Role of dietary fiber-microbiota Interactions in the development and function of small intestinal T cells

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Summary Crohn’s disease and Ulcerative colitis collectively referred as inflammatory bowel disease (IBD) are diseases in which an aberrant intestinal immune response leads to chronic inflammation. IBD affects an estimated 1.5 million Americans, 2.2 million people in Europe and hundreds of thousands in the rest of the world. The pathogenesis of IBD, while not completely elucidated, is thought to be multifactorial and caused by the interplay of genetics, the microbiome and the environment. One of the major environmental factors associated with increasing the risk for IBD is the diet that an individual consumes. Therefore, the ability to harness nutrition to treat disease is a unique opportunity for profound intervention in IBD progression. The major challenge for implementing dietary therapy for IBD is the lack of understanding of detailed mechanistic pathways to explain the impact of dietary interventions on IBD severity or progression. Epidemiological studies of IBD have shown dietary fiber as the most consistent macronutrient associated with changing risk of IBD. Fiber affects several aspects of the digestive process. Notably, it is also a main energy source for several bacterial species of the microbiome, and differences in fiber consumption strongly affect the microbiome composition and metabolic behavior. However, very few studies have systematically addressed the role of fiber consumption in fluctuations of the microbiome that lead to specific changes in the intestinal immune response. The overall goal of this project is to discover relevant dietary fiber-microbe-immune cell interactions that prevent, induce or alter the course of gut inflammation. We will analyze the changes in microbiota composition and intestinal cell populations caused by the lack of fermentable fiber intake using a model in which mice are fed a complex diet that contains fermentable and non-fermentable fiber or semi-purified ingredients diet lacking fermentable fiber. Moreover, we will select purified fibers representing different fiber types and supplement them in the non-fermentable diet to identify those whose consumption modulate intestinal responses in a healthy state and during inflammation. Finally, to assess the impact of consuming a diet lacking fermentable fiber on the immune system in the context of human microbiota, we will colonize germ free mice with healthy human donor fecal samples and feed them either a mixed fiber, a non- fermentable fiber or a non-fermentable fiber diet supplemented with specific fibers to identify specific fiber supplementations that result in the modulation of immune responses by human microbiota, as well as the bacterial members mediating this interaction.