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

应激是肠易激综合征（IBS）和炎症性肠病（IBD）发作的触发因素。患者 IBD患者和至少一部分IBS患者的肠道微生物群也发生了变化（也称为生态失调） 以及肠道免疫反应的改变。虽然研究表明免疫反应可以 对胃肠道动力和症状有影响，这是我们对压力作为IBD触发因素的理解中的一个主要空白 和IBS爆发是如何，如果，压力是导致生态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 我们发现腹泻型IBS（IBSd）患者在16S rDNA测序中存在微生态失调， 粪便中分泌型伊加与粪便细菌的结合增加，表明IBSd患者增加了 抗原特异性免疫反应。使用小鼠模型，我们发现压力同样 诱导的腹泻、内脏高敏感性、生态失调和伊加与肠道细菌结合增加， 我们在IBSd患者中的发现。值得注意的是，应激后的胃肠道症状取决于 无菌小鼠在应激后没有发生腹泻。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的移植（FMT）概括了免疫学特征 压力此外，我们观察到，压力诱导的生态失调允许植物生长素的移位， 细菌向肠系膜淋巴结（MLN）转移促进了结肠杯状细胞的形成 通道（GAP），一种也已知将管腔抗原递送至细胞中的抗原呈递细胞（APC）的途径。 固有层（LP）用于在MLN中诱导T细胞应答。然而，哪些细菌免疫 以及这种免疫反应是否会导致生态失调， 症状仍然是一个显着的差距，我们的理解压力作为一个触发器突发炎症性肠病， IBS.我们假设应激后肠道微生物群的生态失调允许易位， 对特定细菌分类群的适应性免疫应答，其用于使生态失调永久化并有助于 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。定义压力后细菌易位（BT）涉及的分类群和途径，以及如何 这与管腔微生物群的变化有关。 目标2.定义肠道细菌抗原特异性免疫应答对应激诱导的生态失调和BT 目标3.定义对肠道细菌的免疫应答的要求和肠道的损失 应激后诱导和维持生态失调和GI症状的细菌分类群