Indole dysbiosis and mucosal inflammation

University Of Colorado Denver, Aurora CO

Investigators

Linked publications, trials & patents

Abstract

Project Summary/Abstract Mucosal inflammatory diseases such as Crohn's disease and ulcerative colitis, collectively termed Inflammatory Bowel Disease (IBD) remain among the most debilitating chronic 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 contributing factor. This proposal is focused on a precise understanding of the role of microbiota-derived molecules in promoting intestinal resiliency during ongoing inflammation. In particular, we have identified a class of microbiota-sourced molecules derived from dietary tryptophan, termed indoles, that contribute fundamentally to mucosal barrier function and wound healing. Our work in progress has focused on defining endogenous host molecules that interact with indole(s) and become potential targets for the development of new drugs to treat IBD. Ongoing unbiased work has identified neutrophil myeloperoxidase (MPO) as a candidate target for indole(s) with potential importance in promoting healthy barrier function. In this proposal, we hypothesize that this indole-MPO axis determines the extent of bystander tissue damage in active mucosal inflammation. Three synergistic specific aims are proposed to address this goal. In Aim 1, we will profile the direct impact of neutrophil MPO on epithelial tight junction proteins in modeled inflammation. Aim 2 will elucidate the specificity of indole derivatives on MPO inhibition and suppression of epithelial junctional damage. Specific Aim 3 will test the indole-MPO axis in multiple models of intestinal inflammation. Results from these experiments will provide new insights into innate regulation of mucosal barrier and an expanded physiological role for indoles produced by commensal bacteria. The studies proposed in this project are intended to elucidate a novel role for microbial metabolites in innate immune responses during mucosal inflammation using in vitro and in vivo models. This work will provide new insight to the development of improved therapeutic approaches for treating IBD.