The Circadian Clock Mutation Promotes Intestinal Dysbiosis

Robin M. Voigt*, Keith C. Summa, Christopher B. Forsyth, Stefan J. Green, Phillip Engen, Ankur Naqib, Martha H. Vitaterna, Fred W. Turek, Ali Keshavarzian

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

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 ClockΔ19-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 ClockΔ19 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 ClockΔ19 mutation perturbs normal intestinal microbial communities, and this trend was exacerbated in the context of a secondary dietary intestinal stressor.

Original languageEnglish (US)
Pages (from-to)335-347
Number of pages13
JournalAlcoholism: Clinical and Experimental Research
Volume40
Issue number2
DOIs
StatePublished - Feb 1 2016

Keywords

  • Alcohol
  • Circadian Rhythm Disruption
  • Clock Mutation
  • Dysbiosis
  • Stool Microbiota

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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