{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:59:24Z","timestamp":1794013164652,"version":"4.8.0"},"reference-count":170,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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\u2014including short-chain fatty acids (SCFAs), bile acids, tryptophan derivatives, and gaseous molecules\u2014orchestrate 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\/\u03b2-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 \u201cmetabolite-immune-bone triad\u201d 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.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1719445","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T06:18:55Z","timestamp":1780035535000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Multi-omics reveals circadian regulation of bone homeostasis by gut microbiota metabolites: mechanisms and chronotherapeutic implications"],"prefix":"10.3389","volume":"16","author":[{"given":"Mingdong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Affiliated Hospital of Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, 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