LAUSR

AIMS Positive associations between periodontitis (PD) and atherosclerosis have been established, but the causality and mechanisms are not clear. We aimed to explore the causal roles of PD in atherosclerosis and dissect the underlying mechanisms. METHODS AND RESULTS A mouse model of PD was established by ligation of molars in combination with application of subgingival plaques collected from PD patients, and then combined with atherosclerosis model induced by treating atheroprone mice with a high-cholesterol diet (HCD). PD significantly aggravated atherosclerosis in HCD-fed atheroprone mice, including increased en face plaque areas in whole aortas and lesion size at aortic roots. PD also increased circulating levels of triglycerides and cholesterol, hepatic levels of cholesterol, and hepatic expression of rate-limiting enzymes for lipogenesis. Using 16S rRNA gene sequencing, F. nucleatum was identified as the most enriched PD-associated pathobiont that present in both oral cavity and livers. Co-culture experiments demonstrated that F. nucleatum directly stimulated lipid biosynthesis in primary mouse hepatocytes. Moreover, oral inoculation of F. nucleatum markedly elevated plasma levels of triglycerides and cholesterol and promoted atherogenesis in HCD-fed ApoE-/- mice. Results of RNA-seq and Seahorse assay indicated that F. nucleatum activated glycolysis, inhibition of which by 2-deoxyglucose in turn suppressed F. nucleatum-induced lipogenesis in hepatocytes. Finally, interrogation of the molecular mechanisms revealed that F. nucleatum induced glycolysis and lipogenesis by activating PI3K/Akt/mTOR signaling pathway in hepatocytes. CONCLUSIONS PD exacerbates atherosclerosis and impairs lipid metabolism in mice, which may be mediated by F. nucleatum-promoted glycolysis and lipogenesis through PI3K/Akt/mTOR signaling in hepatocytes. Treatment of PD and specific targeting of F. nucleatum are promising strategies to improve therapeutic effectiveness of hyperlipidemia and atherosclerosis. TRANSLATIONAL PERSPECTIVE This study has reinforced the causal relationship between PD and atherosclerosis, and identified F. nucleatum-mediated hepatic glycolysis and lipogenesis as a new mechanism underlying the causal relationship. These findings support that intervention of PD or F. nucleatum may improve lipid homeostasis and contribute to alleviation of atherosclerosis and improvement of cardiovascular health.