Porphyromonas gingivalis OMVs Activate Macrophage-Hepatic Stellate Cells via Thbs1/TGF-β Signalling in NAFLD.

Abstract

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver conditions worldwide, and periodontitis (PD) may be an independent risk factor for the development and progression of NAFLD. However, the underlying mechanisms of how periodontitis promotes the progression of NAFLD remain unclear. METHODS: This study examined the correlation between periodontitis and NAFLD through epidemiological, pathological, and serological analysis. Periodontitis and NAFLD models were established in mice to investigate the role of outer membrane vesicles (OMVs) of Porphyromonas gingivalis (P. gingivalis) in hepatic steatosis. An in vitro study was conducted to confirm the effect of P. gingivalis OMVs on activation of macrophages (MΦs) and hepatic stellate cells (HSCs). RESULTS: The incidence of patients with PD and NAFLD was significantly higher than those with NAFLD only, and this proportion was positively related to the severity of PD. In vivo, P. gingivalis OMVs promoted hepatic injury and steatosis in NAFLD induced by a high-fat diet. In vitro, P. gingivalis OMVs activated HSCs through MΦs phenotype switching from M0 toward M1. Mechanistically, MΦs primed by P. gingivalis OMVs activated HSCs via thrombospondin-1 (Thbs1)/transforming growth factor-β (TGF-β) signalling, contributing to the liver fibrosis of NAFLD. Inhibition of Thbs1 can downregulate TGF-β signalling, preventing the progression of NAFLD promoted by P. gingivalis OMVs. CONCLUSION: Overall, this study verified the correlation between NAFLD and periodontitis and provides novel insights into the vital role of P. gingivalis OMVs in activation of macrophage-hepatic stellate cells through Thbs1/TGF-β signalling pathway in the context of NAFLD and periodontitis.