Abnormal Eating Patterns Cause Circadian Dyssynchrony and Promote Alcohol-Associated Colon Carcinogenesis.. mouse gut metagenome

AbstractBackground and aims: Alcohol intake increases colon cancer risk, with circadian rhythm dyssynchrony (CD) promoting alcohol-associated colon pathologies including cancer. We hypothesized that eating during or around physiologic rest time, a common habit in modern society, causes CD and promotes alcohol-associated colon carcinogenesis.Methods: Effect of feeding time on CD was assessed using B6 PER2::LUC mice. TS4Cre×APClox468 mice were used to model colon polyposis and to assess the effects of feeding schedules, alcohol exposure, and prebiotic treatment on polyposis, microbiota composition, short-chain fatty acid (SCFA) levels, and colon inflammation. B6 mice were used to assess time-specific alcohol effects on the mucosal immune profile. The relationship between butyrate signaling and a pro-inflammatory profile was assessed by inactivating the butyrate receptor GPR109A.Results: Eating at rest (Wrong-time eating: WTE) shifted the phase of the colon rhythm. In polyposis mice, combination of WTE and alcohol exposure (WTE+A) exacerbated polyposis and induced a pro-inflammatory profile, characterized by hyperpermeability and an elevated mucosal Th17/Treg ratio. The WTE+A treatment also altered the intestinal microbiota, decreasing the levels of SCFA-producing bacteria and of butyrate. These microbiota-associated changes preceded polyposis exacerbation, with prebiotic treatment improving the mucosal inflammatory profile and polyposis. Decreased butyrate signaling activated epithelial STAT3 in vitro. WTE+A-induced polyposis was associated with increased STAT3 expression. The relationship between butyrate signaling and a pro-inflammatory profile was confirmed in human colorectal cancers using The Cancer Genome Atlas.Conclusion: Abnormal timing of food intake interacts with alcohol consumption to promote colon carcinogenesis by inducing a pro-tumorigenic inflammatory profile driven by changes in the colon microbiota and butyrate signaling.