ROLE OF STRESS IN GUT IMMUNE INTERACTIONS WITH COMMENSAL BACTERIA

压力是引发肠易激综合征(IBS)和炎症性肠病(IBD)的诱因。病人 患有IBD的患者，以及至少一部分IBS患者，肠道微生物区系也发生了变化(也称为生物失调) 以及肠道免疫反应的改变。虽然研究表明，免疫反应可以 对胃肠动力和症状有影响，这是我们对压力作为IBD诱因的理解的一个主要差距 而IBS的爆发是压力如何以及是否会导致生物失调和肠道免疫反应改变的原因。 如果这些变化导致了症状。 我们发现腹泻型肠易激综合征(IBSd)患者在16S rDNA测序中存在生物失调。 粪便和分泌性IgA与粪便细菌结合增加，表明IBSd患者增加了 针对肠道细菌的抗原特异性免疫反应。使用老鼠模型，我们发现同样的压力 引起腹泻、内脏过敏、生物失调和与肠道细菌结合的IgA增加 我们在人类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 微生物区系作为无菌小鼠，在应激后不会出现腹泻。此外，粪便微生物区系 来自应激但不是对照的小鼠的微生物区系移植(FMT)概括了免疫学特征 压力的影响。此外，我们观察到，应激诱导的生物失调允许共生体移位。 细菌促进肠系膜淋巴结(MLN)结肠杯状细胞的形成 通道(GAP)，也是已知的将管腔抗原输送到体内抗原提呈细胞(APC)的途径 固有层(Lp)用于诱导MLN中的T细胞反应。然而，哪些细菌具有免疫力 系统在应激期间的反应，以及这种免疫反应是否有助于生态失调和 症状仍然是我们对压力作为IBD和IBD爆发的触发因素的理解的一个重大差距 IBS。我们假设，应激后肠道微生物区系的失调允许移位和 对特定细菌类群的适应性免疫反应，这种免疫反应有助于维持生物失调并有助于 应激引起胃肠道症状。为了实现这一假设，我们提出了以下具体目标： 目标1.确定应激后细菌易位(BT)所涉及的分类和途径，以及如何 这与管腔微生物区系的变化有关。 目的2.确定肠道细菌抗原对应激诱导的生物失调和Bt的特异性免疫反应 目的3.确定对共生菌和肠道损失的免疫反应的要求 应激诱导和维持生态失调和胃肠道症状后的细菌分类群

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