Region-specific genomic variation and functional divergence of <i>Helicobacter pylori</i> clinical isolates from the gastric antrum and corpus

The genetic variability of <i>Helicobacter pylori</i> contributes to differences in the severity of gastrointestinal diseases. Within the stomach, <i>H. pylori</i> exhibits diverse strain patterns and genetic variations that enable the evolution of new virulence factors, development of antibiotic resistance, and evasion of the host immune system. However, the comprehensive analysis of whole-genome sequences and their functional impact on gastric epithelial cells remains limited. In this study, we performed whole-genome sequencing, <i>de novo</i> assembly, and comparative genomic analysis on two pairs of <i>H. pylori</i> strains (v225/v226 and v290/v291) isolated from the antrum and corpus of two peptic ulcer patients. Bioinformatic tools were used to annotate and compare genes related to adhesion and virulence. Functional assays were conducted to assess strain-specific pathogenic effects on gastric epithelial cells. The analyses revealed substantial genetic heterogeneity between antral and corpus isolates, particularly in adhesion-related genes (<i>sabA</i>, <i>babA/B</i>), the cytotoxin-associated gene pathogenicity island (<i>cag</i>-PAI) cluster, and <i>vacA</i> sequences. Functional assays demonstrated region-specific differences, with corpus strains showing stronger adhesion and pro-inflammatory responses, whereas antral strains exhibited higher vacuolating activity. These findings demonstrate the ability of <i>H. pylori</i> to colonize specific stomach regions, undergo genetic diversification, and evolve niche-specific adaptations and pathogenicity in different gastric environments.IMPORTANCE<i>Helicobacter pylori</i> is a major cause of severe gastrointestinal diseases. It can establish persistent colonization in different regions of the stomach, where distinct environmental conditions drive niche-specific adaptation. Here, we found that <i>H. pylori</i> evolves genetic diversity in various factors, including virulence factors, adhesion molecules, and outer membrane proteins, to facilitate persistent colonization. Understanding how <i>H. pylori</i> generates genetic diversity to support colonization is crucial for developing more effective infection management strategies, improving molecular detection, and refining personalized treatment approaches.