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(Landmark Ed)"],"abstract":"<jats:p>The gut\u2013bone axis represents a paradigm shift in our understanding of skeletal biology, revealing how the gastrointestinal system and its microbial inhabitants profoundly influence bone homeostasis through complex bidirectional communication. This comprehensive review synthesizes recent high-impact research to elucidate the multifaceted mechanisms underlying gut\u2013bone crosstalk, including microbial metabolite signaling, gut barrier integrity, immune modulation, and endocrine regulation. We examine how short-chain fatty acids (SCFAs), tryptophan metabolites, and bile acid derivatives modulate bone remodeling through epigenetic, immunologic, and hormonal pathways. The translational implications of these findings for the management of osteoporosis, osteoarthritis, and inflammatory bone disorders are critically evaluated, with particular emphasis on microbiome-targeted interventions, gut hormone-based therapies, and innovative approaches such as engineered microbial therapeutics. Furthermore, we explore the roles of farnesoid X receptor (FXR) signaling, G protein\u2013coupled receptor activation, and mitochondrial function in bone cells as modulated by gut-derived factors. This review provides a framework for developing novel diagnostic and therapeutic strategies that target the gut\u2013bone axis, highlighting the transition from traditional calcium-centric bone health paradigms toward integrated microbiome-targeted approaches that address the systemic nature of bone metabolism regulation.<\/jats:p>","DOI":"10.31083\/fbl46147","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T07:25:36Z","timestamp":1780125936000},"source":"Crossref","is-referenced-by-count":2,"title":["The Gut-Bone Axis: Molecular Mechanisms and Therapeutic Perspectives in Skeletal Homeostasis"],"prefix":"10.31083","volume":"31","author":[{"given":"ZhiJun","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Joint Surgery, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZhiBin","family":"Song","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Beijing University of Chinese Medicine, 100029 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8680-6802","authenticated-orcid":true,"given":"DuJiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China"},{"name":"Center for Orthopedic Diseases Research, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, 646000 Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, Chengdu University of Traditional Chinese Medicine, 611137 Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0027-0572","authenticated-orcid":true,"given":"GuoYou","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Joint Surgery, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China"},{"name":"Center for Orthopedic Diseases Research, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, 646000 Luzhou, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Dastghaib S, Koohpeyma F, Shams M, Saki F, Alizadeh A. 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