Endocrine Abstracts

All domains of life feature diverse molecular clock machineries that synchronize physiological processes to diurnal environmental fluctuations. However, no mechanisms are known to cross-regulate prokaryotic and eukaryotic circadian rhythms in multi-kingdom ecosystems. We discovered that the intestinal microbiota, in both mice and humans, exhibits diurnal oscillations, leading to time-specific compositional and functional profiles over the course of a day. The active phase of the host is dominated by microbial energy harvest, DNA repair, and cell growth, while detoxification and environmental sensing pathways dominate during the resting phase. These rhythmic fluctuations are governed by the circadian clock of the host, and ablation of host molecular clock components or induction of jet lag leads to loss of microbiota diurnal fluctuations and dysbiosis. Mechanistically, the host circadian clock controls feeding rhythms, which in turn drive diurnal microbiota oscillations. Scheduled feeding allows for phase reversal of microbiota diurnal activity and rescues loss of microbiota rhythms in mice deficient in the circadian clock.

Disruption of the circadian clock is a hallmark of the modern life style and has been associated with enhanced susceptibility to metabolic disease. We found that jet lag-induced dysbiosis in both mice and humans promotes glucose intolerance and obesity that are transferrable to germ-free mice upon fecal transplantation. Microbiota from jet-lagged humans or mice causes manifestations of the metabolic syndrome in germ-free recipients, while microbiota after recovery from jet lag does not.

Together, these findings provide evidence of coordinated meta-organism diurnal rhythmicity and offer a microbiome-dependent mechanism for common metabolic disturbances in humans with aberrant circadian rhythms, such as those documented in shift workers and frequent flyers.