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 the current study, we sought to determine if 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 one of three experimental diets: (1) a standard chow diet, (2) an alcohol-containing diet, or (3) 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 ^{Δ 19} 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.

Conclusion

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.