Microbiota-dependent early life programming of gastrointestinal motility

项目摘要/摘要 这个项目调查了早期生命肠道微生物区系在肠神经发育中的作用。 控制胃肠(GI)运动的系统。作为转诊到 胃肠病专家表示，肠易激综合征(IBS)等慢性动力障碍使美国 估计每年300亿美元，并降低数百万美国人的生活质量。尽管运动障碍是 通常在成年后首先诊断，然后进行管理，回顾患者报告和其他几个 一系列证据表明，成人运动障碍与早期生命微生物区系-肠道神经系统(ENS)的相互作用有关。 然而，尽管有这些证据，到目前为止还没有研究机械地询问肠道的破坏是如何 生命早期的微生物区系影响慢性动力障碍的严重性和可逆性。然而，我们的 初步数据表明，存在一个出生后发育的关键窗口，在这个窗口中，代谢物 肠道微生物产生的影响Wnt信号的细胞外基质(ECM)结构的成人ENS和 对寄主运动的长期影响。这些发现使我们假设1)中断或耗尽 出生后发育的关键时期的肠道微生物会损害成人的胃肠动力，2)这些影响 部分是由丁酸诱导的Wnt信号的表观遗传调节影响ENS的成熟和 在临界期关闭后，被神经周网络(PNN)样的ECM结构所限制。 我们将在几个发育阶段使用受控微生物操作来验证这些假说。 在诺生菌和常规饲养的小鼠模型中，结合功能运动分析，创新 多尺度成像模式，以及单细胞转录和表观基因组学。拟议的研究形成了 奖学金培训计划的组成部分，该计划利用 芝加哥大学消化疾病研究核心中心，以及合作者在 芝加哥大学、阿贡国家实验室和梅奥诊所。集体资源和 本培训计划中将使用的专业知识不仅将有助于申请者作为 未来的内科医生兼科学家，但也将提供对环境的根本意义的见解 发展过程中的干扰，以及这种干扰与胃肠道健康的相关性。我们预料到 生命早期的印记过程可能会通过恢复关键的发育因素来重新编程，这取决于 干预发生的年龄。这种洞察力对于预防运动障碍和 为数百万因慢性运动障碍而生活质量受损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.