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

TL;DR

Disrupted eating schedules disrupt circadian rhythms, leading to gut changes and bone loss through immune cell activity.

Contribution

Identifies a gut microbiota–Th17–osteomorph axis as a novel mechanism linking circadian disruption to bone loss.

Findings

TRF disrupts circadian rhythms, causing bone loss and gut dysbiosis in mice.

Reduced Muribaculaceae and propionate levels correlate with decreased bone mass.

Th17 cell expansion from FMT promotes osteomorph fusion via RANKL-RANK-OPG signaling.

Abstract

•Long-term rest-phase time-restricted feeding (TRF) disrupts circadian rhythms, leading to bone loss and gut microbiota dysbiosis in male mice.•TRF-fed mice exhibit a reduced abundance of Muribaculaceae and decreased levels of propionate in fecal samples.•The abundance of Muribaculaceae is positively correlated with bone mass.•Fecal microbiota transplantation from TRF donor mice to germ-free recipients results in an increased population of Th17 cells.•The expansion of Th17 cells promotes osteomorph fusion through activation of the RANKL-RANK-OPG signaling pathway.

Long-term rest-phase time-restricted feeding (TRF) disrupts circadian rhythms, leading to bone loss and gut microbiota dysbiosis in male mice.

TRF-fed mice exhibit a reduced abundance of Muribaculaceae and decreased levels of propionate in fecal samples.

The abundance of Muribaculaceae is positively correlated with bone mass.

Fecal microbiota transplantation from TRF donor mice to germ-free recipients results in an increased population of Th17 cells.

The expansion of Th17 cells promotes osteomorph fusion through activation of the RANKL-RANK-OPG signaling pathway.

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.

Circadian rhythms disrupted by misaligned feeding lead to gut microbiota dysbiosis and expansion of intestinal Th17 cells. Microbiota-dependent Th17 cell expansion in misaligned feeding mice drives osteomorphs—a recently discovered osteoclast precursor—to undergo fusion into mature osteoclasts via the RANKL–RANK–OPG signaling pathway, thereby promoting bone loss.Image, graphical abstract

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