title: The Circadian Clock Mutation Promotes Intestinal Dysbiosis.
abstract: BACKGROUND
  Circadian rhythm disruption is a prevalent feature of modern day society that is associated with an increase in pro-inflammatory diseases, and there is a clear need for a better understanding of the mechanism(s) underlying this phenomenon. We have previously demonstrated that both environmental and genetic circadian rhythm disruption causes intestinal hyperpermeability and exacerbates alcohol-induced intestinal hyperpermeability and liver pathology. The intestinal microbiota can influence intestinal barrier integrity and impact immune system function; thus, in this study, we sought to determine whether genetic alteration of the core circadian clock gene, Clock, altered the intestinal microbiota community.
  
  
  METHODS
  Male Clock(Δ19) -mutant mice (mice homozygous for a dominant-negative-mutant allele) or littermate wild-type mice were fed 1 of 3 experimental diets: (i) a standard chow diet, (ii) an alcohol-containing diet, or (iii) an alcohol-control diet in which the alcohol calories were replaced with dextrose. Stool microbiota was assessed with 16S ribosomal RNA gene amplicon sequencing.
  
  
  RESULTS
  The fecal microbial community of Clock-mutant mice had lower taxonomic diversity, relative to wild-type mice, and the Clock(Δ19) mutation was associated with intestinal dysbiosis when mice were fed either the alcohol-containing or the control diet. We found that alcohol consumption significantly altered the intestinal microbiota in both wild-type and Clock-mutant mice.
  
  
  CONCLUSIONS
  Our data support a model by which circadian rhythm disruption by the Clock(Δ19) mutation perturbs normal intestinal microbial communities, and this trend was exacerbated in the context of a secondary dietary intestinal stressor.
authors: Department of Internal Medicine , Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois.
authors: Robin M
authors: RM
authors: Voigt
authors: Center for Sleep and Circadian Biology , Department of Neurobiology, Northwestern University, Evanston, Illinois.
authors: Keith C
authors: KC
authors: Summa
authors: Department of Internal Medicine , Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois.|Department of Biochemistry , Rush University Medical Center, Chicago, Illinois.
authors: Christopher B
authors: CB
authors: Forsyth
authors: DNA Services Facility , Research Resources Center, University of Illinois at Chicago, Chicago, Illinois.|Department of Biological Sciences , University of Illinois at Chicago, Chicago, Illinois.
authors: Stefan J
authors: SJ
authors: Green
authors: Department of Internal Medicine , Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois.
authors: Phillip
authors: P
authors: Engen
authors: DNA Services Facility , Research Resources Center, University of Illinois at Chicago, Chicago, Illinois.
authors: Ankur
authors: A
authors: Naqib
authors: Center for Sleep and Circadian Biology , Department of Neurobiology, Northwestern University, Evanston, Illinois.
authors: Martha H
authors: MH
authors: Vitaterna
authors: Center for Sleep and Circadian Biology , Department of Neurobiology, Northwestern University, Evanston, Illinois.
authors: Fred W
authors: FW
authors: Turek
authors: Department of Internal Medicine , Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois.|Department of Pharmacology , Rush University Medical Center, Chicago, Illinois.|Division of Pharmacology , Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors: Ali
authors: A
authors: Keshavarzian
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000502:physiology; D057906:Circadian Clocks / Q000235:genetics* / Q000502:physiology; D064806:Dysbiosis / Q000235:genetics* / Q000503:physiopathology; D000431:Ethanol / Q000494:pharmacology; D005243:Feces / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012336:RNA, Ribosomal, 16S
chemical_list: D012336:RNA, Ribosomal, 16S; D000431:Ethanol; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: Alcohol; Circadian Rhythm Disruption; Clock Mutation; Dysbiosis; Stool Microbiota