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

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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.