Our previous studies have shown that dietary flavonoids such as polymethoxyflavones, curcumin, resveratrol and pterostilbene interact with gut microbiota to produce various bioactive metabolites, which is critical for their biological activities such as anti-inflammation. Herein, we further studied biotransformation of nobiletin, a major citrus polymethoxyflavone in health mice, colitic mice and germ-free mice. The results showed that orally administered nobiletin was well absorbed in the mouse small intestine. It underwent a dynamic biotransformation along mouse gastrointestinal tract where intestinal mucosa and gut microbiota worked together to produce largely varied amounts of metabolites at different segments of gastrointestinal tract. Dietary nobiletin inhibited colitis in mice, although nobiletin was metabolized and excreted differently in the colon of the colitic mice compared to the healthy mice or germ-free mice due to the difference in gut microbiota composition. Gut microbiota were responsible for the production of multiple metabolites in the mouse colon. The microbially generated colonic metabolites worked together to produce enhanced anti-inflammatory activity in the colonic mucosa. This work elucidates a new gut microbiota-driven mechanism by which orally administered nobiletin exerts anti-inflammatory actions in the colon.

The role of gut microbiota on the biotransformation and biofunction of nobiletin, a major citrus flavonoid

ACS Fall 2021

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