DEFINING HOST-MICROBIAL INTERACTIONS THAT TRIGGER INFLAMMATORY BOWEL DISEASE

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DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is characterized by relapsing/remitting inflammation of the intestinal tract. Genetics and environmental factors play a role in IBD susceptibility. Indigenous microbes are one of the environmental factors that can trigger IBD in a genetically susceptible host. We previously established Koch's postulates for a specific bacterial species, Bacteroides thetaiotaomicron (B. theta) in the dnKO mouse model of colitis, by colonization of antibiotic pre-treated mice. This model contains loss of signaling for two inhibitory cytokines: IL-10 globally and TGF? in CD4+ T cells, both of which have homologous genetic defects in a subset of cases of human IBD. What is now needed is to determine the molecular mechanism by which B. theta can trigger colitis in this genetically susceptible mouse. We have preliminary data to show that deletion of a single gene in B. theta that controls the activity of 28 sulfatases (anSME for anaerobic sulfatase maturating enzyme) completely inhibits colitis in colonized dnKO mice. Importantly, this mutant B. theta colonizes dnKO mice to similar levels as wild- type B. theta. This finding created the overall hypothesis that B. theta can trigger colitis due to its ability to degrade host sulfated-mucus and access the mucosa. We will use this unique functional system to perform molecular Koch's postulates and determine with more precision, the bacterial sulfatase enzymes in B theta that are required for its colitogenic activity. We will also test the role of host sulfation of mucus as well as its production and secretion. Ultimately in this model, T cells are absolutely required to generate colitis. Surprisingly, prior to colonization with B. theta, the CD4+ T cells are activated and produce inflammatory cytokines, but cause no disease. Thus, the identification of B. theta as the colitogenic bacterium also provides the unique opportunity to determine how CD4+ T cells are triggered into becoming pathogenic. We have also identified TCRs that are specific for human B. theta. This tool will be critical to determine the mechanism by which colitis develops in B. theta colonized dnKO mice. We have assembled a multi-disciplinary team to tackle this project. We will investigate this question in three specific aims. Specific Aim 1: Determine the role of B. theta mucus desulfation in dnKO colitis. Specific Aim 2: Determine the role of intestinal mucus as a functional barrier to B. theta in dnKO mice. Specific Aim 3: Determine how CD4+ T cells initiate dnKO colitis. If competed, these studies will establish new paradigms for how colitogenic microbes trigger disease in a genetically susceptible host and should have application to understanding the pathogenesis of, as well as engineering new treatments for, human IBD.