ROLE OF STRESS IN GUT IMMUNE INTERACTIONS WITH COMMENSAL BACTERIA

压力在肠道免疫与共生细菌相互作用中的作用

• 批准号: 10204715
• 负责人: CHYI S HSIEH
• 金额: $ 64.12万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-18 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204715
• 关键词: Antigen-Presenting Cells; Antigens; Area; B-Lymphocytes; Bacteria; Bacterial Antigens; Bacterial Translocation; Binding; Constipation; Diarrhea; Disease; Feces; Flare; Frequencies; Functional disorder; Geography; Germ-Free; Goblet Cells; Human; Hypersensitivity; Immune; Immune response; Immune system; Immunoglobulin A; Immunologics; Inflammatory Bowel Diseases; Irritable Bowel Syndrome; Lamina Propria; Lead; Link; Longevity; Measures; Mus; Output; Pathway interactions; Patients; Pharmacology; Physiological; Play; Process; Recombinant DNA; Reporting; Role; Secretory Immunoglobulin A; Stress; Symptoms; T cell response; T-Lymphocyte; Visceral; Water; Weight; Work; adaptive immune response; antigen-specific T cells; cell motility; cohort; commensal bacteria; dysbiosis; fecal transplantation; gastrointestinal; gut bacteria; gut dysbiosis; gut microbiota; intestinal epithelium; mesenteric lymph node; microbiota; microbiota transplantation; mouse model; patient subsets; prevent; response

Stress is a trigger for flares of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Patients with IBD, and at least a subset of patients with IBS, also have alterations in the gut microbiota (aka dysbiosis) and alterations in the gut immune responses. While studies have demonstrated that immune responses can have effects on GI motility and symptoms, a major gap in our understanding of stress as a trigger for IBD and IBS flares is how, and if, stress is causal in dysbiosis and in alterations in gut immune responses and if these changes contribute to symptoms. We discovered that patients with diarrhea predominant IBS (IBSd) had dysbiosis on 16S rDNA sequencing of feces and increased binding of secretory IgA to fecal bacteria, indicating that IBSd patients had increased antigen specific immune responses to their gut bacteria. Using a mouse model, we found that stress likewise induced diarrhea, visceral hypersensitivity, dysbiosis and increased IgA binding to gut bacteria, recapitulating our findings in human IBSd patients. Notably the GI symptoms following stress were dependent upon the microbiota as germ free mice did not develop diarrhea following stress. Further, fecal microbiota transplantation (FMT) of microbiota from stressed, but not control, mice recapitulated the immunologic features of stress. Moreover, we observed that stress-induced dysbiosis allows the translocation of commensal bacteria to the mesenteric lymph node (MLN) facilitated by the formation of colonic goblet cell associated passages (GAPs), a pathway also known to deliver luminal antigens to antigen presenting cells (APCs) in the lamina propria (LP) for the induction of T cell responses in the MLN. However, which bacteria the immune system is responding to during stress and whether this immune response contributes to dysbiosis and symptoms remains a significant gap in our understanding of stress as a trigger for flares of IBD and IBS. We hypothesize that dysbiosis of the gut microbiota following stress allows for the translocation and adaptive immune responses to specific bacterial taxa which serves to perpetuate dysbiosis and contribute to stress induced GI symptoms. To pursue this hypothesis, we propose the following specific aims: Aim 1. Define the taxa and pathways involved in bacterial translocation (BT) following stress, and how that relates to the changes in the luminal microbiota. Aim 2. Define the gut bacterial antigen specific immune response to stress induced dysbiosis and BT Aim 3. Define the requirement of immune responses to commensal bacteria and the loss of gut bacterial taxa following stress in inducing and maintaining dysbiosis and GI symptoms

压力是肠易激综合症（IBS）和炎症性肠病（IBD）发作的诱因。患者 IBD 患者以及至少一部分 IBS 患者的肠道微生物群也发生改变（又名菌群失调） 以及肠道免疫反应的改变。虽然研究表明免疫反应可以 对胃肠道运动和症状有影响，这是我们对压力作为 IBD 触发因素的理解上的一个重大差距 肠易激综合症（IBS）发作是压力如何以及是否会导致肠道菌群失调和肠道免疫反应改变的原因 以及这些变化是否会导致症状。 我们通过 16S rDNA 测序发现，腹泻为主的 IBS (IBSd) 患者存在菌群失调。 粪便中分泌型 IgA 与粪便细菌的结合增加，表明 IBSd 患者的肠道菌群增加 针对肠道细菌的抗原特异性免疫反应。使用小鼠模型，我们发现压力同样 诱发腹泻、内脏过敏、生态失调以及 IgA 与肠道细菌的结合增加，概括起来 我们在人类 IBSd 患者中的研究结果。值得注意的是，压力后的胃肠道症状取决于 无菌小鼠的微生物群在压力后不会出现腹泻。此外，粪便微生物群 来自应激小鼠而非对照小鼠的微生物群移植（FMT）重现了免疫学特征 的压力。此外，我们观察到压力引起的生态失调允许共生体易位 结肠杯状细胞的形成促进细菌到达肠系膜淋巴结（MLN） 通道（GAP），也称为将管腔抗原递送至抗原呈递细胞（APC）的途径 固有层 (LP) 用于诱导 MLN 中的 T 细胞反应。然而，哪些细菌免疫 系统在压力期间做出反应，以及这种免疫反应是否会导致生态失调和 我们对压力作为 IBD 发作触发因素的理解仍然存在重大差距 肠易激综合症。我们假设应激后肠道微生物群的失调导致了易位和 对特定细菌类群的适应性免疫反应，有助于维持生态失调并有助于 压力引起的胃肠道症状。为了实现这一假设，我们提出以下具体目标： 目标 1. 定义应激后细菌易位 (BT) 所涉及的类群和途径，以及如何 这与腔内微生物群的变化有关。 目标 2. 定义肠道细菌抗原对应激引起的生态失调和 BT 的特异性免疫反应 目标 3. 明确对共生细菌的免疫反应和肠道损失的要求 应激后细菌分类群诱导和维持菌群失调和胃肠道症状