Host-Microbiota-Diet Interactions in Metabolic Syndrome and IBD

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Humanity is increasingly afflicted by chronic inflammatory diseases, including inflammatory bowel disease (IBD) and metabolic syndrome (Met Syn), which collectively refers to the constellation of metabolic problems associated with obesity. The grant this application seeks to renew has developed our hypothesis that IBD and Met Syn share commonalities of disease pathophysiology, namely that poor management of gut microbiota plays a key role in driving inflammation that is central to both disease states. A central feature of the microbiota dysbiosis observed in both IBD and Met Syn is a more “aggressive” microbiota that encroaches upon the gut epithelium, which is likely germane to its promotion of inflammation. One means of inducing microbiota encroachment and its inflammatory consequences is via consumption of a diet lacking fermentable fiber. We found that such low fiber diet-induced encroachment involves ablation of microbiota-mediated innate lymphoid cell (ILC) IL-22 production that normally serves to fortify the epithelium. Consequently, enriching such diets with the fermentable fiber inulin, but not the insoluble/non-fermentable fiber cellulose, restored IL-22 production, reduced microbiota encroachment, ameliorated low-grade inflammation, and protected mice from diet-induced Met Syn. However, we’ve also observed that enriching refined diets with some fermentable fibers also induced some IL-22-independent negative consequences, including exacerbating experimentally-induced colitis and promoting liver cancer thus highlighting that, at present, we lack the knowledge to safely engineer health-promoting foods. Hence, our central overall hypothesis is that better mechanistic understanding of how dietary fiber impacts the host-microbiota relationship will inform efforts to design diets and/or more safely and effectively engineer foods that promote beneficial intestine-microbiota interactions, thus ameliorating gut inflammation and its associated disease states, including IBD and Met Syn. We will investigate this hypothesis via 3 specific aims: Aim 1: Identify means by which nourishing microbiota with fiber results in ILC-mediated IL-22 production. Aim 2: Define mechanism underlying psyllium’s ability to protect against metabolic syndrome and colitis. Aim 3: Develop a means of targeted delivery of colonic IL-22 and investigate its ability to restore gut health and ameliorate inflammatory diseases.