Role of Dietary Fiber-Microbiota Interactions in the development and function

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SUMMARY Global incidence of Inflammatory Bowel Disease (IBD) has increased 6% in the past 30 years, reducing quality of life for more than 6.8 million individuals. IBD is characterized by chronic inflammation of the gastrointestinal tract, resulting in Crohn’s Disease (CD) or Ulcerative Colitis (UC). Although its etiology is unknown, IBD is thought to be the result of abnormal mucosal immune responses caused by genetic factors, the microbiome, and the environment. Dietary interventions have been proposed as therapeutic measures for IBD. However, studies that delineate the mechanism of how dietary fiber impacts microbiome composition and development of the mucosal immune response are still very scarce. Such studies are needed to discover diet-microbiota-immune system interactions that can be harnessed to control disease. Results obtained from the parent award R01DK129950- 01 of this application, showed a relationship between dietary fiber, Segmented filamentous bacteria, and CD4+CD8αα+ IEL T cells (DP IELs), a population of intestinal T cells with local regulatory functions in the small intestine. The main aim of this Diversity Supplement Application is to delineate the molecular mechanism of the intestinal epithelial cells-SFB-DP IEL interaction and constitutes a new direction different from the aims proposed in the parent grant. To accomplish this, we propose to determine the effects of fiber and SFB on small intestinal epithelial cells (sIECs) using RNAseq, qPCR and flow cytometry, and determine the role of SFB-dependent expression of MHC II on sIECs cells on the development and turnover of DP IELs using genetically modified in vivo models to remove MHC II expression on intestinal epithelial cells. The studies in this proposal will identify interactions between small intestine epithelial cells and SFB that are necessary for the development of DP IELs and how the absence of fermentable fiber affects these interactions. Our proposed studies will complement and extend the studies proposed in the parent R01 grant, which long-term goal is to identify how the consumption of dietary fiber affects interactions between members of the microbiota and the immune system. These studies will further our understanding of the mucosal immune system to aid in the development and implementation of dietary therapeutic measures that will improve the outcomes of IBD patients.