Circadian rhythms regulate osteoclast recycling through gut microbiota-dependent Th17 cell expansion

 Highlights

• Impairment of circadian rhythm by long-term rest-phase time-restricted feeding (TRF) induces bone loss and gut microbiota dysbiosis in male mice

• TRF feeding mice showed a decreased Muribaculaceae and propionate in feces

• Muribaculaceae abundance level is positively correlated with bone mass

• Fecal microbiota transplantation from TRF donors to germ-free recipients leaded to increased Th17 cell populations

• Increased Th17 cell populations enhanced osteomorphs fusion by RANKL-RANK-OPG signaling pathway

• Osteomorphs fusion into osteoclasts resulted in bone loss

Abstract

The circadian clock coordinates diverse biological processes to maintain physiological function and homeostasis in mammals under the day-night light cycle. Disruption of circadian rhythms impairs immune and metabolic functions and increases susceptibility to various diseases. Here, we demonstrate that long-term rest-phase time-restricted feeding (TRF), which disrupts circadian rhythmicity, induces bone loss and gut microbiota dysbiosis in male mice. Fecal microbiota transplantation (FMT) from circadian-misaligned feeding donors to germ-free recipients increased Th17 cell populations, thereby promoting the fusion of osteomorphs—a recently identified osteoclast precursor—into mature osteoclasts through the RANKL–RANK–OPG signaling pathway. Collectively, our findings identify a gut microbiota–Th17–osteomorph axis as a critical mediator of circadian disruption–induced bone loss, uncovering a previously unrecognized mechanism by which circadian rhythms regulate skeletal homeostasis.

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https://www.sciencedirect.com/science/article/pii/S2666517426000167