REVIEW article
Front. Immunol.
Sec. Microbial Immunology
Multi-Omics Reveals Circadian Regulation of Bone Homeostasis by Gut Microbiota Metabolites: Mechanisms and Chronotherapeutic Implications
Provisionally accepted
- 1Shaoxing University Affiliated Hospital, Shaoxing, China
- 2Shaoxing University, Shaoxing, China
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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.
Keywords: Gut Microbiota, Bone Diseases, Circadian Rhythm, multi-omics, microbial therapeutics
Received: 06 Oct 2025; Accepted: 01 Dec 2025.
Copyright: © 2025 Liu, Gong, Liu, Yu, Hu and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zheng Liu
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