Roseburia intestinalis-derived extracellular vesicles alleviate osteoporosis through gut microbiota-regulated histidylleucine via Akt/FOXO1 signaling.

Osteoporosis (OP), characterized by reduced bone mass and microarchitectural deterioration, significantly impairs patient health and quality of life. Conventional therapies are often limited by long-term safety concerns and adverse effects. Recent studies suggest that extracellular vesicles (EVs) play a critical role in bone remodeling by promoting osteoblast differentiation and mineralization while inhibiting osteoclast activity, offering a potential therapeutic avenue for OP. In this study, we observed a significant reduction of Roseburia intestinalis (R.intestinalis), an anaerobic, gram-positive bacterium, in both OP patients and ovariectomized (OVX) model rats by 16S rRNA sequencing. We successfully isolated and characterized R.intestinalis-derived EVs (REVs), which were found to promote the differentiation and mineralization of human bone marrow mesenchymal stromal cells (hBMSCs) in vitro. Mechanistically, REVs were shown to enhance the production of histidylleucine, and the administration of histidylleucine alone was sufficient to promote hBMSCs differentiation and mineralization through the Akt/FOXO1 signaling pathway. Furthermore, both REVs and histidylleucine were effective in reversing gut microbiota dysbiosis and improving bone mineral density in vivo. These findings highlight the therapeutic potential REVs and their metabolite histidylleucine in OP treatment through modulation of the "gut-bone" axis, which providing insights into histidylleucine as a promising therapeutic agent for OP.