Cold exposure-induced loss of beneficial gut bacterial sEV is associated with the pathogenesis of bone loss through pyroptosis pathway.

Recent studies suggest that cold temperature (CT) exposure contributes to osteoporosis. While the gut microbiota (GM) is a key regulator of host physiology, CT conditions significantly alter its composition. In this study, we found that co-housing with room temperature (RT) mice, as well as colonization with RT-donor GM, conferred protection against CT-induced bone loss. Using 16 S rRNA gene sequencing, we demonstrated that the CT-triggered decline in intestinal Bifidobacterium pseudolongum (B. p) abundance was rescued by co-housing with RT mice. Furthermore, oral administration of B. p effectively alleviated CT-induced bone loss. Mechanistically, we identified that small extracellular vesicles derived from Bifidobacterium. pseudolongum (B. p-sEVs) were taken up by bone tissue, where they enhanced osteogenesis and suppressed pyroptosis in bone marrow stromal cells (BMSCs). Collectively, our findings suggest that the GM helps preserve bone mass via bacterial sEVs, and that the reduction of B. p and its derived sEVs drives CT-induced bone loss.