Extracellular Vesicles of Streptococcus anginosus Mediate Gastritis via Epithelial Barrier Disruption and Macrophage‐driven Inflammation

ABSTRACT Recent studies suggest Streptococcus anginosus ( SA ) contributes to gastric disease beyond Helicobacter pylori, yet its pathogenic mechanisms remain unclear. This study demonstrates that SA ‐derived extracellular vesicles ( SA ‐EVs) accumulate in gastric tissue, enter epithelial cells, and induce acute gastritis characterized by neutrophil infiltration and elevated cytokines (TNF‐α, IL‐6, IL‐17A). Chronic exposure leads to sustained inflammation, tight junction disruption (Claudin‐18, Occludin, ZO‐1), and mucosal damage. Proteomic analysis identified TMPC and FBP62 as virulence‐associated proteins enriched in SA ‐EVs, while transcriptomics revealed activation of macrophage polarization and cytokine‐receptor pathways. Metabolomic profiling indicated dysregulated aspartate metabolism and inflammation‐related metabolic changes, alongside increased gut SA abundance. Notably, genetic deletion of Tmpc or Fbp62 significantly attenuated SA ‐EVs pathogenicity in vivo, reducing gastric inflammation, cytokine production, and macrophage infiltration. These findings establish SA ‐EVs as key mediators of non‐ H. pylori gastritis, with TMPC and FBP62 orchestrating epithelial barrier disruption, immune activation, and metabolic dysregulation, highlights their potential as therapeutic targets.