Multi-omics reveals circadian regulation of bone homeostasis by gut microbiota metabolites: mechanisms and chronotherapeutic implications

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The gut-bone axis plays a pivotal role in skeletal health, yet the integration of multi-omics approaches to elucidate circadian metabolite-bone interactions remains limited. This review synthesizes evidence from metagenomics, metabolomics, and germ-free models to uncover how microbiota-derived metabolites-including short-chain fatty acids (SCFAs), bile acids, tryptophan derivatives, and gaseous molecules-orchestrate bone remodeling in osteoporosis, osteoarthritis, and bone malignancies. Many studies demonstrate that SCFAs inhibit osteoclastogenesis via GPR43/HDAC signaling and promote osteoblast metabolic reprogramming, while bile acids enhance osteogenesis through FXR/Wnt/β-catenin activation. Tryptophan metabolites repair intestinal barrier integrity and modulate osteoimmunity via the AhR pathway. Single-cell omics reveal circadian oscillations of metabolite receptors (e.g., GPR43, FXR) in bone stromal cells, linking microbial diurnal rhythms to epigenetic regulation of bone turnover. We propose a novel "metabolite-immune-bone triad" model, highlighting microbiome-driven immunometabolic reprogramming as a central regulator of skeletal homeostasis. These insights advance precision microbial therapeutics and chrono-nutritional strategies, bridging multi-omics discoveries with clinical applications for bone disorders.