Oral Bacterial Extracellular Vesicles as Systemic Messengers: A Mouth–Gut–Systemic Axis Paradigm

Abstract

ABSTRACT Oral microbiome dysbiosis not only associated with localized periodontal disease but also with multiple systemic diseases, including cardiovascular disease, diabetes mellitus, Alzheimer's disease, rheumatoid arthritis, and cancer. However, the efficiency with which intact viable bacteria cross biological barriers to reach distant organs is extremely low, making it difficult to fully explain the sustained and profound pathogenic impact of oral dysbiosis on systemic health. In recent years, bacterial extracellular vesicles (BEVs) have emerged as candidate messengers linking oral and systemic diseases. BEVs constitute a broad category of vesicles encompassing outer membrane vesicles (OMVs) from Gram‐negative bacteria and membrane vesicles (MVs) from Gram‐positive bacteria. OMVs are nanoscale lipid‐bilayer vesicles naturally secreted by Gram‐negative bacteria, whereas MVs are produced by Gram‐positive bacteria through mechanisms distinct from classical outer membrane blebbing. Carrying diverse bioactive molecules, including lipopolysaccharide (LPS), gingipains, adhesins, and virulence DNA, BEVs may leverage their nanoscale dimensions, vesicular stability, and the capacity to exert pathogenic effects independently of bacterial colonization to traverse gingival epithelium, intestinal mucosa, and the blood–brain barrier, thereby delivering local oral inflammatory signals to distant organs. This review proposes a “mouth–gut–systemic” three‐tiered delivery framework, delineating the proposed cascade from oral dysbiosis through BEV release, cross‐barrier translocation, gut microenvironment remodeling, intestinal barrier disruption, and immune activation to pathological effects in distant organs. At the intestinal level, BEVs may induce gut dysbiosis, disrupt intestinal epithelial tight junctions, and activate chronic low‐grade immune responses, converting local oral inflammatory signals into a sustained systemic inflammatory burden. At the systemic level, BEVs have been implicated in the pathogenesis of atherosclerosis, insulin resistance, nonalcoholic fatty liver disease, rheumatoid arthritis, Alzheimer's disease, and colorectal cancer through three convergent mechanisms: Toll‐like receptor (TLR)/nuclear factor‐κB (NF‐κB) pathway activation, oxidative stress induction, and M1 macrophage polarization. However, these mechanisms are not BEV‐specific, and disease phenotypes also depend on host genetic background, tissue microenvironment, exposure dose and duration, and OMV‐specific cargo. Moreover, direct human evidence remains limited, and the relative contribution of different translocation routes may vary with disease state. This review also discusses the translational potential of BEVs as therapeutic targets, drug delivery vehicles, vaccine adjuvants, and diagnostic biomarkers, while identifying critical evidence gaps in the translation from animal models to human application. This framework awaits validation through in vivo tracing, microbiota transplantation, selective depletion, and standardized multicenter studies.