Akkermansia muciniphila alleviates osteoporosis by suppressing bone marrow adiposity through the gut microbiota-UDCA-TGR5 axis.

Osteoporosis (OP) is characterized not only by progressive bone loss but also frequently by pathological bone marrow adiposity (BMA) expansion. Akkermansia muciniphila (AKK), implicated in lipid metabolic homeostasis, was previously found to be markedly depleted during estrogen deficiency-associated bone loss. However, whether AKK suppresses pathological BMA expansion and the corresponding receptor-mediated mechanisms remain poorly understood. Here, we demonstrated that AKK significantly attenuated bone loss and potently suppressed pathological BMA expansion in ovariectomized rats. Integrated untargeted metabolomics and targeted bile acid profiling revealed that AKK supplementation notably restored ursodeoxycholic acid (UDCA) levels in both serum and feces. Metagenomic analyses showed that AKK reshaped bile salt hydrolase (BSH)-related microbial functions, thereby promoting the intestinal deconjugation of tauroursodeoxycholic acid to generate UDCA. The enhanced UDCA-producing capacity of gut microbiota from the AKK-treated group was abolished by inhibition of microbial BSHs. Consistently, oral UDCA supplementation replenished circulating UDCA levels and reproduced the bone- and marrow-protective effects of AKK. In the host, elevated circulating UDCA activated TGR5-dependent TGF-β/SMAD2 signaling in bone marrow mesenchymal stem cells (BMSCs), thereby suppressing adipogenic differentiation and promoting osteogenesis. These effects were reversed by a TGR5 inhibitor and Tgfbr1 knockdown. Collectively, our study reveals a novel mechanism underlying the anti-osteoporotic effects of AKK, whereby AKK suppresses pathological BMA expansion through the gut microbiota-UDCA-TGR5 signaling axis. These findings provide a potential therapeutic strategy for osteoporosis and bone marrow lipid metabolic dysfunction.