The mouse microbiome is required for sex-specific diurnal rhythms of gene expression and metabolism. The mouse microbiome is required for sex-specific diurnal rhythms of gene expression and metabolism

The circadian clock and associated feeding rhythms have a profound impact on metabolism and the gut microbiome. To what extent microbiota reciprocally affect daily rhythms of physiology in the host remains elusive. Here, we analyzed transcriptome and metabolome profiles of male and female germ-free mice. While mRNA expression of circadian clock genes revealed subtle changes in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated to rhythmic physiology. Strikingly, absence of microbiome severely compromised liver sexual dimorphism, showing strongly attenuated sex-specific rhythmicity. The resulting feminization of male and masculinization of female germ-free animals is likely caused by altered sexual development and growth hormone secretion, associated to differential activation of xenobiotic receptors. This defines a novel mechanism by which the microbiome regulates host metabolism. Overall design: Total RNA-Seq of conventional raised (convR) and Germ-free (GF) male and female mice under ad libitum feeding regime. Cry1/2 KO mice were night fed. Temporal mRNA profiles of liver were assessed every 4 hours during the diurnal cycle.