The Gut Microbiota Regulates Host Metabolism through Circadian Clock Genes Nr1d1 and Nr1d2

Alterations in the gut microbiota and circadian rhythms of gene expression are known to underlie metabolic disorders. We explored the interplay between the gut microbiota, circadian rhythms, and metabolism by targeting two homologs of the core circadian clock, Nr1d1 and Nr1d2 in the mouse intestine. Nr1d1 and Nr1d2 are repressed by the gut microbiota. The absence of the gut microbiota leads to decreased relative amplitude of cyclic patterns of these genes. A knockout of Nr1d1 and Nr1d2 in the intestinal epithelial cells (IEC) (Nr1d1/2^ΔIEC) showed no difference in body weights, glucose and insulin tolerance, but the expression of core circadian clock and metabolic genes was disrupted. Circadian clock genes like Nr1d1 and Nr1d2 are known to act on epigenetic modifications to alter gene expression. We found that circadian rhythms of the epigenetic modifications H3K9ac and H3K27ac were disrupted in Nr1d1/2^ΔIEC mice IECs. The global gene expression pattern for Nr1d1/2^ΔIEC and germ-free mice showed lower overall circadian amplitude than that of the wildtype, indicating disrupted circadian rhythms. To further study the role of Nr1d1 and Nr1d2 in metabolism, mice were challenged with a high-fat diet, where Nr1d1/2^ΔIEC mice gained more weight, had heavier fat pads, higher fasting glucose and triglycerides levels, and showed impaired glucose and insulin tolerance. Depletion of the gut microbiota during a high-fat diet challenge prevented the previously observed weight gain difference. These findings reveal connections between the gut microbiota, circadian rhythms, and mammalian metabolism.