:99-106. doi: 10.1016/j.coph.2019.08.001. Epub 2019 Sep 14.
The wealth of biotransformational capabilities encoded in the microbiome expose the host to an array of bioactive xenobiotic products. Several of these metabolites participate in the communication between the gastrointestinal tract and the central nervous system and have potential to modulate central physiological and pathological processes. This biochemical interplay can occur through various direct and indirect mechanisms. These include binding to host receptors in the brain, stimulation of the vagus nerve in the gut, alteration of central neurotransmission, and modulation of neuroinflammation. Here, the potential for short chain fatty acids, bile acids, neurotransmitters and other bioactive products of the microbiome to participate in the gut-brain axis will be reviewed.
85Dietary metabolism, the gut microbiome, and heart failure.PubMed
W H Wilson Tang, Daniel Y Li, Stanley L Hazen
Nat Rev Cardiol. 2019 Mar;16(3):137-154. doi: 10.1038/s41569-018-0108-7.
Advances in our understanding of how the gut microbiota contributes to human health and diseases have expanded our insight into how microbial composition and function affect the human host. Heart failure is associated with splanchnic circulation congestion, leading to bowel wall oedema and impaired intestinal barrier function. This situation is thought to heighten the overall inflammatory state via increased bacterial translocation and the presence of bacterial products in the systemic blood circulation. Several metabolites produced by gut microorganisms from dietary metabolism have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabolites that can directly or indirectly affect host physiology. In this Review, we discuss several newly discovered gut microbial metabolic pathways, including the production of trimethylamine and trimethylamine N-oxide, short-chain fatty acids, and secondary bile acids, that seem to participate in the development and progression of cardiovascular diseases, including heart failure. We also discuss the gut microbiome as a novel therapeutic target for the treatment of cardiovascular disease, and potential strategies for targeting intestinal microbial processes.
86Deciphering the role of probiotics in mental health: a systematic literature review of psychobiotics.PubMed
A Hussain, N Koser, S M Aun, et al.
Benef Microbes. 2024 Nov 27;16(2):135-156. doi: 10.1163/18762891-bja00053.
Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host. The selection criteria for probiotics include strain safety, viability, tolerance, metabolite production and/or the ability to modulate the immune system. Probiotics are commonly used in industries, such as food, agriculture, medicine, biotechnology, pharmaceuticals, and aquaculture. Recently, the medicinal applications of probiotics have gained attention and are being explored for the prevention and treatment of various diseases. One emerging area of interest is their potential role in psychological disorders. Mental illnesses, characterised by disturbances in behaviour, mood, thinking, and emotions, affect over one billion people globally. While various preventive and treatment options for mental disorders exists, each is associated with certain limitations. A new avenue being explored is the gut-brain axis, a complex bi-directional communication between the gut and the brain, that is facilitated by hormonal, neuronal, humoral, and immunological pathways. This system plays an important role in mental health. Probiotics, as a key modulator of the gut microbiome, could play a vital role in this communication. However, the underlying mechanisms remain to be explored. Probiotics may act through the production of metabolites and neuroactive substances, as well as through immunomodulation and cytokine production. Current data shows promising effects on stress, mood, and depression, presenting probiotics as a potential natural treatment option for psychological disorders. Nevertheless, major limitations in the existing research include insufficient clinical outcomes, limited sample sizes, and variable dosing. Future advancements may be achieved through stratifications based on gut microbiota, the use of next-generation probiotic strains, and the conduct of comprehensive validation studies.
87From Probiotics to Psychobiotics: Live Beneficial Bacteria Which Act on the Brain-Gut Axis.PubMed
Luis G Bermúdez-Humarán, Eva Salinas, Genaro G Ortiz, et al.
Nutrients. 2019 Apr 20;11(4):890. doi: 10.3390/nu11040890.
There is an important relationship between probiotics, psychobiotics and cognitive and behavioral processes, which include neurological, metabolic, hormonal and immunological signaling pathways; the alteration in these systems may cause alterations in behavior (mood) and cognitive level (learning and memory). Psychobiotics have been considered key elements in affective disorders and the immune system, in addition to their effect encompassing the regulation of neuroimmune regulation and control axes (the hypothalamic-pituitary-adrenal axis or HPA, the sympathetic-adrenal-medullary axis or SAM and the inflammatory reflex) in diseases of the nervous system. The aim of this review is to summarize the recent findings about psychobiotics, the brain-gut axis and the immune system. The review focuses on a very new and interesting field that relates the microbiota of the intestine with diseases of the nervous system and its possible treatment, in neuroimmunomodulation area. Indeed, although probiotic bacteria will be concentrated after ingestion, mainly in the intestinal epithelium (where they provide the host with essential nutrients and modulation of the immune system), they may also produce neuroactive substances which act on the brain-gut axis.
88The Vagus Nerve in Appetite Regulation, Mood, and Intestinal Inflammation.PubMed
Kirsteen N Browning, Simon Verheijden, Guy E Boeckxstaens
Gastroenterology. 2017 Mar;152(4):730-744. doi: 10.1053/j.gastro.2016.10.046. Epub 2016 Dec 15.
Although the gastrointestinal tract contains intrinsic neural plexuses that allow a significant degree of independent control over gastrointestinal functions, the central nervous system provides extrinsic neural inputs that modulate, regulate, and integrate these functions. In particular, the vagus nerve provides the parasympathetic innervation to the gastrointestinal tract, coordinating the complex interactions between central and peripheral neural control mechanisms. This review discusses the physiological roles of the afferent (sensory) and motor (efferent) vagus in regulation of appetite, mood, and the immune system, as well as the pathophysiological outcomes of vagus nerve dysfunction resulting in obesity, mood disorders, and inflammation. The therapeutic potential of vagus nerve modulation to attenuate or reverse these pathophysiological outcomes and restore autonomic homeostasis is also discussed.
89The role of psychotherapeutic approaches in treatment of functional dyspepsia, systematic review, and meta-analysis.PubMed
W Zhang, Y Shen, J Hao, et al.
Acta Gastroenterol Belg. 2024 Apr-Jun;87(2):294-303. doi: 10.51821/87.2.13044.
BACKGROUND: Functional dyspepsia is a common functional gastrointestinal disorder that is often challenging to treat. Psychotherapeutic interventions have been proposed as an alternative or adjunctive approach to conventional treatments, but their efficacy remains unclear. OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the efficacy of psychotherapeutic interventions in the treatment of functional dyspepsia. METHODS: A comprehensive search of electronic databases was conducted, from inception to March 2023, for randomized controlled trials (RCTs) that evaluated the effects of psychotherapeutic interventions on patients with functional dyspepsia. The primary outcome measures were gastrointestinal symptoms, quality of life, depression, and anxiety. Data were extracted and analyzed using Review Manager 5.3 software. The risk of bias of the included studies was assessed using the Cochrane Risk of Bias tool. RESULTS: Sixteen RCTs comprising 1550 patients with functional dyspepsia were included in the meta-analysis. The types of psychotherapeutic interventions used in the included studies were cognitive-behavioral therapy (CBT), hypnotherapy, and mindfulness-based stress reduction (MBSR). The control groups were usual care, placebo, supportive therapy, or no treatment. The meta-analysis showed that psychotherapeutic interventions had a significant effect on reducing gastrointestinal symptoms,depression and anxiety in patients with functional dyspepsia. However, no significant improvement was observed in the quality-of-life scores of patients who received psychotherapeutic interventions compared to those in the control group. CONCLUSION: Psychotherapeutic interventions, such as CBT, hypnotherapy, and MBSR, could be a useful adjunct to conventional treatments for functional dyspepsia, as they were found to significantly reduce gastrointestinal symptoms and anxiety in patients. However, further studies are needed to assess the long-term effects and generalizability of these interventions.
90Cognitive behavioural therapy-based interventions for gastroduodenal disorders of gut-brain interaction: A systematic review.PubMed
Mikaela Law, Isabella Pickering, Esme Bartlett, et al.
J Psychosom Res. 2023 Dec;175:111516. doi: 10.1016/j.jpsychores.2023.111516. Epub 2023 Oct 10.
OBJECTIVE: Cognitive behavioural therapy (CBT) is increasingly used to manage Disorders of Gut-Brain Interaction (DGBIs). This systematic review aimed to review the evidence for the effectiveness of CBT-based interventions for patients with gastroduodenal DGBIs. METHODS: Medline, Embase, PubMed, Cochrane Central, and Scopus were searched in July 2022. Studies were included if they investigated the effects of a CBT-based intervention on gastrointestinal symptoms and/or psychological outcomes pre- and post-intervention in patients with gastroduodenal DGBIs. Case studies, studies not in English, and studies with patients under 18 years were excluded. Results were synthesised narratively, and standardised effect sizes were calculated where possible. RESULTS: Nine studies (seven RCTs and two pre/post studies) were identified, with data reported in 10 articles (total N = 602). The studies investigated patients with functional dyspepsia (n = 7), rumination syndrome (n = 1), and supragastric belching (n = 1). The studies had heterogeneous interventions, methodologies, and outcomes, precluding meta-analysis, as well as a moderate-high risk of bias and high drop-outs rates. Findings demonstrated decreased gastrointestinal symptoms and improved anxiety, depression, and quality of life, from pre- to post-intervention, with medium to large effect sizes for symptoms and small to large effect sizes for psychological outcomes. Efficacy was maintained at follow-up, up to one year later. CONCLUSIONS: This review suggests promising evidence that CBT effectively improves gastrointestinal symptoms and psychological outcomes in patients with gastroduodenal DGBIs. However, heterogeneity, risk of bias, and lack of statistical reporting were noted, indicating the need for more robust research and standardisation.
91Psychological interventions for non-ulcer dyspepsia.PubMed
S Soo, P Moayyedi, J Deeks, et al.
Cochrane Database Syst Rev. 2001(4):CD002301. doi: 10.1002/14651858.CD002301.
BACKGROUND: Studies have also shown that NUD patients have higher scores of anxiety, depression, neurotism, chronic tension, hostility, hypochondriasis, and tendency to be more pessimistic when compared with the community controls. OBJECTIVES: This review aims to determine the effectiveness of psychological interventions including psychotherapy, psychodrama, cognitive behavioral therapy, relaxation therapy, guided imagery or hypnosis in the improvement of either individual or global dyspepsia symptom scores and also quality of life scores patients with non-ulcer dyspepsia (NUD). SEARCH STRATEGY: Trials were located through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and PsycLIT, using appropriate subject headings and text words and searching bibliographies of retrieved articles. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-randomised studies assessing the effectiveness of psychological interventions (including psychotherapy, psychodrama, cognitive behavioural therapy, relaxation therapy, guided imagery or hypnosis) for non-ulcer dyspepsia (NUD). DATA COLLECTION AND ANALYSIS: Data were collected on individual, global dyspepsia symptom scores, as well as measures of quality of life (QoL) scores and adverse effects. MAIN RESULTS: The three trials identified showed that there was improvement in the dyspepsia symptom scores at the end of treatment and one trial showed improvement in the psychological parameters. However, meta-analysis was not possible as these trials used different psychological interventions and two of the trials only reported mean change in symptoms and did not give standard deviations of this change. REVIEWER'S CONCLUSIONS: Psychological intervention in the form of psychodynamic psychotherapy and cognitive behavioral therapy may be useful in the treatment of NUD. However, we need more trials to assess dyspepsia symptom scores and also psychological intervention in order to give us a clearer picture of the role of psychological intervention in NUD.
92Psychological interventions for non-ulcer dyspepsia.PubMed
S Soo, P Moayyedi, J Deeks, et al.
Cochrane Database Syst Rev. 2005 Apr 18(2):CD002301. doi: 10.1002/14651858.CD002301.pub4.
BACKGROUND: Studies have also shown that non-ulcer dyspepsia (NUD) patients have higher scores of anxiety, depression, neurotism, chronic tension, hostility, hypochondriasis and tendency to be more pessimistic when compared with the community controls. However, the role of psychological interventions in NUD remains uncertain. OBJECTIVES: This review aims to determine the effectiveness of psychological interventions including psychotherapy, psychodrama, cognitive behavioural therapy, relaxation therapy and hypnosis in the improvement of either individual or global dyspepsia symptom scores and quality of life scores in patients with NUD. SEARCH STRATEGY: Trials were identified by searching the Cochrane Controlled Trials Register (Issue 3-1999), MEDLINE (1966-99), EMBASE (1988-99), PsycLIT (1987-1999) and CINAHL (1982-99). Bibliographies of retrieved articles were also searched and experts in the field were contacted. Searches were updated on 10 December 2002 and 21 January 2004. The searches were re-run on 24 January 2005 and no new trials were found SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-randomised studies assessing the effectiveness of psychological interventions (including psychotherapy, psychodrama, cognitive behavioural therapy, relaxation therapy and hypnosis) for non-ulcer dyspepsia (NUD) were identified. DATA COLLECTION AND ANALYSIS: Data collected included both individual and global dyspepsia symptom scores and quality of life (QoL) scores. MAIN RESULTS: We identified only four trials each using different psychological interventions; three presented results in a manner that did not allow synthesis of the data to form a meta-analysis. All trials suggested that psychological interventions benefit dyspepsia symptoms and this effect persists for one year. However, all trials used statistical techniques that adjusted for baseline differences between groups. This should not be necessary for a randomised trial that is adequately powered suggesting that the sample size was too small. Unadjusted data was not statistically significant. The other problems of psychological intervention included low recruitment and high drop out rate, which has been shown to be greater in patients receiving group therapy. AUTHORS' CONCLUSIONS: There is insufficient evidence from this review to confirm the efficacy of psychological intervention in NUD.
93Mindfulness-based cognitive therapy in functional dyspepsia: A pilot randomized trial.PubMed
Kevin Kim-Jun Teh, Yi-Kang Ng, Kinjal Doshi, et al.
J Gastroenterol Hepatol. 2021 Aug;36(8):2058-2066. doi: 10.1111/jgh.15389. Epub 2021 Jan 14.
BACKGROUND AND AIM: Patients with functional dyspepsia (FD) often have concomitant anxiety and depression. Mindfulness-based cognitive therapy (MBCT) combines the principles of cognitive behavioral therapy and mindfulness. It is a group-based therapy and has been shown to be efficacious in functional gastrointestinal disorders. There are no randomized controlled trials (RCTs) evaluating MBCT in FD. We aimed to evaluate feasibility and efficacy of MBCT in FD management. METHODS: We performed a mixed-method single-center pilot randomized trial of 28 patients fulfilling ROME-III criteria for FD. Fifteen patients were randomized to an 8-week MBCT program while 13 underwent treatment-as-usual (TAU). Patients completed questionnaires at baseline and at week 8. Two focus-groups were conducted. Feasibility of recruitment, acceptability of randomization, procedures and intervention, handout compliance and feasibility of quantitative measures were assessed. The primary outcome was subjective-clinical-assessment of FD symptoms (SCA-FD). Secondary outcome measures included Short-form Nepean Dyspepsia Index (SF-NDI), subjective-clinical-assessment of general health (SCA-GH), EuroQoL-Visual Analog Scale (EuroQoL-VAS), and Depression, Anxiety and Stress Scale-21 Items (DASS-21). RESULTS: Twelve of 15 patients in the MBCT group completed the program. There was a trend towards symptom improvement, with 90% in the MBCT group reporting improvement in SCA-FD compared with 45% in TAU(P = 0.063). Patients who underwent MBCT reported greater improvement in SF-NDI (mean change: -8.8 (SD: 7.5) vs -0.7 (7.2), P = 0.018) and DASS-21 (-19.8 (29.5) vs -5.5 (6.6) P = 0.13) compared with TAU. There was no difference in SCA-GH and EuroQoL-VAS. Based on SCA-FD improvement, the eventual RCT will require 50 patients (25 in each group). CONCLUSIONS: Mindfulness-based cognitive therapy is likely efficacious for FD, and it would be feasible to conduct a RCT.
94Serotonin: a review.PubMed
L F Mohammad-Zadeh, L Moses, S M Gwaltney-Brant
J Vet Pharmacol Ther. 2008 Jun;31(3):187-99. doi: 10.1111/j.1365-2885.2008.00944.x.
5-Hydroxytryptamine, or serotonin, is a biogenic amine most noted for its role as a neurotransmitter. Manipulation of serotonin in animal models was used as a tool for studying its role in humans. Through such research serotonin has been shown to modulate gastrointestinal motility, peripheral vascular tone, cerebral vascular tone, and platelet function and has been implicated in the pathophysiology of mood disorders, emesis, migraine, irritable bowel syndrome (IBS), and pulmonary and systemic hypertension. The knowledge gained is being directly applied back to animals in research on drugs that manipulate the serotonergic system in dogs and cats. Increasing use and availability of drugs that manipulate the serotonergic system has created a circumstance through which a novel toxicity was discovered in both humans and animals. Serotonin Syndrome describes the clinical picture seen in humans and animals with serotonin toxicity. This paper provides a review the physiology of serotonin and its involvement in the pathophysiologic mechanisms of various conditions, including the Serotonin Syndrome.
95Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood.PubMed
Lin Y Hung, Nuno D Alves, Andrew Del Colle, et al.
Gastroenterology. 2025 Apr;168(4):754-768. doi: 10.1053/j.gastro.2024.11.012. Epub 2024 Dec 11.
BACKGROUND & AIMS: Mood disorders and disorders of gut-brain interaction (DGBI) are highly prevalent, commonly comorbid, and lack fully effective therapies. Although selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for these disorders, they may impart adverse effects, including anxiety, anhedonia, dysmotility, and, in children exposed in utero, an increased risk of cognitive, mood, and gastrointestinal disorders. SSRIs act systemically to block the serotonin reuptake transporter and enhance serotonergic signaling in the brain, intestinal epithelium, and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development. METHODS: We used transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial serotonin reuptake transporter or serotonin on mood and gastrointestinal function, as well as relevant communication pathways. We also conducted a prospective birth cohort study to assess effects of gestational SSRI exposure on DGBI development. RESULTS: Serotonin reuptake transporter ablation targeted to the intestinal epithelium promoted anxiolytic and antidepressive-like effects without causing adverse effects on the gastrointestinal tract or brain; conversely, epithelial serotonin synthesis inhibition increased anxiety and depression-like behaviors. Afferent vagal pathways were found to be conduits by which intestinal epithelial serotonin affects behavior. In utero SSRI exposure is a significant and specific risk factor for development of the DGBI, functional constipation, in the first year of life, irrespective of maternal depressive symptoms. CONCLUSION: These findings provide fundamental insights into how the gastrointestinal tract modulates emotional behaviors, reveal a novel gut-targeted therapeutic approach for mood modulation, and suggest a new link in humans between in utero SSRI exposure and DGBI development.
96Functional Dyspepsia and Gastroparesis.PubMed
Michael Camilleri
Dig Dis. 2016;34(5):491-9. doi: 10.1159/000445226. Epub 2016 Jun 22.
BACKGROUND: Upper gastrointestinal disorders typically present with common symptoms. The most relevant non-mucosal diseases are gastroparesis, functional dyspepsia and rumination syndrome. The literature pertaining to these 3 conditions was reviewed. KEY MESSAGES: Gastroparesis is characterized by delayed gastric emptying in the absence of mechanical obstruction of the stomach. The cardinal symptoms include postprandial fullness (early satiety), nausea, vomiting and bloating. The most frequently encountered causes of these symptoms are mechanical obstruction (pyloric stenosis), iatrogenic disease, gastroparesis, functional dyspepsia, cyclical vomiting and rumination syndrome. The most common causes of gastroparesis are neuropathic disorders such as diabetes, idiopathic, post-vagotomy and scleroderma among myopathic disorders. Principles of management of gastroparesis include exclusion of mechanical obstruction with imaging and iatrogenic causes with careful medication and past surgical history. Prokinetics and anti-emetics are the mainstays of treatment. Functional dyspepsia is characterized by the same symptoms as gastroparesis; in addition to delayed gastric emptying, pathophysiological abnormalities include accelerated gastric emptying, impaired gastric accommodation and gastric or duodenal hypersensitivity to distension and nutrients. Novel treatments include tricyclic antidepressants in patients with normal gastric emptying, acotiamide (acetyl cholinesterase inhibitor) and 5-HT1A receptor agonists such as buspirone. Rumination syndrome is characterized by repetitive regurgitation of gastric contents occurring within minutes after a meal. Episodes often persist for 1-2 h after the meal, and the regurgitant consists of partially digested food that is recognizable in its taste. Regurgitation is typically effortless or preceded by a sensation of belching. This has been summarized as a 'meal in, meal out, day in, day out' behavior for weeks or months, differentiating rumination from gastroparesis. Patients often have a background of psychological disorder or a prior eating disorder. Treatment is based on behavioral modification. CONCLUSION: Precise identification of the cause and pathophysiology of upper gastrointestinal symptoms is essential for optimal management.
97Safety and side effect profile of fluoxetine.PubMed
Joachim F Wernicke
Expert Opin Drug Saf. 2004 Sep;3(5):495-504. doi: 10.1517/14740338.3.5.495.
Fluoxetine was the first selective serotonin re-uptake inhibitor to be widely available for treatment of depression and numerous other neuropsychiatric disorders. Its attributes have been described in numerous scientific papers, and it has been the subject of a considerable volume of lay press. Fluoxetine is generally safe and well-tolerated. Common adverse events reported with the recommended dose of 20 mg/day are referable to the gastrointestinal system and the nervous system. The approved dose range is up to 80 mg/day, and when higher doses are used, adverse events are more common. The long half-life of fluoxetine and its active metabolite essentially preclude a withdrawal phenomenon. It is an inhibitor of cytochrome P450 (CYP) 2D6 and other CYP enzymes, which increases the potential for drug interactions. However, most of these are not clinically important. The purpose of this review is to provide an overview of some of the most important information related to safety and side effects of this drug.
98Gastrointestinal adverse events associated with SNRIs: A FAERS-based pharmacovigilance study.PubMed
Jiayi Lin, Sijia Wei, Ying Peng, et al.
J Affect Disord. 2025 Oct 15;387:119484. doi: 10.1016/j.jad.2025.119484. Epub 2025 May 27.
Major depressive disorder is a prevalent mental illness, with SNRIs constituting a mainstay of the psychopharmacological approach to its clinical management. Despite their impact on adherence, efficacy, and relapse risk, gastrointestinal adverse events (AEs) linked to SNRIs remain under-explored. This study systematically evaluated gastrointestinal adverse events associated with SNRIs by leveraging the FDA Adverse Event Reporting System (FAERS) database. A retrospective analysis of FAERS data from 2004 to 2024 identified 114,148 reports involving five SNRI drugs (venlafaxine, desvenlafaxine, milnacipran, levomilnacipran, and duloxetine). Gastrointestinal adverse events ranked among the top ten System Organ Classes for all five drugs. At the pharmacovigilance level, we identified 18 positive signals, with significant risks for five specific adverse events: constipation, dry mouth, oral hypoaesthesia, nausea, and vomiting. Descriptive analyses revealed that middle-aged (45-64 years) and elderly (65-74 years) patients were more susceptible to gastrointestinal adverse events compared to younger age groups, although the specific effects varied across different drugs and age groups. These findings highlight the significant risks of gastrointestinal AEs associated with SNRIs, underscoring the need for individualized drug selection, close monitoring, and further research into underlying mechanisms and long-term impacts.
99Selective Serotonin Reuptake Inhibitor Use and Risk of Gastrointestinal and Intracranial Bleeding.PubMed
Wei Cheng Yuet, Dhvani Derasari, Jon Sivoravong, et al.
J Am Osteopath Assoc. 2019 Feb 1;119(2):102-111. doi: 10.7556/jaoa.2019.016.
Selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in the United States. Although SSRIs are highly tolerable relative to other antidepressants, they are associated with a number of adverse effects, including increased gastrointestinal tract bleeding and intracranial bleeding. Mechanisms include increased gastric acid secretion and inhibition of serotonin entrance into platelets. Patients with other bleeding risk factors, such as warfarin, clopidogrel, or aspirin use, may be at heightened risk of these adverse effects. The purpose of this article is to review the incidence of gastrointestinal tract bleeding or intracranial bleeding associated with concomitant SSRI use, the proposed mechanisms of, and the potential pharmacokinetic/pharmacodynamic interactions with anticoagulants and antiplatelets. Given the prevalence of SSRI use in the ambulatory setting, osteopathic physicians should be aware of potential drug-drug interactions and the clinical implications of SSRI-associated bleeding risk.
101Ranitidine and depression.PubMed
A Stocky
Aust N Z J Psychiatry. 1991 Sep;25(3):415-8. doi: 10.3109/00048679109062644.
Three cases are described in which the cessation of the H2-antagonist ranitidine was followed by a rapid improvement in severe depressive symptoms. The literature concerning H2-receptor antagonists and depression is reviewed, and an alternative drug (omeprazole) for severe peptic ulceration is discussed.
102Omega-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.
103Current Trends in Gastric Cancer Surgery and Postoperative Care.PubMed
Sin Hye Park, Ara Cho, Dong Jin Kim
Korean J Helicobacter Up Gastrointest Res. 2025 Dec;25(4):308-318. doi: 10.7704/kjhugr.2025.0063. Epub 2025 Dec 4.
The surgical management of gastric cancer has evolved rapidly, with minimally invasive, function-preserving, and fluorescence-guided techniques increasingly adopted as standard practice. Laparoscopic and robotic gastrectomies have shown comparable long-term oncologic outcomes while providing improved perioperative recovery, and individualized reconstruction methods further enhance postoperative quality of life. Recent trials support the use of neoadjuvant chemotherapy for locally advanced disease, demonstrating improved recurrence-free survival. Postoperative management has shifted its focus from early complication prevention to long-term care, addressing nutritional deficiencies and functional syndromes such as anemia, osteoporosis, dumping syndrome, and gastrointestinal dysfunction. Close coordination between surgeons and multidisciplinary care teams is crucial to ensure the prompt management of postoperative complications, including bleeding, leakage, and abscess formation. The implementation of structured protocols for nutritional assessment, micronutrient supplementation, and comprehensive long-term surveillance is strongly advocated to optimize patient survival and preserve postoperative quality of life. This review summarizes the latest evidence and trends in surgical and postoperative care for gastric cancer, highlighting the importance of standardized, evidence-based protocols and individualized patient care strategies.
104Nutritional status of gastric cancer patients after total gastrectomy.PubMed
J M Bae, J W Park, H K Yang, et al.
World J Surg. 1998 Mar;22(3):254-60; discussion 260-1. doi: 10.1007/s002689900379.
A number of causes of malnutrition after total gastrectomy have been proposed. The purpose of this study was to assess nutritional status and to determine the cause of malnutrition after total gastrectomy. We studied 20 gastric cancer patients who had undergone total gastrectomy and immunochemotherapy and 6 normal controls. Nutritional status was assessed by dietary history, anthropometric methods, and serologic measurements. Malabsorption tests included the fecal fat excretion test, D-xylose absorption test, glucose tolerance test, vitamin B12 absorption test using dual isotopes, bacterial culture of jejunal aspirates, and jejunal biopsy. Weight loss was compared to the preoperative status in all patients (average 15%: 59.0 +/- 9.9 vs. 50.2 +/- 7.8 kg, preoperatively vs. postoperatively). Average daily calorie intake was 1586.2 kcal, which is lower than the normal intake of Korean adults (1838 kcal). Malnutrition of skeletal and visceral protein was not found. There was, however, severe fat malnutrition and a deficit of body fat. Postoperatively the body mass index was considerably lower than that preoperatively (22.2 +/- 0.4 vs. 18.9 +/- 0.4 kg/m2; preoperatively vs. postoperatively). With malabsorption tests, the daily excreted amount of fecal fat was 28.6 +/- 3.4 g (mean +/- SD) in patients and 6.9 +/- 0.2 g in controls. There was no significant malabsorption of carbohydrates. In 64.3% (9/14) of patients, vitamin B12 absorption was abnormal; and the serum concentration of vitamin B12, which was significantly related to malabsorption of this vitamin, was lower than normal in 73.7% (14/19). Bacterial overgrowth was not found, and there were no abnormal histologic findings in the jejunal mucosa. These results suggest that poor oral intake and fat malabsorption following total gastrectomy cause malnutrition and that fat malabsorption may be related to relative pancreatic insufficiency.
105Nutritional consequences of total gastrectomy.PubMed
E L Bradley, J Isaacs, T Hersh, et al.
Ann Surg. 1975 Oct;182(4):415-29. doi: 10.1097/00000658-197510000-00007.
Nutritional status was investigated in 10 patients who had previously undergone total gastrectomy without evidence of malignancy. The ability of these patients to ingest and absorb adequate amounts of nutrients was examined. Metabolic balance studies were also performed to discover how effectively these patients could accumulate and use the absorbed nutrients. In the controlled hospital situation, the amount of food ingested was greater than the amount required for maintenance of Ideal Body Weight. Although mild malabsorption of fat and nitrogen was documented, weight gain and positive nitrogen balance occurred. In direct contrast, food intake significantly decreased when the patients returned to their home environment. While severe malabsorption may contribute to malnutrition in the individual patient, the most common mechanism responsible for postoperative malnutrition was inadequate intake. In the occasional patient with severe malabsorption, the universal demonstration of jejunal anaerobic bacterial overgrowth offers important therapeutic implications. The relative importance of pancreatico-biliary insufficiency in promoting malabsorption remains to be determined. Construction of a Hunt-Lawrence jejunal pouch was not found to favorably affect caloric intake, weight gain, degree of malabsorption, or dumping symptoms. Although some degree of malnutrition does result from total gastric resection, in most cases it is mild and potentially correctable. Avoidance of indicated total gastrectomy due to fears of progressive postoperative malnutrition is unwarranted.
106Clinical application of ghrelin administration for gastric cancer patients undergoing gastrectomy.PubMed
Shuji Takiguchi, Akihiro Takata, Kohei Murakami, et al.
Gastric Cancer. 2014 Apr;17(2):200-5. doi: 10.1007/s10120-013-0300-8. Epub 2013 Sep 20.
Loss of body weight is a common (and the most serious) sequela after gastrectomy. It impairs quality of life, increases various diseases including infection, and may affect long-term survival. Ghrelin, an intrinsic ligand of the growth hormone secretagogue receptor, was discovered in the stomach in 1999. In addition to growth hormone secretion, ghrelin has pleiotropic functions including appetite stimulation, increasing bowel movement and absorption, and anti-inflammatory reactions. In consequence, ghrelin comprehensively leads positive energy balance and weight gain. The fundic gland of the stomach produces the majority of ghrelin, and plasma ghrelin declines to 10-30 % of the preoperative level after total gastrectomy and 50-70 % after distal gastrectomy. Although plasma ghrelin is never restored after total gastrectomy, it gradually recovers to the preoperative level within a few years after distal gastrectomy. Chronic gastritis due to Helicobacter pylori infection and vagotomy are additional factors that perturb the ghrelin secretion of gastric cancer patients after gastrectomy. A randomized clinical trial that revealed that recombinant ghrelin administration successfully increased both food intake and appetite, and ameliorated weight loss after total gastrectomy. Ghrelin administration could thus be a promising strategy to transiently improve the nutritional status of patients who who have undergone gastrectomy, but its effect in the long term remains unclear. Further studies are warranted to elucidate the mechanism of ghrelin and to create and evaluate the analogs that could be administered orally or subcutaneously.
107Risk factors and post-operative complications after gastrectomy for cancer.PubMed
T Jínek, L Adamčík, R Vrba, et al.
Rozhl Chir. 2018 Summer;97(8):384-393.
INTRODUCTION: Gastric resections due to carcinoma belong to the most demanding procedures in visceral surgery. This is due to the requirements for the extent of resection and lymphadenectomy, coupled with the need for functional reconstruction of the digestive tract. The procedure is associated with 18-46% morbidity, which delays administration of adjuvant therapy and worsens oncological results. Identification of risk factors for potential complications may play an important role in the indication and perioperative care. The aim of our study is to (i) evaluate the morbidity a mortality of a patient group with post-gastrectomy complications and to (ii) identify associated risk factors. METHOD: This retrospective analysis comprises patients treated in 2005-2016. Gastric resection was performed in 266 adenocarcinoma patients, 172 men and 94 women (median age 66 years). Early post-operative complications following gastrectomy were observed within 60 days. Complications and their severity were evaluated according to the extended form of the Accordion Severity Grading System. Selected demographic risk factors, operative factors and malignancy-related factors were analyzed. Multivariate regression (orthogonal projections to latent structure) was used for statistical processing. RESULTS: Overall morbidity and mortality was 34.6% and 3.4%. Serious complications occurred in 51 operated patients (19.2%). 24 patients had two or three complications (9%). The most common grades of severity were grade 2 in 31 patients (11.7%) and grade 4 in 20 patients (10.9%). The duration of hospital stay correlated with the severity of the complication. Most common surgical complications were: intra-abdominal abscess (16.4%, 17 cases), wound complications (5.3%, 14 cases), pancreatitis (4.9%, 13 cases), anastomotic leakage (3.4%, 9 cases), postoperative ileus (3.4%, 9 cases). Respiratory and cardiac complications were the most common non-surgical complications (8.6%, 23 cases and 3.8%, 20 cases, respectively). In the derived statistical model, BMI, the presence of more comorbidities, lesser surgical experience, the length of hospital stay and hospitalization at ICU were identified as risk factors associated with the grade of complication, morbidity, presence of serious complication and multiple complications. CONCLUSION: Gastrectomy plays a fundamental role in the curative treatment of gastric carcinoma; it is, however, associated with substantial morbi-dity and mortality. The best management of complications is their prevention. Preoperatively, the greatest attention should be paid to patients with several comorbidities and higher BMI. Resections should be performed by experienced surgeons. During resection, consideration should be given to the extent of resection and lymphadenectomy. In the postoperative period, the length of hospital stay, especially at ICU, should be reduced to minimum. Analyses of these risk factors may decrease the incidence of complications. Key words: gastric cancer - gastrectomy - risk factors - complications.
108Clinical pathways in gastric cancer care.PubMed
Maria Bencivenga, Ilaria Palla, Lorenzo Scorsone, et al.
Updates Surg. 2018 Jun;70(2):279-291. doi: 10.1007/s13304-018-0544-2. Epub 2018 Jun 19.
The diagnostic-therapeutic pathways (DTPs) are emerging as useful instruments for clinical management of complex diseases as gastric cancer, whose treatment is challenging and requires a multidisciplinary approach. However, the DPTs of patients with gastric cancer are still not defined yet. The aim of this study was to define the optimal DPT to be applied for patients with gastric cancer in the Veneto region. Rather than defining the ideal DTPs a priori, we conducted a preliminary research by analyzing the differences in the actual DPTs for patients with gastric cancer among different hospitals (hub and spokes) in Veneto. Then, the final DPT was elaborated based on the current available best clinical evidences; however, also the areas of homogeneity among the actual DPTs of the included centers as well as the critical issues that had emerged by our preliminary analysis were taken into account for pathway design. High heterogeneity in actual DTPs of patients with gastric cancer was observed among the analyzed centres. Moreover, some of the major criticisms have been found at crucial points of the current pathways. Based on these data, a reference path that is applicable to the whole-regional health network was constructed. The reference DTP is focused on multidisciplinary team management of patients with gastric cancer. Clinical pathways are essential tools to properly manage complex diseases such as gastric cancer. As such, more efforts should be done to implement their use.
109Nutritional Support in Esophagogastric Cancers.PubMed
Elliott Birnstein, Mark Schattner
Surg Oncol Clin N Am. 2017 Apr;26(2):325-333. doi: 10.1016/j.soc.2016.10.003. Epub 2017 Feb 9.
Esophageal and gastric cancers are common malignancies, both in the United States and worldwide, that carry significant morbidity and mortality. Malnutrition is a common complication in patients with esophageal and gastric cancers and it portends a poor prognosis. For patients who undergo surgical therapy for these types of cancers, preoperative and postoperative nutritional optimization have been shown to improve outcomes. The support can be accomplished in different manners, including orally, enterally, or parentally. In patients who do not undergo surgery but receive chemotherapy and/or radiation, nutritional support is also an important aspect of the multidisciplinary care approach.
110Best practices for home nutritional management in postoperative gastric cancer patients: an evidence summary.PubMed
Wang Shanshan, Wen Lian, Dong Lu, et al.
BMC Cancer. 2025 Aug 29;25(1):1399. doi: 10.1186/s12885-025-14608-9.
OBJECTIVE: To review and summarize the most compelling evidence on home nutritional management for postoperative gastric cancer patients, with the aim of providing a reference to improve patients' nutritional status at home. METHODS: A comprehensive search was conducted across both Chinese and English-language databases according to the '6S' evidence resource model to identify relevant literature on home nutritional management for postoperative gastric cancer patients. The selected studies were screened, evaluated, and synthesized to extract high-quality evidence. RESULTS: A total of 19 articles were included in the final review, including 6 evidence-based guidelines, 4 expert consensus, 2 systematic reviews, 1 evidence summary, 1 qualitative study, 1 class experiment, and 4 RCTs. Through induction and integration, 27 best evidences were formed, which was cat-egorized into seven key areas: nutritional monitoring and assessment, multidisciplinary teamwork, home nutritional management, home nutritional support, health promotion, symptom management, and post-discharge follow-up. These evidences provide clear practical recommendations, such as the selection of home nutrition assessment tools (NRS-2002), the frequency of nutrition assessment (Every two weeks for the first three months), the order of home nutrition during rehabilitation (Diet-ONS-HEN), and the treatment of postoperative adverse nutritional symptoms. CONCLUSION: This study presents a systematic compilation of the best available evidence on home nutritional management for postoperative gastric cancer patients. The findings provide a scientifically grounded framework for healthcare professionals and patients to optimize nutritional care at home. In the future, investigations should focus on translating these evidences into practice through implementation science methodologies, while systematically evaluating the contextual barriers of the implementation of theoretical evidence and the gap between it and the real demand.
111Introduction Long-Term Effects of Professional and Non-professional Support on a Healthy Lifestyle Following Bariatric Surgeries.PubMed
Lani Ofri, Sharon Barak, Dror Dicker, et al.
Obes Surg. 2025 Mar;35(3):970-976. doi: 10.1007/s11695-025-07737-4. Epub 2025 Feb 11.
BACKGROUND: Obesity, defined as a body mass index (BMI) of ≥ 30 kg/m, is a global health crisis with severe physical and mental health implications. While bariatric surgery offers the most effective solution for severe obesity, long-term success depends on sustained behavioral changes and support (non-professional and professional). This study explores the role of support in promoting a healthy lifestyle after surgery. METHODS: This study surveyed 211 individuals, aged 18-65, who had bariatric surgery more than 2 years ago, using random selection. Data were collected via phone interviews, ensuring anonymity. Questionnaires assessed healthy lifestyle (physical activity and nutrition) as well as professional and non-professional support participants received. Analysis methods encompassed χ tests, Pearson correlations, t-tests, and multiple regressions for predicting a healthy lifestyle. RESULTS: Most participants underwent sleeve gastrectomy with varied BMIs (17-47), and only 19.4% had a healthy weight. Two-thirds engaged in physical activities, with generally healthy diets. While 78.7% received post-surgery support, most of this support was provided by surgeons. However, less than half had access to professional psychological support or participated in non-professional support, such as joining support groups. Regression models showed that support significantly predicted nutrition but not physical activity level. However, years from surgery were also an important predictor with the overall model predicting 2% (general nutrition-not appropriate) to 12% (bariatric nutrition) of healthy lifestyle variability. CONCLUSIONS: Most participants sought surgical consultation early post-surgery, but long-term follow-up and engagement with professional services were low. Support from dietitians or psychologists was linked to improved nutritional outcomes, highlighting the importance of sustained professional guidance.
112Spiritual practices are associated with improved weight management following bariatric surgery.PubMed
Kellsey N Launius, Leslie M Schuh, Karen Saules, et al.
Surg Obes Relat Dis. 2022 Sep;18(9):1176-1182. doi: 10.1016/j.soard.2022.05.026. Epub 2022 Jun 1.
BACKGROUND: Research shows that spirituality and religiosity may positively impact various health outcomes, but little is known about their role in supporting weight management efforts, particularly in the context of bariatric surgery. OBJECTIVE: This study examined spiritual practices and health-related behaviors of bariatric surgery patients 1-2 years postoperatively. SETTING: Large bariatric center in the Midwest of the United States. METHODS: Patients (n = 152) completed questionnaires 1-2 years postoperatively examining weight, physical activity, eating behaviors, and spiritual practices and experiences related to bariatric surgery. RESULTS: Participants were primarily married (59.2%), Caucasian (81.6%), and female (84.2%) who had undergone Roux-en-Y gastric bypass (64.5%) or sleeve gastrectomy (32.9%) 17.3 months previously. Most participants (71%) believed their spirituality did or could impact weight loss after surgery. Practices including connecting with nature, art and music, meditation, yoga, and attending spiritual or religious-based activities were positively correlated with weight loss, healthy eating, or exercise participation. CONCLUSION: Findings provide preliminary evidence for the benefits of spirituality in bariatric patients making lifestyle changes after surgery.