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，如应激性 肠道综合征(IBS)。值得注意的是，IBS和应激相关精神疾病的发病率很高。 严重抑郁障碍(MDD)等疾病，IBS和MDD是最常见的两种 以及世界各地令人衰弱的疾病。这种共同发病的潜在原因是最近的发现，慢性 压力会引起低度炎症，这与IBS和MDD都有关联。此外， 越来越多的证据表明，肠道-脑轴，或中枢和肠道神经之间的联系 系统，有助于IBS的病因学。然而，一种情绪状态 由于慢性应激影响肠道的病理生理，包括炎症，仍然知之甚少。在……里面 采用慢性社会失败应激(CSDS)模型对小鼠进行了初步实验，我们发现肠道 在雄性和雌性小鼠中，CSDS使炎症和屏障通透性增加，并且 这些现象与社交回避等类似抑郁的行为有关。在这个项目中，我将 调查心理社会压力是如何导致这种肠道病理生理学的。使用逆行病毒跟踪策略 从肠道到大脑，再到全脑成像，我已经生成了一份候选压力激活大脑的清单 直接支配肠道的区域。在这项提议的第一个目标中，我将使用综合神经科学和 免疫学技术，如化学遗传学和流式细胞术，以确定这些大脑的激活 区域可引发肠道炎症和屏障通透性。此外，我的目标是确定肠道细菌的亚群 肠道中的神经元，在应激期间接收来自大脑的信号，传播IBS样症状。在……里面 第二个目标，然后我将评估肠道中的炎症信号是如何传递到大脑以影响 与压力相关的行为。因为大脑可以通过感官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的大脑区域接受肠道的输入。然后我将使用 纤维光度法评估肠道炎症如何调节这些脑区的神经元活动及其 对行为的后果。同时，我将调查受损的肠道屏障是否允许细菌 毒素从肠腔转移到循环中促进全身炎症和抑郁样反应 行为。总而言之，这个项目旨在定义双向应激激活的肠脑回路， 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.