Light/Dark Shifting Promotes Alcohol-Induced Colon Carcinogenesis: Possible Role of Intestinal Inflammatory Milieu and Microbiota

Background: Colorectal cancer (CRC) is associated with the modern lifestyle. Chronicalcohol consumption—a frequent habit of majority of modern societies—increases the risk ofCRC. Our group showed that chronic alcohol consumption increases polyposis in a mouse modeof CRC. Here we assess the effect of circadian disruption—another modern life style habit—inpromoting alcohol-associated CRC. Method: TS4Cre _ adenomatous polyposis coli (APC)lox468 miceunderwent (a) an alcohol-containing diet while maintained on a normal 12 h light:12 h dark cycle;or (b) an alcohol-containing diet in conjunction with circadian disruption by once-weekly 12 h phasereversals of the light:dark (LD) cycle. Mice were sacrificed after eight weeks of full alcohol and/orLD shift to collect intestine samples. Tumor number, size, and histologic grades were comparedbetween animal groups. Mast cell protease 2 (MCP2) and 6 (MCP6) histology score were analyzed andcompared. Stool collected at baseline and after four weeks of experimental manipulations was usedfor microbiota analysis. Results: The combination of alcohol and LD shifting accelerated intestinalpolyposis, with a significant increase in polyp size, and caused advanced neoplasia. Consistent witha pathogenic role of stromal tryptase-positive mast cells in colon carcinogenesis, the ratio of mMCP6(stromal)/mMCP2 (intraepithelial) mast cells increased upon LD shifting. Baseline microbiota wassimilar between groups, and experimental manipulations resulted in a significant difference in themicrobiota composition between groups. Conclusions: Circadian disruption by Light:dark shiftingexacerbates alcohol-induced polyposis and CRC. Effect of circadian disruption could, at least partly,be mediated by promoting a pro-tumorigenic inflammatory milieu via changes in microbiota.