Brain-gut interactions regulating stress-related gut inflammation and barrier permeability

项目摘要 慢性心理社会压力是功能性胃肠疾病的主要危险因素，如易激惹 肠综合征（IBS）。值得注意的是，IBS和应激相关精神疾病之间存在高共发病率。 例如重度抑郁症（MDD），其中IBS和MDD代表两种最普遍的疾病， 和使人衰弱的疾病。潜在的潜在潜在的共同发病率是最近的发现，慢性 应激诱发低度炎症，这与IBS和MDD都相关。此外，委员会认为， 越来越多的证据表明，肠-脑轴，或中枢和肠神经系统之间的连接， 系统，有助于IBS的病因学。然而，这种情绪状态的机制 因为慢性应激影响肠道病理生理学，包括炎症，仍然知之甚少。在 在小鼠慢性社会失败应激（CSDS）模型的初步实验中，我们发现肠道 在雄性和雌性小鼠中，CSDS后炎症和屏障通透性升高， 这些现象与抑郁样行为如社交回避相关。在这个项目中，我将 研究心理社会压力是如何导致这种肠道病理生理学的。使用逆向病毒追踪策略 从肠道到大脑，以及全脑成像，我已经生成了一个候选人名单， 直接支配肠道的区域。在这个建议的第一个目标中，我将使用综合神经科学， 免疫学技术，如化学遗传学和流式细胞术，以确定这些脑的激活是否 区域可以触发肠道炎症和屏障渗透性。此外，我的目标是确定肠道的子集， 肠道中的神经元在压力期间接收来自大脑的信号以传播IBS样症状。在 第二个目标，然后我将评估肠道中的炎症信号如何传递到大脑， 压力相关行为。由于大脑可以通过感觉神经系统检测周围组织的炎症状态， 传入神经，我将首先确定哪些应激反应大脑区域接收来自肠道的输入。然后我将使用 纤维光度法来评估肠道炎症如何调节这些脑区域的神经元活动及其 行为的后果。同时，我将研究受损的肠道屏障是否允许细菌 毒素从肠腔移位进入循环，促进全身炎症和抑郁样 行为。总的来说，这个项目的目的是定义双向压力激活的肠道-大脑回路， 导致IBS和MDD相关症状。

Project Summary Chronic psychosocial stress is a major risk factor for functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Notably, there is high co-morbidity between IBS and stress-related psychiatric disorders such as major depressive disorder (MDD), with IBS and MDD representing two of the most prevalent and debilitating illnesses worldwide. Potentially underlying this co-morbidity is the recent finding that chronic stress elicits low-grade inflammation, which has been associated with both IBS and MDD. Moreover, increasing evidence suggests that the gut-brain axis, or connections between the central and enteric nervous systems, contributes to the etiology of IBS. However, the mechanisms through which an emotional state such as chronic stress influences gut pathophysiology, including inflammation, remain poorly understood. In preliminary experiments using the chronic social defeat stress (CSDS) model in mice, we find that intestinal inflammation and barrier permeability become elevated following CSDS in both male and female mice, and these phenomena correlate with depression-like behaviors such as social avoidance. In this project, I will investigate how psychosocial stress causes this gut pathophysiology. Using retrograde viral tracing strategies from the gut to the brain, and whole-brain imaging, I have generated a list of candidate stress-activated brain regions that directly innervate the gut. In the first aim of this proposal, I will use integrated neuroscience and immunology techniques, such as chemogenetics and flow cytometry, to determine if activation of these brain regions can trigger gut inflammation and barrier permeability. Moreover, I aim to identify subsets of enteric neurons in the intestine that receive signals from the brain during stress to propagate IBS-like symptoms. In the second aim, I will then assess how inflammatory signals in the gut are conveyed to the brain to influence stress-relevant behaviors. As the brain can detect the inflammatory state of peripheral tissues through sensory afferent nerves, I will first identify which stress-responsive brain regions receive input from gut. I will then use fiber photometry to evaluate how gut inflammation modulates neuronal activity in these brain regions and its consequences on behavior. In parallel, I will investigate if a compromised intestinal barrier allows bacterial toxin translocation from the gut lumen into circulation to promote systemic inflammation and depression-like behaviors. Collectively, this project aims to define bi-directional stress-activated gut-brain circuits that contribute to IBS- and MDD-related symptoms.