The Mouse Microbiome Is Required for Sex-Specific Diurnal Rhythms of Gene Expression and Metabolism

Abstract

SummaryThe 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 with rhythmic physiology. Strikingly, the absence of the microbiome attenuated liver sexual dimorphism and 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 with differential activation of xenobiotic receptors. This defines a novel mechanism by which the microbiome regulates host metabolism.

At the Intersection of Microbiota and Circadian Clock: Are Sexual Dimorphism and Growth Hormones the Missing Link to Pathology?

“…These metabolites oscillate in the intestine and the serum of conventional mice, but stop fluctuating in antibiotic‐treated mice . However, we were not able to detect rhythmic serum levels of these amino acids in conventionally raised (ConvR) mice, indicating that the amino acid serum level rhythms are dependent on food or microbiota composition. Secondly, bacteria‐derived products like lipopolysaccharides have been shown to signal through a toll‐like receptor–PPAR‐α signaling pathway that is required to control corticosterone synthesis in the ileum .…”

“…Strikingly, the absence of microbiota not only provokes loss of rhythms in peripheral tissues but also elicits a gain of diurnal oscillations. In contrast to organs that are in contact with microbiota such as ileum or duodenum) genes gaining rhythms in GF mice surprisingly outnumber the genes losing rhythmicity in distal organs, indicating that microbiota have the capacity to dampen rhythms of certain metabolic pathways. Together, the circadian core clock machinery of the host is robustly oscillating even in the absence of microbiota and is thus virtually independent of their impact.…”

“…These results have to be interpreted with care as antibiotic treatment per se alters glucose homeostasis in the colon . In addition, the gene expression profile of hepatic gluconeogenesis in GF mice is different to those of ABX mice …”

“…These data, however, harbor strong inconsistencies describing alteration in circadian core clock gene expression in peripheral tissues ranging from mild to severe changes in phase and/or amplitude. Recent studies applying next‐generation sequencing to quantify gene expression showed that GF or ABX mice exhibit only mild changes in clock gene expression in the intestine and in distal organs, including the liver and white adipose tissue (WAT) . Nevertheless, the host–microbiota interaction is crucial to sustain host rhythmic output gene expression and metabolite levels in many pathways (Figure ) .…”

“…Recent studies applying next‐generation sequencing to quantify gene expression showed that GF or ABX mice exhibit only mild changes in clock gene expression in the intestine and in distal organs, including the liver and white adipose tissue (WAT) . Nevertheless, the host–microbiota interaction is crucial to sustain host rhythmic output gene expression and metabolite levels in many pathways (Figure ) . Strikingly, the absence of microbiota not only provokes loss of rhythms in peripheral tissues but also elicits a gain of diurnal oscillations.…”