title: Light/Dark Shifting Promotes Alcohol-Induced Colon Carcinogenesis: Possible Role of Intestinal Inflammatory Milieu and Microbiota.
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.
  
  
  METHODS
  TS4Cre × adenomatous polyposis coli (APC)lox468mice 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.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA. Faraz_Bishehsari@rush.edu.
authors.forename: Faraz
authors.initials: F
authors.lastname: Bishehsari
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA. Saadalla.Abdulrahman@mayo.edu.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Saadalla
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA. Khazaie@mayo.edu.
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.affiliation: Department of Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA. Phillip_Engen@rush.edu.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Engen
authors.affiliation: Department of Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA. Robin_Voigt@rush.edu.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Voigt
authors.affiliation: Northwestern Medicine, Central DuPage Hospital, Winfield, IL 60190, USA. Brandon.Shetuni@CadenceHealth.org.
authors.forename: Brandon B
authors.initials: BB
authors.lastname: Shetuni
authors.affiliation: Department of Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA. Christopher_Forsyth@rush.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Forsyth
authors.affiliation: Department of Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA. Maliha_Shaikh@rush.edu.
authors.forename: Maliha
authors.initials: M
authors.lastname: Shaikh
authors.affiliation: Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL 60208, USA. m-vitaterna@northwestern.edu.
authors.forename: Martha Hotz
authors.initials: MH
authors.lastname: Vitaterna
authors.affiliation: Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL 60208, USA. fturek@northwestern.edu.
authors.forename: Fred
authors.initials: F
authors.lastname: Turek
authors.affiliation: Department of Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA. Ali_Keshavarzian@rush.edu.
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
mesh_terms: D000437:Alcoholism / Q000150:complications*; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000382:microbiology / Q000473:pathology; D064806:Dysbiosis / Q000150:complications / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D005247:Feeding Behavior; D007249:Inflammation / Q000473:pathology*; D007422:Intestines / Q000382:microbiology* / Q000473:pathology*; D008407:Mast Cells / Q000473:pathology; D051379:Mice; D064307:Microbiota; D017440:Photoperiod
keywords: alcohol; circadian disruption; colon cancer; inflammation; microbiota