Culture-free Helicobacter pylori genomics reveals within-host virulence heterogeneity and antibiotic resistance
- 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Abstract
Helicobacter pylori (Hp) infects over 40% of the world population and causes most cases of gastric cancer worldwide, yet fundamental questions about its within-host genetic diversity remain unresolved. Decades of work on Hp genomics depends on culturing clinical isolates, which can distort within-host genetic heterogeneity that informs Hp virulence and antimicrobial resistance. Culture-free alternatives have been limited by the extremely low Hp abundance in gastric tissue (usually 10-3 to 10-7 of total genomic DNA), making direct metagenomics prohibitively expensive and existing enrichment strategies insufficient for whole-genome recovery. Here we develop ultra-sensitive Hp sequencing (uHp-seq) for reconstructing Hp genomes directly from gastric biopsies. uHp-seq achieves a thousand-fold Hp DNA enrichment and recovers near-complete genomes across samples spanning orders of magnitude in Hp abundance. Notably, individual hosts may harbor multiple co-existing Hp strains or cagA EPIYA variants with different oncogenic potential. Resistance-associated variants for six commonly used antibiotics are resolved with greater accuracy than PCR-based and probe-based commercial panels. Applied to minimally invasive gastric string samples, uHp-seq delivers reliable resistance profiles without endoscopy, opening a path to genome-guided Hp eradication.
Related
- Molecular Detection Technologies for Helicobacter pylori Antibiotic Resistance: Current Status and Clinical Implications.
- Advances in Research on the Genotype–Phenotype Correspondence of Antibiotic Resistance in Helicobacter pylori and Its Molecular Mechanisms: A Narrative Review
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- Biotope-dependent resistance to reactive oxygen species, antibiotic tolerance, and virulence of Staphylococcus aureus
- Comparative genomics of Helicobacter pylori isolated from liver fluke endemic regions in Thailand
BibTeX
@misc{liu2026culturefree,
title = {{Culture-free Helicobacter pylori genomics reveals within-host virulence heterogeneity and antibiotic resistance}},
author = {Y. Liu and M. Ni and X.-S. Zhang and J. Bass and P. Deshpande and J. Romero-Gallo and H. Chen and Y. Fan and D. Wang and W. Qiao and Y. Zhang and E. A. Mead and E. Dias-Neto and A. Corvalan and R. Brody and C. M. Camargo and W. Szymczak and A. D. Klion and R. M. Peek and M. J. Blaser and G. Fang},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.23.26365955},
url = {https://www.medrxiv.org/content/10.64898/2026.10.23.26365955v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Culture-free Helicobacter pylori genomics reveals within-host virulence heterogeneity and antibiotic resistance
AU - Y. Liu
AU - M. Ni
AU - X.-S. Zhang
AU - J. Bass
AU - P. Deshpande
AU - J. Romero-Gallo
AU - H. Chen
AU - Y. Fan
AU - D. Wang
AU - W. Qiao
AU - Y. Zhang
AU - E. A. Mead
AU - E. Dias-Neto
AU - A. Corvalan
AU - R. Brody
AU - C. M. Camargo
AU - W. Szymczak
AU - A. D. Klion
AU - R. M. Peek
AU - M. J. Blaser
AU - G. Fang
PY - 2026
DA - 2026/10/23
PB - medRxiv
DO - 10.64898/2026.10.23.26365955
UR - https://www.medrxiv.org/content/10.64898/2026.10.23.26365955v1
AB - Helicobacter pylori (Hp) infects over 40% of the world population and causes most cases of gastric cancer worldwide, yet fundamental questions about its within-host genetic diversity remain unresolved. Decades of work on Hp genomics depends on culturing clinical isolates, which can distort within-host genetic heterogeneity that informs Hp virulence and antimicrobial resistance. Culture-free alternatives have been limited by the extremely low Hp abundance in gastric tissue (usually 10-3 to 10-7 of total genomic DNA), making direct metagenomics prohibitively expensive and existing enrichment strategies insufficient for whole-genome recovery. Here we develop ultra-sensitive Hp sequencing (uHp-seq) for reconstructing Hp genomes directly from gastric biopsies. uHp-seq achieves a thousand-fold Hp DNA enrichment and recovers near-complete genomes across samples spanning orders of magnitude in Hp abundance. Notably, individual hosts may harbor multiple co-existing Hp strains or cagA EPIYA variants with different oncogenic potential. Resistance-associated variants for six commonly used antibiotics are resolved with greater accuracy than PCR-based and probe-based commercial panels. Applied to minimally invasive gastric string samples, uHp-seq delivers reliable resistance profiles without endoscopy, opening a path to genome-guided Hp eradication.
ER -