Extrinsic Gut-Innervating Neurons as Regulators of Intestinal Microbiota Sensing and Response

标题：肠外神经支配神经元作为肠道微生物群感知和反应的调节器。 项目概要/摘要 本计画的目的是探讨肠道神经元感受微生物刺激的机制 (from病原体、致病菌和病原体）来调节肠内稳态和免疫应答。 肠神经支配神经元（GIN）是外周自主神经系统的一部分，并调节肠神经系统的功能。 功能包括运动、分泌和免疫稳态。它们可以被分类为内在的（或神经元的） 肠神经系统的组成部分; ENS），在肠内具有细胞体，和外源性，具有细胞 肠外神经节中的体，例如来自迷走结状神经节的支配肠的神经元 (NG迷走神经）、背根神经节（DRG）或腹腔神经节/上级肠系膜神经节（CG-SMG）。的 传入和传出外周回路以反射方式组织以调节免疫应答， 炎症尽管长期以来有证据表明GIN功能障碍与生态失调、动力障碍和 结肠炎，很少有方法研究外源性GIN和结肠炎中的微生物群之间的串扰。 调节免疫反应，即使微生物群的组成涉及影响免疫反应， 疾病如炎症性肠病（IBD）、类风湿性关节炎和多发性硬化症（MS）。更好地 阐明哪些外源性GIN负责感知微生物群并调节肠道内稳态 和免疫反应，我们将联合收割机结合一系列的分子，成像和遗传技术。肠 微生物群调节促炎性辅助性T细胞1（Th 1）和Th 17细胞之间的平衡， 肠子里的粘液。在稳态条件下，肠道微生物群介导的Th 17细胞应答是非稳态的。 炎症和宿主组织保护。然而，在免疫挑战或免疫功能丧失的情况下， 耐受性，肠道微生物群可以驱动炎症性Th 17细胞反应，这可能有助于炎症性Th 17细胞反应。 疾病使用我的赞助实验室的各种模型，我们建议阐明外源性GIN是如何感知 肠道中的微生物和调节上皮屏障以及免疫反应。了解如何 外源性GINs感觉肠道微生物群可能提供对宿主对肠道易感性机制的见解， 感染以及器官特异性自身免疫性疾病，包括IBD和MS。

Title: Extrinsic Gut-Innervating Neurons as Regulators of Intestinal Microbiota Sensing and Response. Project Summary/Abstract The goal of this project is to investigate the mechanisms by which gut-innervating neurons sense microbial stimuli (from commensals, pathobionts, and pathogens) to modulate intestinal homeostasis and immune responses. Gut-innervating neurons (GINs) are part of the peripheral autonomic nervous system and regulate intestinal functions including motility, secretion, and immune homeostasis. They can be classified as intrinsic (or neuronal component of the Enteric Nervous System; ENS), with cell bodies within the intestine, and extrinsic, with cell bodies in ganglia outside of the intestine such as neurons innervating the intestine from the vagus nodose ganglia (NG; vagal nerve), dorsal root ganglia (DRG), or celiac ganglia/superior mesenteric ganglia (CG-SMG). The afferent and efferent peripheral circuits are organized in a reflexive manner to regulate immune responses and inflammation. Despite the longstanding evidence of GINs dysfunction associated with dysbiosis, dysmotility and colitis, few if any approaches have investigated the crosstalk between the extrinsic GINs and the microbiota in modulating immune responses, even though the composition of the microbiota has been implicated in influencing diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis and multiple sclerosis (MS). To better elucidate which extrinsic GINs are responsible for sensing the microbiota and modulate intestinal homeostasis and immune responses, we will combine a series of molecular, imaging and genetic techniques. Intestinal microbiota regulate the balance between pro-inflammatory T helper 1 (Th1) and Th17 cells and anti-inflammatory Tregs in the gut. Under homeostatic conditions, intestinal microbiota-mediated Th17 cell responses are non- inflammatory and host tissue-protective. However, in the context of immune challenge or loss of immunological tolerance, intestinal microbiota can drive inflammatory Th17 cell responses that can contribute to inflammatory disease. Using various models from my sponsoring lab, we propose to elucidate how extrinsic GINs sense microbes in the gut and modulate both the epithelial barrier as well as immune responses. Understanding how extrinsic GINs sense gut microbiota may provide insights into mechanisms of host susceptibility to intestinal infection, as well as organ-specific autoimmune disease, including IBD and MS.