Exploring the protective effects of resveratrol and interactions with dietary fat in a mouse model of BRAFV600E driven colorectal cancer

Resveratrol, a naturally occurring polyphenol found in red wine and a variety of plants, is widely known for its cancer preventive activity and has been shown to counteract the pro-tumorigenic effects of high-fat diets (HFD) in mouse models of colorectal cancer (CRC). However, little is known regarding the underlying mechanisms. This project aims to provide mechanistic insight on how HFD promotes tumourigenesis and how this is ameliorated by resveratrol, with a focus on effects in BRAFV600E-driven CRC.

BRAFV600E male mice were randomised to a standard-fat or HFD supplemented with low or high-dose resveratrol (0.07ppm or 143ppm, respectively) for ~9-weeks. Microbiome, metabolomics, cytokine-array approaches were employed for the analysis of mouse plasma and intestinal tissue, as well as immunofluorescence analysis of lipid distribution. A HFD in the presence of a BRAFV600E mutation was not associated with microbial signature alternations, however pronounced alterations in the metabolome and inflammatory profiles were observed upon dietary-fat challenge in the BRAFV600E mice. A 143ppm resveratrol-dose protected against the alterations arising as a consequence of BRAFV600E combined with HFD, via suppression of metabolic and inflammatory changes including RAGE, and FGF-21 proteins. In addition, immunofluorescence staining revealed that resveratrol can counteract the HFD alterations in lipid metabolism in a dose-dependent manner, as evidenced by a reduction in lipid droplet-bound proteins PLIN2 and CIDEB within intestinal sections of BRAFV600E and APCMIN mice, which was explored as a second model of CRC.

Overall, results indicate that a high, clinically-achievable dose of resveratrol is able to counteract the metabolic, inflammatory and lipid metabolism derangements associated with HFD in the mouse models of CRC employed. These findings provide new insights into the mechanisms of resveratrol action that may help the clinical translation of this polyphenol for use in the prevention and treatment of conditions caused by HFDs and metabolic disorders, including CRC.