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

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.