Longitudinal remodeling of gastric microbiota following Helicobacter pylori eradication reveals an eradication-associated microbial signature in gastric cancer

Introduction Helicobacter pylori ( H. pylori ) is a major cause of gastric cancer (GC); however, GC also develops in H. pylori –negative patients, and the characteristics of non- H. pylori microbial communities remain unclear. Methods We characterized gastric microbiota in patients with GC according to H. pylori status, sex, GC subtype, and longitudinal changes following H. pylori eradication therapy. Gastric corpus mucosal samples were collected from 35 patients with GC who underwent endoscopic therapy and longitudinal follow-up. Some patients were followed for more than 10 years, and gastric microbiota were analyzed using 16S rRNA gene sequencing. Results H. pylori –negative samples exhibited significantly higher microbial diversity and distinct community structures compared with H. pylori –positive samples, which was consistent across sex and GC subtypes. Multiple non- H. pylori taxa were enriched in H. pylori –negative samples, including organisms with reported urease and nitrate-reducing activities. Longitudinal analyses demonstrated that successful eradication induced significant but non-uniform microbial shifts, whereas persistent infection maintained stable H. pylori –dominated profiles. Notably, species-level analyses revealed selective and H. pylori eradication-specific microbial changes, with Actinomyces naeslundii consistently enriched only in the H. pylori eradicated group across longitudinal modeling and differential abundance analyses. Functional prediction analyses revealed a reduced representation of host–pathogen interaction–related pathways in H. pylori –negative samples. Discussion These findings suggest that H. pylori –negative gastric microbiota harbor functionally distinct microbial communities that may contribute to gastric carcinogenesis through alternative microbial and ecological pathways. In addition, H. pylori eradication revealed a longitudinal remodeling of gastric microbiota.