Metabolic Regulation of Inflammation by Microbial-Derived Short Chain Fatty Acids

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The Inflammatory Bowel Diseases (IBD), including Crohn's disease and ulcerative colitis, remain among the most debilitating inflammatory disorders of the western world. It is estimated that more than 1.5 million Americans suffer with IBD, with incidence rates on the rise in many populations. The precise etiology of IBD is not known. Our interest is focused on the identification of inflammation-associated changes in tissue metabolism during active inflammation. In particular, we aim to better understand how microbial- derived factors, such as short chain fatty acids (SCFA), contribute to mucosal barrier function and wound healing. Our work in progress has focused on defining molecular pathways and microbial targets associated with metabolic shifts in inflammation. In ongoing work using unbiased single cell RNA sequencing (scRNAseq), we identified a cohort of butyrate-induced genes with potential importance in barrier function and mucosal wound healing responses. This butyrate-elicited epithelial gene signature serves as a template to understand host-microbial interactions at a molecular level. In this proposal, we will define how microbe-derived SCFA are essential for integrated epithelial functional responses that promote barrier function and coordinate wound healing. Three synergistic specific aims are proposed. In Aim 1, we will elucidate the contribution of butyrate- induced target gene(s) to barrier formation and wound healing. Aim 2 will define the relative contribution of HIF stabilization and/or HDAC inhibition to SCFA-elicited mucosal barrier function and wound healing. Specific Aim 3 will determine the relevance of butyrate-induced signaling and gene expression in acute and chronic mucosal inflammation models in vivo. Results from these experiments will provide new insights into innate regulation of mucosal barrier and an expanded physiological role for SCFA produced by commensal bacteria. It is our hope that extensions of this will lead to the identification of new therapeutic targets for mucosal inflammatory disease