Identifying Microbial, Epithelial and Immune Cell Interactions that Mediate Mucosal Homeostasis and Determine IBD Phenotype

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This Diversity Supplement request (PA21-071) related to P01DK094779 is directly integrated into the goals and aims of P01 Project 2 by exploring the functional activities of clinically relevant sulfur-reducing bacteria (SRB) derived from IBD patients and healthy subjects. Shifts in microbial communities and functions characteristic of many intestinal and systemic diseases are promoted by environmental, pharmacological, nutritional and dietary factors. Several clues place sulfur metabolism at the center of the pathogenesis of inflammatory bowel diseases (IBD), with characteristic increased sulfated bile acid and increased SRB. Healthy gut microbiota contain SRB, which are expanded in IBD patients. These SRB can exploit and metabolize an increased sulfur-rich compound pool in IBD patients eating a Western diet to promote intestinal inflammation through toxic H2S production that permeabilizes the mucosal barrier by dissolving the mucus layer, impairs epithelial cell mitochondrial function and alters SCFA-producing bacterial populations and related microbial imbalances that dysregulate bile acids, as seen in IBD. Our work will establish the roles of SRB in IBD and use the latest scientific approaches and humanized murine colitis models developed in P01 Project 2 to test functional properties of these strains that are derived from IBD patients and healthy controls. Hypothesis: sulfur availability modulates the abundance, function and H2S-production of SRB in complex human fecal bacterial communities and influences aggressiveness of experimental colitis. Specific Aims: 1. Characterize the abilities of identified dietary sulfur substrates and H2S to modulate intestinal sulfur-reducing bacteria numbers and fecal bacterial community structure. 2. Determine the inflammatory vs. protective effects of enriched vs. depleted SRB fecal populations and selected SRB strains from IBD clinical isolates. 3. Characterize the ability of high IL-10-inducing bacterial strains to inhibit in vivo SRB populations, H2S production and colitis in humanized IL-10-/- mice. These clinically relevant molecular, strain level and functional characterizations of clinically relevant SRB and the effects of dietary manipulations will expand our understanding of SRB influences on mucosal homeostasis vs chronic inflammation as well as the scope and impact of P01 Project 2 studies.