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Author

Fang LiFollow

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Food Science

Year Degree Awarded

2018

Month Degree Awarded

September

First Advisor

Hang Xiao

Subject Categories

Food Biotechnology | Food Microbiology

Abstract

Resveratrol (RES) is a natural polyphenol compound with a wide range of health-promoting activities, including protective effects against colon cancer and renal disease. However, the premise of these benefits has been dampened since RES shows a poor oral bioavailability due to its rapid and extensive biotransformation after oral consumption. The paradox (low bioavailability but high bioactivity) warrants further investigations to determine the contribution of RES metabolites to the health benefits associated with RES. We identified 11 metabolites of RES in mice with high-resolution HPLC-MS/MS, then quantified two major metabolites - dihydro-resveratrol (DHR) and lunularin (LUN). To further understand the chemopreventative effects of RES metabolites in the kidney and colon, the inhibitory effects of RES, DHR, LUN, and their combinations at the concentrations equivalent to those found in mouse tissues were determined in corresponding cell models. Our results demonstrated that DHR and LUN exhibited much stronger anti-inflammatory, anti-clonogenic and anti-proliferative effects than did RES at physiologically relevant levels. Moreover, the combination of RES, DHR and LUN produced the strongest inhibitory effects, while the contribution of RES was marginal. DHR and LUN might be the main force that responsible for the chemopreventative effects attributed to RES.

Accumulating evidence indicated that gut microbiota plays important roles in the pathogenesis of colitis, and microbiota composition could be modulated by dietary components. Therefore, ameliorating colitis-associated bacterial dysbiosis by dietary components may be a unique strategy to improve gut health. Herein, we determined the effects of resveratrol on gut microbiota and their implications in anti-colonic inflammation in mice with colitis induced by dextran sodium sulfate (DSS). Our results reinforce the protective effects of resveratrol in intestinal inflammation by alleviating the body weight loss, reducing the disease activity index, attenuating tissue damage and down-regulating the expression of pro-inflammatory cytokines such as IL-2, GM-CSF, IL-1β, IL-6 and TNF-α in the colon of DSS-treated mice. Moreover, dietary resveratrol restored the microbial richness and evenness in DSS-treated mice. Specifically, at the genus level resveratrol effectively reduced the richness of Akkermansia, Dorea, Sutterella and Bilophila and increased the abundance of Bifidobacterium in colitic mice. Furthermore, a Pearson’s correlation analysis indicated that resveratrol suppressed pro-inflammatory cytokines were strongly correlated with gut microbiota composition. Overall, our results suggested that dietary resveratrol attenuated inflammation perhaps by modulating the microbial composition.

The necessary role of gut microbiota in the biotransformation of RES was evidenced by antibiotic treated mice. DHR, LUN, and their conjugates were completely absent in the antibiotic treated mice. Moreover, we found that in colitic mice LUN and its conjugates were extinguished, which may associate with the altered gut microbiota composition and structure. Most interestingly, we found that RES metabolites at the concentrations equivalent to that observed in the colonic tissues in colitic mice exhibited significantly stronger chemopreventative effects than that observed in the healthy mice. These results suggested that absence of LUN may resulted in stronger biological activities of RES. Overall, our results provided a solid scientific basis for understanding the chemopreventative mechanisms of RES from the perspective of biotransformation and gut microbiota and are of great value for future research on RES in prevention and treatment of colonic diseases in humans.

Available for download on Sunday, September 01, 2019

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