Characterization of Microbiota-derived Polymethoxyflavone Metabolites and their Anti-inflammatory Actions in the Colon

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PROJECT SUMMARY Accumulating evidence suggested that gut microbiota-derived metabolites of dietary flavonoids are important for their biological actions in the colon such as anti-inflammation. However, currently, there is only a poor understanding of the formation and biofunctions of microbiota-derived flavonoid metabolites, which greatly limits our ability to develop dietary flavonoid-based strategies for inhibiting colonic inflammation. Consumption of citrus fruits and their components has been found to associate inversely with inflammation- related chronic diseases in humans. Polymethoxyflavones (PMFs), a unique class of citrus flavonoids, displayed potent anti-inflammatory properties in the colon in our animal studies. We found that gut microbiota mediated the production of an array of colonic metabolites of PMFs after their oral administration in mice, and these metabolites possessed much stronger anti-inflammatory effects than their parental PMFs. Importantly, our results showed that oral intake of PMFs by human volunteers resulted in the production of these bioactive metabolites in human stool. Furthermore, we identified multiple strains of PMF-metabolizing bacteria from human stool and found that dietary PMFs modulated the abundance and metabolic functions of these bacteria in mice with colitis. Overall, our results provided a strong basis for the application of citrus PMFs in the prevention of colonic inflammation and associated diseases. The objective of this project is to elucidate the mode of interaction between PMFs and gut microbiota, and its implication in inhibiting colonic inflammation. Based on our preliminary results, we hypothesize that gut microbiota mediates the production of bioactive PMF metabolites, and these metabolites are critical for the anti- inflammatory actions of PMFs in the colon. To test our hypothesis, we will pursue the following 3 specific aims: 1) Identify novel microbiota-derived metabolites of PMFs in the colon and characterize their tissue profiles in PMF-fed mice; 2) Determine the role of microbiota-derived PMF metabolites in inhibiting colonic inflammation; and 3) Characterize the interaction between PMFs and PMF-metabolizing fecal bacteria in both healthy mice and mice with colitis. Our rationale is that the successful completion of this project will contribute to the development of effective dietary strategies for amelioration of colonic inflammation and associated diseases through the PMF/microbiota interaction.