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

Int J Mol Sci. 2016 Dec 2;17(12):2017. doi: 10.3390/ijms17122017.


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.

Keywords: alcohol; circadian disruption; colon cancer; inflammation; microbiota.

MeSH terms

  • Alcoholism / complications*
  • Animals
  • Carcinogenesis / pathology*
  • Colorectal Neoplasms / etiology*
  • Colorectal Neoplasms / microbiology
  • Colorectal Neoplasms / pathology
  • Dysbiosis / complications
  • Dysbiosis / microbiology
  • Dysbiosis / pathology
  • Epithelial Cells / pathology
  • Feeding Behavior
  • Inflammation / pathology*
  • Intestines / microbiology*
  • Intestines / pathology*
  • Mast Cells / pathology
  • Mice
  • Microbiota*
  • Photoperiod*