Prevotella copri impairs bone mass via osteoclast activation in mice.

Prevotella copri, a predominant commensal bacterium in the human gut, exhibits positive or negative correlations with multiple metabolic disorders through its abundance dynamics. Although its association with rheumatoid arthritis pathogenesis is established, the effect of P. copri on bone metabolism remains elusive. This study demonstrates that P. copri exposure induces systemic bone metabolic imbalance in both normal physiological murine models and in vitro-cultured bone marrow-derived adherent cells (BMDCs), which is characterized by exacerbated osteoclastogenesis. Notably, succinate acts as a critical bioactive metabolite, with its specific receptor SUCNR1 being involved in its regulation on bone metabolism. P. copri or succinate intervention triggers bone inflammatory responses, prominently elevating IL-6 expression. Intriguingly, the osteoclastic activation is abolished in Il-6-knockout mice upon P. copri or succinate challenge. These findings delineate a ‌succinate-SUCNR1-IL-6 signaling axis‌ through which P. copri disrupts bone homeostasis, proposing novel therapeutic strategies for bone disorders such as osteoporosis via modulating gut microbiota composition (e.g., diet-mediated Prevotella suppression), reducing succinate bioavailability, and pharmacological antagonism of SUCNR1.