Abnormal Food Timing Promotes Alcohol-Associated Dysbiosis and Colon Carcinogenesis Pathways

Background: Alcohol consumption is an established risk factor for colorectal cancer (CRC). Identifying cofactor(s) that modulate the effect of alcohol on colon inflammation and carcinogenesis could help risk stratification for CRC. Disruption of circadian rhythm by light/dark shift promotes alcohol-induced colonic inflammation and cancer. More recently, we found that abnormal food timing causes circadian rhythm disruption and promotes alcohol associated colon carcinogenesis. In this study, we examined the interaction of wrong-time feeding (WTF) and alcohol on CRC-related pathways, in relation to changes in microbial community structure.

Methods: Polyposis mice (TS4Cre ×cAPC^Δ468) underwent four conditions: alcohol or water and feeding during the light (wrong-time fed/WTF) or during the dark (right-time fed). Colonic cecum mucosal gene expression was analyzed by RNA-seq. Microbiota 16S ribosomal RNA sequencing analysis was used to examine colonic feces. Modeling was used to estimate the extent of the gene expression changes that could be related to the changes in the colonic microbial composition.

Results: The circadian rhythm pathway was the most altered pathway by the WTF treatment, indicating that WTF is disruptive to the colonic circadian rhythm. Pathway analysis revealed interaction of WTF with alcohol in dysregulating pathways related to colon carcinogenesis. Similarly, the interaction of alcohol and WTF was detected at multiple parameters of the colonic microbiota including α and β diversity, as well as the community structure. Our modeling revealed that almost a third of total gene alterations induced by our treatments could be related to alterations in the abundance of the microbial taxa.

Conclusion: These data support the promoting effect of abnormal food timing alcohol-associated CRC-related pathways in the colon and suggest colon dysbiosis as a targetable mechanism.