Helicobacter pylori adaptation in vivoin response to a high salt diet

Helicobacter pylori exhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification of H. pylori is influenced by the composition of the diet. Specifically, we investigated the effect of a high salt diet (a known risk factor for gastric adenocarcinoma) on H. pylori diversification within a host. We analyzed H. pylori strains isolated from Mongolian gerbils fed either a high salt diet or a regular diet for four months, using proteomic and whole genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high salt diet produced higher levels of proteins involved in iron acquisition and oxidative stress resistance. Several of these changes were attributable to a non-synonymous mutation in fur (fur-R88H). Further experiments indicated that this mutation conferred increased resistance to high salt conditions and oxidative stress. We propose a model in which a high salt diet leads to high levels of gastric inflammation and associated oxidative stress in H. pylori-infected animals, and that these conditions along with the high intraluminal concentrations of sodium chloride lead to selection of H. pylori strains that are most fit for growth in this environment

Helicobacter pylori genetic diversification in the Mongolian gerbil model

Helicobacter pylori requires genetic agility to infect new hosts and establish long-term colonization of changing gastric environments. In this study, we analyzed H. pylori genetic adaptation in the Mongolian gerbil model. This model is of particular interest because H. pylori-infected gerbils develop a high level of gastric inflammation and often develop gastric adenocarcinoma or gastric ulceration. We analyzed the whole genome sequences of H. pylori strains cultured from experimentally infected gerbils, in comparison to the genome sequence of the input strain. The mean annualized single nucleotide polymorphism (SNP) rate per site was 1.5e−5, which is similar to the rates detected previously in H. pylori-infected humans. Many of the mutations occurred within or upstream of genes associated with iron-related functions (fur, tonB1, fecA2, fecA3, and frpB3) or encoding outer membrane proteins (alpA, oipA, fecA2, fecA3, frpB3 and cagY). Most of the SNPs within coding regions (86%) were non-synonymous mutations. Several deletion or insertion mutations led to disruption of open reading frames, suggesting that the corresponding gene products are not required or are deleterious during chronic H. pylori colonization of the gerbil stomach. Five variants (three SNPs and two deletions) were detected in isolates from multiple animals, which suggests that these mutations conferred a selective advantage. One of the mutations (FurR88H) detected in isolates from multiple animals was previously shown to confer increased resistance to oxidative stress, and we now show that this SNP also confers a survival advantage when H. pylori is co-cultured with neutrophils. Collectively, these analyses allow the identification of mutations that are positively selected during H. pylori colonization of the gerbil model