The Role of Oral and Gut Microbiota in Bone Health: Insights from Bacterial Extracellular Vesicles

Bone health is critically influenced by the oral and gut microbiota, which are among the largest microbial reservoirs in the human body. These microbiota play essential roles in maintaining bone mass through immune modulation, metabolite production, and nutrient resorption. Recent observations have underscored that extracellular vesicles (EVs) derived from oral and gut microbiota may circulate to the brain and bone marrow, suggesting their integral roles in the gut-brain-bone axis and oral-brain-bone axis. This review outlines the current research status of bacterial extracellular vesicles (BEVs), including their biogenesis, classification, structural features, and cargo composition, with emphasis on factors influencing cargo heterogeneity and the consequences of cellular uptake and presentation. Oral-microbiota-derived BEVs and their cargo associated with bone health are highlighted, along with recent evidence linking BEVs to systemic dis-eases and the potential integration into the oral-gut-bone axis. Preclinical animal studies on BEV dosage, routes of administration, and disease models are summarized, together with the limitations of current approaches and strategies for engineering BEVs. Finally, an overview of translational applications and future therapeutic prospects is provided, aiming to advance the understanding of BEVs as innovative tools for the treatment and prevention of bone-related diseases.