Self‐Replenishable Metabolically Augmented Synbiotic Microspheres Remodel Gut‐Bone Homeostasis

Abstract Gut microbiota dysbiosis in postmenopausal osteoporosis (PMO) is frequently accompanied by aberrant metabolism and absorption of short‐chain fatty acids (SCFAs). However, current oral probiotic therapies neglect the crucial role of probiotic‐driven SCFAs metabolism in restoring gut‐bone homeostasis. In this study, commencing with the sequencing of fecal samples from clinical patients with PMO, a self‐replenishable metabolically augmented synbiotic microsphere (SMASM) is fabricated via a thiol–ene click reaction to restore gut‐bone homeostasis using Lactobacillus rhamnosus GG (LGG) as a viable metabolic niche and hyaluronic acid (HA) as a self‐replenishable 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–X axis.