Identifying novel mechanisms by which fermentable fibers modulate intestinal structure and function

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My NSERC-funded research program focuses on defining how various dietary factors, such as fat, prebiotics, and fiber, affect mammalian intestinal structure and function. Long-term consumption of a Western style "high-fat and low-fiber" diet has been associated with changes in the intestinal microbiota and impaired immune function in the gut1. In my NSERC-funded studies (2005-2010), I used several rodent models to show that the intake of dietary fat at different life stages modulates intestinal epithelial cell morphology and function, the intestinal microbiota composition, and intestinal immune responses. Interestingly, adding fiber to a high-fat diet partially reverses the intestinal dysfunction linked to high-fat intake, which has contributed to our understanding of how different sources, types, and dose of fibers modulate the interaction between intestinal microbiota and mucosal immunity. However, we do not yet understand the complex mechanisms underlying the beneficial effects of fibers in the mammalian gut. During my current NSERC funding period (2016-2022), I demonstrated that a fiber enriched diet reduced microbe-based expansion of colonic proinflammatory immune cells, potentially due to its well-known ability to promote production of beneficial microbial metabolites such as butyrate as well as its ability to preserve the intestinal mucus layer from microbe-based degradation. To test if fiber exerted intestinal protection via other mechanisms, I tested a fermentable fiber enriched diet in weanling mice deficient in Mucin-2 and thus lacking an intestinal mucus layer (Muc2-/-) as compared to a fiber-free diet. Mice fed the fiber-free diet showed a rapid expansion of local immune cells, as well as epithelial cell deterioration likely resulting from direct contact of commensal gut microbes with the mucosal surface. In contrast, Muc2-/- mice fed the fiber enriched diet showed no signs of immune cell proliferation, nor mucosal damage, as the microbiome appeared to remain segregated from the mucosal surface. Notably, this protection occurred in the absence of an increased in butyrate (Muc2-/- mice are impaired in its production) and in the absence of the intestinal mucus layer. I propose to explore novel host and microbiome mechanisms that are at play in elucidating the protective effect fermentable fiber has on intestinal homeostasis outside of butyrate and the mucus layer. I will investigate how fiber given at the weaning period affects: (1) the structure, function of the intestinal microbiota in wild type and Muc2-/- mice, as well as the geospatial location of key protective microbes; (2) the function of intestinal epithelium; and (3) the molecular and cellular mechanisms underlying these effects. Together, these studies will define novel interactions between fermentable fiber, gut microbes and the intestinal mucosa.