Metabolic Regulation of Inflammation by Microbial SCFA

PROJECT ABSTRACT 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 3 million Americans suffer with IBD, with incidence rates on the rise in many populations. The precise etiology of IBD is not known but emerging evidence implicates shifts in the constellation of microbes in the intestine (dysbiosis) as a significant factor. Our interest in this proposal is aimed at capitalizing on the importance of microbiota- derived metabolites in promoting intestinal homeostasis. In particular, we aim to better understand how microbial- derived factors, such as short chain fatty acids (SCFA, esp. butyrate), contribute to mucosal barrier function and wound healing. Our work in progress has focused on developing and testing a panel of butyrate mimetics that may best serve mucosal barrier function and wound healing in models of IBD. Additional ongoing work using unbiased single cell RNA sequencing (scRNAseq), we identified a cohort of butyrate- induced genes with potential importance in barrier function. In this proposal, we will elucidate whether butyrate mimicry can elicit selectively integrated epithelial functional responses that promote barrier function and coordinate wound healing. Three synergistic specific aims are proposed to address this goal. In Aim 1, we will expand on molecular mimicry of butyrate analogs to optimize epithelial function. Aim 2 will elucidate the mechanisms of selective epithelial control butyrate analogs. Specific Aim 3 define disease-relevant influences of butyrate mimicry on 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 work will lead to the discovery of new therapeutic templates for mucosal inflammatory disease.