Microbiota-dependent early life programming of gastrointestinal motility

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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.