Light/dark shifting promotes alcohol-induced colon carcinogenesis: Possible role of intestinal inflammatory milieu and microbiota

Faraz Bishehsari, Abdulrahman Saadalla, Khashayarsha Khazaie, Phillip A. Engen, Robin M. Voigt, Brandon B. Shetuni, Christopher Forsyth, Maliha Shaikh, Martha Hotz Vitaterna, Fred Turek, Ali Keshavarzian

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Article number2017
JournalInternational journal of molecular sciences
Volume17
Issue number12
DOIs
StatePublished - Dec 2 2016

Keywords

  • Alcohol
  • Circadian disruption
  • Colon cancer
  • Inflammation
  • Microbiota

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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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. (2016). Light/dark shifting promotes alcohol-induced colon carcinogenesis: Possible role of intestinal inflammatory milieu and microbiota. International journal of molecular sciences, 17(12), [2017]. https://doi.org/10.3390/ijms17122017