Global phylogenomic insights into the evolutionary adaptation of Helicobacter pylori: evidence from 1467 isolates and the fixation of cage D792 mutation

Abstract

Helicobacter pylori (H. pylori) is a globally prevalent gastric pathogen with substantial genetic diversity shaped by human co-evolution. Although extensive research has been conducted on H. pylori, the mechanisms underlying its adaptation and virulence remain incompletely understood. Here, we performed a phylogenomic analysis of 1467 isolates from 26 countries by constructing a core-genome single-nucleotide polymorphism (SNP) phylogeny and analyzing population structure, revealing five major lineages with distinct regional adaptations. A genome-wide Fixation Index (Fst) analysis identified 20 highly differentiated genes, with cagE (Fst = 0.8041)—a key component of the Type IV Secretion System (T4SS)—showing the strongest signal of positive selection. We discovered a novel N792D mutation in cagE, fixed in cluster c1, particularly in North America, which may enhance immune evasion and promote persistent colonization. Bayesian Evolutionary Analysis Sampling Trees 2 (BEAST2) analysis estimated that the most recent common ancestor (tMRCA) of highly virulent H. pylori emerged around 1934 (95% HPD: 1933–1934), coinciding with global conflicts and migrations that likely facilitated its spread. This study provides new insights into H. pylori evolution, highlighting the cagE mutation as a potential therapeutic target.

Keywords

Helicobacter pylori evolution / Phylogenomic / cagE D792 mutation / Adaptive evolution

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Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare