Emerging Roles of Periodontal Pathogen-Derived Outer Membrane Vesicles in NAFLD

Abstract

The rising incidence of nonalcoholic fatty liver disease (NAFLD) poses a great socioeconomic burden worldwide. Also, periodontitis is the most common chronic inflammatory disease caused by a group of oral pathogens, affecting both oral health and systemic conditions, especially liver disease. Although accumulating evidence has elucidated an association between periodontal pathogens and NAFLD, the role of periodontal pathogen-derived outer membrane vesicles (OMVs) has not yet been clarified. In this comprehensive review, we aim to address this gap by summarising the progression and pathogenesis of NAFLD and revealing the relationship between periodontal disease and NAFLD multidimensionally. Additionally, this review sheds light on the multifunctional roles of periodontal pathogens OMVs and emphasises that periodontal pathogen-derived OMVs promote the development of NAFLD by stimulating Kupffer cells to produce inflammatory factors and inducing the activation of Hepatic stellate cells. However, it is still controversial whether periodontal pathogen-derived OMVs can be transferred to the liver through the bloodstream route or the oral-gut-liver axis. This highlights the pressing need for continued research efforts to develop new and optimised research schemes to observe the formation of the systemic distribution pathway of periodontal pathogen-derived OMVs. Finally, it is notable that there are currently no relevant clinical treatment guidelines to make specific provisions on controlling the level of periodontal pathogen-derived OMVs in patients with NAFLD. Guidelines developed based on our findings may contribute to the standardisation of practices. It can also provide effective strategies and potential therapeutic targets for NAFLD patients with periodontitis to alleviate the development of NAFLD diseases by inhibiting periodontal pathogens OMVs.

Keywords: Nonalcoholic fatty liver disease; Outer membrane vesicles; P. gingivalis; Periodontal disease; Periodontal pathogens; Systemic disease.

Fig. 1

Progression of chronic liver diseases. This diagram illustrates the sequential stages of chronic liver conditions, starting from a healthy liver, advancing through nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), cirrhosis and ultimately leading to hepatocellular carcinoma or the necessity for liver transplantation or death. The process highlights the reversibility of early stages and the dire consequences of disease progression.

Fig. 2

Common risk factors between NAFLD and periodontitis. This schematic presentation is based on data reported in a systematic review with a meta-analysis.[10]

Fig. 3

Mechanisms of OMVs influence on hepatic pathology. This figure illustrates the dynamic interactions between OMVs, macrophages, hepatic stellate cells and hepatocytes within the liver environment. It highlights the process of OMV-mediated modulation of cellular pathways leading to hepatic fibrosis, including the activation of hepatic stellate cells, enhancement of pro-inflammatory cytokine production and stimulation of fibrogenesis. This visualisation underscores the multifaceted role of OMVs in the progression of liver diseases, from initial cellular interaction to the eventual pathological outcome.

Fig. 4

Diagram of the systemic blood route distribution of OMVs. The figure describes the circulatory pathway of adventitial OMVs derived from oral pathogens to various organs. The key processes include the transfer of microbial components from the oral cavity to blood vessels and their subsequent effects on the pathogenesis of organ injury.

Fig. 5

Illustration of the oral-gut-liver axis. This figure depicts the complex interactions between oral microbiota, the gut microbiome and liver health and the path of oral pathogen–derived OMVs. Key processes include the translocation of oral microbial components to the gut and their subsequent influence on the gut-liver axis.

Fig. 6

Innovative treatment and future prospect of periodontitis complicated with NAFLD. The innovative treatment plan encompasses four main aspects: (a) using antibiotics and probiotics to inhibit inflammation in nonalcoholic fatty liver disease; (b) reducing bacterial outer membrane vesicles through periodontal treatment; (c) using traditional Chinese medicines (e.g. curcumin and paeony glucosides) to inhibit inflammatory pathways; and (d) delivering therapeutic RNA, proteins and small molecules via OMVs for targeted therapy.