Impact of fiber supplementation on the butyrate synthesis of the intestinal microbiota and how it affects the risk for colorectal cancer.

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Evidence from epidemiological studies suggests that the consumption of fiber is associated with a reduced risk for colorectal cancer (CRC), but the specific mechanisms underlying the protective effects of fiber and its causal relationship with the human gut microbiota remain unclear. In the intestine, fiber is degraded by the commensal microbiota to short-chain fatty acids such as butyrate. Butyrate serves as energy source for colonic epithelial cells, affects gene transcription and cell cycle regulation and has significant anti-neoplastic and anti-inflammatory effects in vitro. CRC patients often exhibit an altered composition of the intestinal microbiota that is characterized by a reduced diversity and an impaired metabolic capacity to synthesize butyrate. Recent studies in CRC mouse models indicate that members of the intestinal microbiota and their capacity to synthesize butyrate affect colonic tumorigenesis, but evidence with regard to a causal link in a clinically relevant setting is lacking: the question arises, if high fiber consumption can shift a CRC-associated microbiota in such a way that higher amounts of intestinal butyrate are produced, which promote attenuated colonic tumorigenesis and ultimately reduce the risk for CRC in humans?To target this question, we are conducting a randomized controlled intervention trial in healthy Alaska Native (AN) people (n=60), which show one of the world’s highest CRC rates. Using a dietary intervention (fiber supplementation vs. control for 4 weeks) as proof-of-concept study for high fiber-mediated CRC risk reduction, we aim to identify the potentially beneficial effects of fiber on intestinal inflammation, proliferation, the gut microbiota and its metabolome in a CRC high-risk population. The proposal submitted here will enable us to show, if the microbiota-dependent effects of a high fiber diet, observed in the clinical trial, also confer an attenuated colonic tumorigenesis. For this, we will use a CRC mouse model to determine the impact of fiber/butyrate on colonic tumor formation as clinically relevant end-point and identify related microbe-host interactions. Germ-free wild-type mice are associated with the fecal microbiota from representative healthy AN people (“humanized mice”) and receive a high-fiber or control diet. AOM/DSS treatment reveals the impact of microbiota-dependent butyrate synthesis on colonic tumorigenesis including markers of inflammation/proliferation associated with CRC. Completing the observations from the clinical trial, the submitted experiments will provide significant insight into the role of fiber- and microbiota-dependent levels of butyrate in CRC risk. Using this dual approach, correlations from the clinical trial can be validated regarding their functional consequences (=colonic tumorigenesis) and potential markers of human CRC risk identified and analyzed in parallel.