Influence of gut microbiota strain variation on mucosal T-cell phenotype

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PROJECT SUMMARY Inflammatory bowel diseases (IBD) are chronic inflammatory conditions characterized by a dysregulated immune response that results in intestinal inflammation and tissue damage. Over the past decade, an increasing body of evidence has associated IBD with inappropriate interactions between the gut microbiota and the mucosal immune system. Despite these associations, there have been few studies identifying causal links between specific components of the human gut microbiota and intestinal inflammation. This proposal is focused on discovering specific bacterial strains within the gut microbiota that induce inflammatory T cell responses, with the goal of identifying key strains that contribute to colitis progression. To interrogate T cell responses to individual strains, we will utilize gnotobiotic mice coupled with an ex vivo restimulation assay to measure T cell responses by ELISPOT and flow cytometry. Aim 1 – In our preliminary findings, we provide two examples where our approach successfully identified candidate Th17 stimulating strains from culture collections derived from two IBD donors. Both these results were validated in vivo, demonstrating proof-of- concept for rational modulation of immune tone by selective removal of candidate strains. To expand on these findings, we will extend our method to further explore the influence of genus, species, and strain diversity on Th17 stimulation within IBD-associated microbiotas. This data will indicate if there are particular taxonomic groups that stimulate Th17 cells, or if diversity at the strain level drives variation in T cell responses. Aim 2 – In our preliminary results, we find no difference in colitis progression between groups of microbes that drive Th17 induction and groups of microbes that do not drive Th17 induction, suggesting the microbes that determine Th17 frequency in a homeostatic setting may not be the same microbes that drive colitis in a disease setting. To expand on these findings, we will assess how individual microbes within IBD- associated microbiotas potentiate colitis. These approaches will determine if the colitogenic capacity of a culture collection can be abrogated by the selective removal of particular strains.