Abstract
Background: Colorectal cancer (CRC) is associated with the modern lifestyle. Chronic alcohol consumption—a frequent habit of majority of modern societies—increases the risk of CRC. Our group showed that chronic alcohol consumption increases polyposis in a mouse mode of CRC. Here we assess the effect of circadian disruption—another modern life style habit—in promoting alcohol-associated CRC. Method: TS4Cre × adenomatous polyposis coli (APC)lox468 mice underwent (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 phase reversals of the light:dark (LD) cycle. Mice were sacrificed after eight weeks of full alcohol and/or LD shift to collect intestine samples. Tumor number, size, and histologic grades were compared between animal groups. Mast cell protease 2 (MCP2) and 6 (MCP6) histology score were analyzed and compared. Stool collected at baseline and after four weeks of experimental manipulations was used for microbiota analysis. Results: The combination of alcohol and LD shifting accelerated intestinal polyposis, with a significant increase in polyp size, and caused advanced neoplasia. Consistent with a 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 was similar between groups, and experimental manipulations resulted in a significant difference in the microbiota composition between groups. Conclusions: Circadian disruption by Light:dark shifting exacerbates 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.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer-associated mortality in the US [1]
Our data suggests that LD shifting resulting in circadian rhythm disruption exacerbates alcohol-induced colon carcinogenesis and polyposis, and this “aggressive” phenotype change is associated with dysbiosis
Emerging evidence has demonstrated that lifestyle-related factors such as obesity and metabolic syndrome are associated with low-grade inflammation, and these are known to be risk factors for CRC [46,47,48]
Summary
Colorectal cancer (CRC) is the second leading cause of cancer-associated mortality in the US [1]. Consistent with the known effect of circadian rhythm disruption on immunity, we found that LD shift increased intestinal tumorigenesis in alcohol-fed mice by promoting a pro-tumorigenic inflammatory milieu. Sci. 2016, 17, 2017 alcohol together, causing a rapid transition from adenoma to invasive cancer Overall, these findings are consistent with enhanced colon carcinogenesis in response to a combination of circadian disruption aInntd. While densities of intra-polyp mMCP2 and mMCP6 mast cells dropped with LD shift, the ratio of mMCP6 (stromal)/mMCP2 (intraepithelial) mast cells increased (0.87 relative to 0.68) (Figure 2) This finding is consistent with a pathogenic role of stromal localization of tryptase-positive mast cells in colon carcinogenesis [28]. Alcohol-fed shifted (experimental) mice showed a decrease in Firmicutes/Bacteroidetes ratio, which is reported to correlate with a decrease in short-chain fatty acid (SCFA) production, bacterial metabolites long known to have protective effects in colonic neoplastic transformation [36].
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