Abnormal Eating Patterns Cause Circadian Disruption and Promote Alcohol-Associated Colon Carcinogenesis

Abstract Background and aims Alcohol intake with circadian rhythm disruption (CRD) increases colon cancer risk. We hypothesized that eating during or around physiologic rest time, a common habit in modern society, causes CRD and investigated the mechanisms by which it promotes alcohol-associated colon carcinogenesis. Methods Effect of feeding time on CRD 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 consumption, and prebiotic treatment on microbiota composition, short-chain-fatty-acid (SCFA) levels, colon inflammation and cancer risk. The relationship between butyrate signaling and a proinflammatory profile was assessed by inactivating the butyrate receptor GPR109A. Results Eating at rest (Wrong-time eating: WTE) shifted the phase of the colon rhythm PER2::LUC mice. In TS4Cre×APClox468 mice, a combination of WTE and alcohol exposure (WTE+Alcohol) decreased the levels of SCFA-producing bacteria and of butyrate, reduced colonic densities of Tregs, induced a proinflammatory profile, characterized by hyperpermeability and an elevated mucosal Th17/Treg ratio, and promoted CRC. Prebiotic treatment improved the mucosal inflammatory profile and attenuated inflammation and cancer. WTE+Alcohol-induced polyposis was associated with increased STAT3 expression. Decreased butyrate signaling activated epithelial STAT3 in vitro. The relationship between butyrate signaling and a proinflammatory profile was confirmed in human colorectal cancers using The Cancer Genome Atlas. Conclusion Abnormal timing of food intake caused CRD and 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.