Helicobacter pylori Infection Remodels Neutrophil‐Derived Extracellular Vesicles, Promoting Stress and Apoptosis in Infected Epithelial Cells

ABSTRACT

Helicobacter pylori is a Gram‐negative bacterium that establishes colonization in the human stomach and is estimated to infect over half of the global population. It is recognized as a significant causative agent of chronic gastritis, peptic ulcers, and gastric cancer. Neutrophils play a central role in innate defence against H. pylori ; however, dysregulated neutrophil activation contributes to epithelial injury and persistent inflammation. Here, we show that H. pylori enhance neutrophil exocytosis and stimulates the release of extracellular vehicles (EVs) with distinct biophysical and molecular characteristics. Infected neutrophils released smaller and more abundant EVs than uninfected controls. These H. pylori –induced neutrophil EVs (HPN‐EVs) suppressed PI3K/Akt signalling, increased reactive oxygen species, disrupted mitochondrial integrity, and induced cytochrome c release, caspase activation, and apoptosis in infected gastric epithelial cells. Proteomics profiling revealed enrichment of neutrophil granule proteins, particularly LL‐3, and depletion of proteins associated with cellular homeostasis. EV‐mediated LL‐37 delivery reproduced key pro‐apoptotic effects of HPN‐EVs, supporting its functional role in epithelial injury. Consistent with these findings, circulating EVs from H. pylori ‐infected patients exhibited elevated LL‐37 levels and induced similar pro‐apoptotic responses. Together, these findings identify LL‐37‐enriched HPN‐EVs as important mediators of neutrophil–epithelial crosstalk and investigating EV‐associated cargo as a potential therapeutic target in H. pylori ‐associated disease.