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Int. J. Mol. Sci. 2016, 17(12), 2017;

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

Department of Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
Northwestern Medicine, Central DuPage Hospital, Winfield, IL 60190, USA
Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL 60208, USA
Author to whom correspondence should be addressed.
Academic Editors: Takuji Tanaka and Masahito Shimizu
Received: 27 October 2016 / Revised: 23 November 2016 / Accepted: 28 November 2016 / Published: 2 December 2016
(This article belongs to the Special Issue Inflammation and Cancer)
Full-Text   |   PDF [1474 KB, uploaded 2 December 2016]   |  


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. View Full-Text
Keywords: colon cancer; alcohol; circadian disruption; inflammation; microbiota colon cancer; alcohol; circadian disruption; inflammation; microbiota

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Bishehsari, F.; Saadalla, A.; Khazaie, K.; Engen, P.A.; Voigt, R.M.; Shetuni, B.B.; Forsyth, C.; Shaikh, M.; Vitaterna, M.H.; Turek, F.; Keshavarzian, A. Light/Dark Shifting Promotes Alcohol-Induced Colon Carcinogenesis: Possible Role of Intestinal Inflammatory Milieu and Microbiota. Int. J. Mol. Sci. 2016, 17, 2017.

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