Gut microbiota directs PPARγ-driven reprogramming of the liver circadian clock by nutritional challenge

The liver circadian clock is reprogrammed by nutritional challenge through the rewiring of specific transcriptional pathways. As the gut microbiota is tightly connected to host metabolism, whose coordination is governed by the circadian clock, we explored whether gut microbes influence circadian homeostasis and how they distally control the peripheral clock in the liver. Using fecal transplant procedures we reveal that, in response to high‐fat diet, the gut microbiota drives PPARγ‐mediated activation of newly oscillatory transcriptional programs in the liver. Moreover, antibiotics treatment prevents PPARγ‐driven transcription in the liver, underscoring the essential role of gut microbes in clock reprogramming and hepatic circadian homeostasis. Thus, a specific molecular signature characterizes the influence of the gut microbiome in the liver, leading to the transcriptional rewiring of hepatic metabolism. Synopsis High‐fat diet‐induced reprogramming in the mouse liver is driven by the gut microbiota through PPARγ. The microbiota in the gut exerts a distal effect on an otherwise non‐cyclic liver metabolic and transcriptional program. Gut microbes distally influence the liver circadian clock. High‐fat diet microbiota‐driven transcriptional reprogramming is mediated by PPARγ. Antibiotic treatment prevents HFD‐induced reprogramming of the liver clock. Graphical Abstract High‐fat diet‐induced reprogramming in the mouse liver is driven by the gut microbiota through PPARγ. The microbiota in the gut exerts a distal effect on an otherwise non‐cyclic liver metabolic and transcriptional program.