Global Diversity of
                    <scp>
                      <i>Helicobacter pylori</i>
                    </scp>
                    Prophages Reveals Genetic Drivers of Virulence and Associations With Gastric Cancer

doi:10.1111/hel.70140

DOI: 10.1111/hel.70140 ISSN: 1083-4389

Global Diversity of Helicobacter pylori Prophages Reveals Genetic Drivers of Virulence and Associations With Gastric Cancer

Zhenkai Li, Ying Li, Shixuan Huang, Yanyan Shang, Yuecong Li, Tiantian Zhang, Xianhu Wei, Xinqiang Xie, Qingping Wu, Xinyu Zhao

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ABSTRACT

Background

Helicobacter pylori is a globally prevalent gastric pathogen, and chronic infection accounts for most gastric cancer (GC) cases worldwide. Major oncogenic determinants, including CagA, VacA, and the type IV secretion system, show marked geographic heterogeneity, yet the evolutionary forces shaping this uneven distribution remain unclear. Prophages can mediate horizontal gene transfer and modulate bacterial fitness and virulence, but their contribution to H. pylori carcinogenicity has not been systematically evaluated.

Methods

We characterized prophage diversity, population structure, and virulence potential using 2379 H. pylori host genomes and 139 complete prophage genomes. Prophage population structure and intergenomic relatedness were inferred, and the prophage pangenome and protein‐sharing network were reconstructed. Homology‐based association analyses were performed to test enrichment of prophage orthologous groups (POGs) with major oncogenic virulence factors (CagA and/or VacA) across the 2379 host genomes.

Results

Prophages segregated into geographically structured populations. The EastAsia and EastAsia2 prophage groups were tightly coupled to high‐risk hspEAsia hosts and exhibited the largest and most diverse accessory repertoires. Virulence‐associated genes were strongly population‐specific and were detected only in the EastAsia/EastAsia2 prophage populations. Moreover, carriage of POGs homologs from 1961P, HPy1R, and phiHP33 showed significant positive associations with CagA and/or VacA across the 2379 genomes, whereas no enrichment was observed for KHP30 or KHP40.

Conclusions

H. pylori prophages are not passive genomic remnants but population‐structured reservoirs whose gene repertoires track high‐risk virulence backgrounds and may contribute to the bacterium's carcinogenic potential.