The Circadian Clock Mutation Promotes Intestinal Dysbiosis.
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.
['Voigt|Robin M|RM|', 'Summa|Keith C|KC|', 'Forsyth|Christopher B|CB|', 'Green|Stefan J|SJ|', 'Engen|Phillip|P|', 'Naqib|Ankur|A|', 'Vitaterna|Martha H|MH|', 'Turek|Fred W|FW|', 'Keshavarzian|Ali|A|']
D000818:Animals D056926:CLOCK Proteins D057906:Circadian Clocks D064806:Dysbiosis D000431:Ethanol D005243:Feces D000069196:Gastrointestinal Microbiome D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008817:Mice, Mutant Strains D012336:RNA, Ribosomal, 16S
Clock Mutation Dysbiosis Circadian Rhythm Disruption Alcohol Stool Microbiota