High throughput genomic analysis of Helicobacter pylori within-host diversity

Helicobacter pylori is a globally significant human pathogen and is the causative agent of a wide range of diverse gastroduodenal diseases such as gastritis, peptic ulceration and gastric adenocarcinoma. Antimicrobial resistance is a growing problem, with H. pylori recently listed as one of the top ten antibiotic resistant pathogens of global concern by the World Health Organisation. This species has been shown to be a globally diverse pathogen expressing large genetic variation, even within geographically clustered sub populations. Furthermore, individuals infected with H. pylori are thought to harbour unique and diverse populations of quasispecies, but diversity between and within different niches of the human stomach and the process of bacterial adaptation to, and infection persistence within each niche are not yet well understood. This study utilises whole genome deep population and single colony sequencing to quantify and characterise the within- and between-niche genetic diversity of H. pylori populations from paired antrum and corpus biopsies from the stomachs of individual patients. This revealed extensive genetic diversity both within and between different niches of the same stomach. Subsets of highly variable genes including outer membrane proteins, restriction modification systems, DNA repair, chemotaxis and virulence associated genes were observed. In addition, this study investigated the between niche (antrum versus corpus) antimicrobial resistance profiles of individual patients. The within and between niche (antrum and corpus) diversity of two sequential datasets were also investigated and results from the same patient before and after failed eradication therapy were compared. For one sequential dataset there was a big increase in H. pylori allelic diversity both within and between niches of the patient's stomach approximately five months after failed eradication therapy