TITLE

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

AUTHOR(S)
Bishehsari, Faraz; Saadalla, Abdulrahman; Khazaie, Khashayarsha; Engen, Phillip A.; Voigt, Robin M.; Shetuni, Brandon B.; Forsyth, Christopher; Shaikh, Maliha; Vitaterna, Martha Hotz; Turek, Fred; Keshavarzian, Ali
PUB. DATE
December 2016
SOURCE
International Journal of Molecular Sciences;Dec2016, Vol. 17 Issue 12, p2017
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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 x 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.
ACCESSION #
120516840

 

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