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

外在肠道神经元作为肠道微生物群感应和反应的调节器

• 批准号: 10156964
• 负责人: Zoila Areli Lopez Bujanda
• 金额: $ 6.6万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10156964
• 关键词: Address; Afferent Neurons; Anti-Cholinergics; Anti-Inflammatory Agents; Autoimmune Diseases; Autonomic nervous system; Bacteria; Brain; CD4 Positive T Lymphocytes; Calcium; Celiac ganglion; Cell Nucleus; Cells; Colitis; Communication; Cues; Development; Disease; Enteric Nervous System; Epithelial; Equilibrium; Functional disorder; Ganglia; Genetic Techniques; Goals; Homeostasis; Imaging Techniques; Immune; Immune Tolerance; Immune response; Immune system; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-17; Intestines; Lead; Mediating; Mesentery; Microbe; Modeling; Multiple Sclerosis; Nerve; Nervous system structure; Neuroimmune; Neurons; Neuropeptides; Nodose Ganglion; Organ; Pathogenicity; Pathway interactions; Peripheral; Play; Positioning Attribute; Predisposition; Process; Production; Reflex action; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Role; Sensory; Series; Signal Transduction; Spinal Ganglia; Stimulus; Surface; Surveys; T cell differentiation; TNF gene; Tissues; Viral; adaptive immune response; antigen-specific T cells; autoinflammatory; cell motility; commensal bacteria; commensal microbes; cytokine; design; dysbiosis; enteric infection; gut microbiota; insight; intestinal epithelium; intestinal homeostasis; microbial; microbiota; molecular imaging; motility disorder; novel strategies; optogenetics; pathobiont; pathogen; receptor; response; sensory system; targeted treatment

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.

标题：作为肠道微生物区系感知和反应调节器的外源性肠道神经细胞。 项目摘要/摘要 这个项目的目标是研究肠道神经细胞感知微生物刺激的机制。 (从共生体、病原体和病原体)调节肠道内稳态和免疫反应。 肠道神经细胞(Gins)是周围自主神经系统的一部分，负责调节肠道。 功能包括运动、分泌和免疫动态平衡。它们可以被归类为固有的(或神经元的) 肠道神经系统的组成部分(ENS)，在肠道内有细胞体，在肠外有细胞 肠外神经节中的小体，如迷走神经结状神经节中支配肠道的神经元 (NG；迷走神经)、背根神经节(DRG)或腹腔神经节/肠系膜上神经节(CG-SMG)。这个 传入和传出外周电路以反射的方式组织起来，以调节免疫反应和 发炎。尽管长期有证据表明GINS功能障碍与生物失调有关，但运动障碍和 结肠炎，几乎没有任何方法研究了外源性Gins和微生物区系之间的串扰 调节免疫反应，即使微生物区系的组成已被牵连到影响 炎症性肠病(IBD)、类风湿性关节炎和多发性硬化症(MS)等疾病。为了更好地 阐明哪些外源性GIN负责感知微生物区系并调节肠道内环境平衡 和免疫反应，我们将结合一系列分子、成像和基因技术。肠道 微生物区系调节促炎T辅助细胞1(Th1)和Th17细胞之间的平衡与抗炎 Tregs在肠子里。在动态平衡条件下，肠道微生物区系介导的Th17细胞反应是非 炎症和宿主组织保护。然而，在免疫挑战或免疫丧失的背景下， 耐受性，肠道微生物区系可驱动炎性Th17细胞反应，从而促进炎症 疾病。使用我的赞助实验室的各种模型，我们建议阐明外在杜松子酒是如何感觉到的。 肠道中的微生物并调节上皮屏障和免疫反应。了解如何 外源性Gins感觉肠道微生物区系可能为宿主对肠道易感性的机制提供洞察 感染以及器官特异性自身免疫性疾病，包括IBD和MS。