Microbiota-dependent early life programming of gastrointestinal motility

项目总结/摘要 该项目研究了早期生活肠道微生物群在肠神经发育中的作用， 系统，其控制胃肠（GI）运动。最常见的原因是转介到 胃肠病学家，慢性动力障碍，如肠易激综合征（IBS）的成本国家和 估计每年300亿美元，并降低数百万美国人的生活质量。虽然运动障碍是 通常首先诊断，然后在成年后进行管理，回顾性患者报告和其他几个 一系列证据表明，在成年运动障碍中，早期生活微生物-肠神经系统（ENS）相互作用。 然而，尽管有这些证据，迄今为止还没有研究从机制上探讨肠道的破坏是如何发生的。 在生命早期的微生物群影响慢性动力障碍的严重性和可逆性。但我们的 初步数据表明，存在一个关键的窗口出生后的发展，其中代谢物 影响成年ENS中Wnt信号传导细胞外基质（ECM）结构， 对宿主运动的长期影响。这些发现使我们假设：1）破坏或耗尽 在出生后发育的关键窗口期，肠道微生物会损害成年人的胃肠道运动，2）这些影响 部分由丁酸盐诱导的影响ENS成熟的Wnt信号传导的表观遗传调节介导， 在关键期关闭后受到神经元周网（PNN）样ECM结构的限制。 我们将在几个发育阶段使用受控的微生物操作来询问这些假设 在gnotobiotic和常规饲养的小鼠模型中，结合功能性运动测定， 多尺度成像模式，以及单细胞转录组学和表观基因组学。拟议的研究构成一个 这是研究金培训计划的一个组成部分，该计划利用了研究所最先进的研究设施， 芝加哥大学消化疾病研究核心中心，以及合作者的专业知识， 芝加哥大学、阿贡国家实验室和马约诊所。集体资源和 在本培训计划中使用的专业知识不仅有助于申请人作为一个 未来的物理学家，科学家，但也将提供洞察环境的根本意义， 发展过程中的干扰，以及这些干扰对GI健康的相关性。我们预计 生命早期的印记过程可能通过恢复关键的发育因素而重新编程，这取决于 进行干预的年龄。这些见解对于预防运动障碍和 为数百万生活质量受到慢性运动障碍损害的患者开发有效的治疗方法。

PROJECT SUMMARY/ABSTRACT This project investigates the role of the early life gut microbiota in the development of the enteric nervous system, which controls gastrointestinal (GI) motility. As the most common reason for referral to a gastroenterologist, chronic motility disorders such as irritable bowel syndrome (IBS) cost the nation an estimated $30 billion annually and reduce quality of life for millions of Americans. Though motility disorders are generally first diagnosed and then managed in adulthood, retrospective patient accounts and several other lines of evidence implicate early life microbiota-enteric nervous system (ENS) interactions in adult dysmotility. Despite this evidence, however, no studies to date have mechanistically interrogated how disruptions to the gut microbiota during early life influence the severity and reversibility of chronic dysmotility. However, our preliminary data suggest the presence of a critical window of postnatal development, in which metabolites produced by gut microbes affect Wnt signaling extracellular matrix (ECM) structures in the adult ENS and have long-term implications for host motility. These findings lead us to hypothesize that 1) disruption or depletion of gut microbes during a critical window of postnatal development impairs adult GI motility, and 2) these effects are partially mediated by butyrate-induced epigenetic regulation of Wnt signaling affecting ENS maturation and are limited after critical period closure by perineuronal net (PNN)-like ECM structures. We will interrogate these hypotheses using controlled microbial manipulations at several developmental stages in gnotobiotic and conventionally raised mouse models, coupled with functional motility assays, innovative multiscale imaging modalities, and single cell transcriptomics and epigenomics. The proposed studies form an integral part of a fellowship training plan, which takes advantage of state-of-the-art research facilities at the University of Chicago Digestive Diseases Research Core Center, as well as the expertise of collaborators at the University of Chicago, Argonne National Laboratories, and the Mayo Clinic. The collective resources and expertise to be utilized in this training plan not only will be instrumental for the applicant's development as a future physician-scientist, but will also provide insights into the fundamental significance of environmental disturbances during development, and the relevance of such disturbances for GI health. We anticipate that imprinting processes early in life may be reprogrammed by restoring key developmental factors, depending on the age at which intervention occurs. Such insights will be critical for the prevention of motility disorders and for developing effective therapies for the millions of patients whose quality of life is harmed by chronic dysmotility.