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 ClockΔ19 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 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. Conclusion 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.

Liver Injury, Endotoxemia, and Their Relationship to Intestinal Microbiota Composition in Alcohol‐Preferring Rats

“…We stained formalin‐fixed, paraffin‐embedded tissue sections (3 μ m thick) with hematoxylin and eosin to assess liver and distal colon pathology. According to previous studies (Song et al., ; Voigt et al., ), we defined hepatic microvesicular steatosis as multiple lipid droplets smaller than the central nucleus, whereas macrovesicular steatosis was defined as a single lipid droplet larger than the peripherally displaced nucleus of the cell. Steatosis severity was scored as percent hepatocyte involvement (0 = <5%; 1 = 5 to 33%; 2 = 34 to 66%; 3 = >67%) according to the fraction of fat‐containing hepatocytes.…”

Circadian rhythms, time-restricted feeding, and healthy aging

“…Diet induced obesity and erratic eating patterns can disrupt and dampen these rhythms. Both behavioral and genetically induced circadian disruption have also been shown to decrease the taxonomic diversity and induce intestinal dysbiosis (Voigt et al, 2016, 2014). However, enforced feeding-fasting patterns can restore some of these oscillations (Zarrinpar et al, 2014).…”

Dietary Prebiotics and Bioactive Milk Fractions Improve NREM Sleep, Enhance REM Sleep Rebound and Attenuate the Stress-Induced Decrease in Diurnal Temperature and Gut Microbial Alpha Diversity

“…Maternal separation of infant monkeys, for example, produces a selective reduction in gut Lactabacilli (Bailey and Coe, 1999); and rats exposed to tail shock stress have rapid reductions of Provetella measured in both fecal and cecum samples (Maslanik et al, 2012a). Whereas, mice exposed to chronic social disruption (Bailey et al, 2010, 2011), circadian disruption plus alcohol consumption (Voigt et al, 2016) or 8 weeks of circadian disorganization plus a high fat diet (Voigt et al, 2014) have clear reductions in alpha diversity. Thus, stressor exposure induces dysbiosis by impacting specific bacteria and by reducing measures of alpha diversity.…”