Acetylcholine Suppression by P. gingivalis Extracellular Vesicles Drives Osteoclastogenesis and Bone Loss via the Cyp4f40

ABSTRACT Porphyromonas gingivalis ( P. gingivalis ), a major pathogen in chronic periodontitis, is increasingly implicated in the pathogenesis of systemic diseases, including neurodegeneration and bone‐related conditions. A central mechanism of its systemic impact is the release of bacterial extracellular vesicles (EVs), which function as efficient transporters of virulence factors that can trigger pathological processes in distal tissues and organs. This study explores the role of P. gingivalis ‐derived EVs in systemic bone loss and their effects on neural function. Intraperitoneal administration in mice revealed EV accumulation in both brain tissue and long bones. Further analysis reveals that P. gingivalis EVs impair neural function in mice, as evidenced by elevated neurofilament light chain (NF‐L) levels in the blood and cognitive deficits in behavioral assessments. Notably, the cholinergic nerve in the femur has been affected, with a reduction in acetylcholine (ACh) expression. ACh typically inhibits osteoclastogenesis induced by P. gingivalis EVs; however, P. gingivalis EVs counteract this protective effect by suppressing ACh secretion through inhibiting Cyp4f40, a cytochrome P450 enzyme. These findings underscore the critical role of P. gingivalis EVs in the development of systemic bone loss and neurodegeneration, offering new insights into potential therapeutic strategies to mitigate the harmful effects of periodontal pathogens on bone and neurological health.