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However, current oral probiotic therapies neglect the crucial role of probiotic\u2010driven SCFAs metabolism in restoring gut\u2010bone homeostasis. In this study, commencing with the sequencing of fecal samples from clinical patients with PMO, a self\u2010replenishable metabolically augmented synbiotic microsphere (SMASM) is fabricated via a thiol\u2013ene click reaction to restore gut\u2010bone homeostasis using <jats:italic>Lactobacillus rhamnosus<\/jats:italic> GG (LGG) as a viable metabolic niche and hyaluronic acid (HA) as a self\u2010replenishable prebiotic substrate. In vitro, the SMASMs exhibit favorable biocompatibility, enhanced resistance to gastric acid, and improved mucosal adhesion for colonization. In vivo, oral administration of SMASMs in ovariectomized mice improves intestinal barrier integrity, mitigates inflammation, and suppresses bone loss, accompanied by alterations in microbial biomarkers and predicted metabolic functions. Notably, HA serves as a sustainable prebiotic substrate that supports the LGG metabolic niche and microbial homeostasis, enhances the production of SCFAs, including butyric, isobutyric, and valeric acids, and contributes to the downregulation of key osteoclastic signaling factors. Importantly, this strategy of oral SMASMs through in situ fermentation offers novel insights into addressing metabolic disorders associated with gut microbiota via the gut\u2013X axis.<\/jats:p>","DOI":"10.1002\/adma.202500746","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T04:57:38Z","timestamp":1748581058000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Self\u2010Replenishable Metabolically Augmented Synbiotic Microspheres Remodel Gut\u2010Bone Homeostasis"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6662-1892","authenticated-orcid":false,"given":"Zhijie","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine  197 Ruijin 2nd Road Shanghai 200025 P. 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