Abstract
The human gastric pathogen Helicobacter pylori colonizes the stomachs of half of the human population, and causes development of peptic ulcer disease and gastric adenocarcinoma. H. pylori-associated chronic atrophic gastritis (ChAG) with loss of the acid-producing parietal cells, is correlated with an increased risk for development of gastric adenocarinoma. The majority of H. pylori isolates produce lipopolysaccharides (LPS) decorated with human-related Lewis epitopes, which have been shown to phase-vary in response to different environmental conditions. We have characterized the adaptations of H. pylori LPS and Lewis antigen expression to varying gastric conditions; in H. pylori isolates from mice with low or high gastric pH, respectively; in 482 clinical isolates from healthy individuals and from individuals with ChAG obtained at two time points with a four-year interval between endoscopies; and finally in isolates grown at different pH in vitro. Here we show that the gastric environment can contribute to a switch in Lewis phenotype in the two experimental mouse models. The clinical isolates from different human individuals showed that intra-individual isolates varied in Lewis antigen expression although the LPS diversity was relatively stable within each individual over time. Moreover, the isolates demonstrated considerable diversity in the levels of glycosylation and in the sizes of fucosylated O-antigen chains both within and between individuals. Thus our data suggest that different LPS variants exist in the colonizing H. pylori population, which can adapt to changes in the gastric environment and provide a means to regulate the inflammatory response of the host during disease progression.
Highlights
Helicobacter pylori colonization leads to gastritis in virtually all infected hosts, and a subset progresses to peptic ulcer, gastric adenocarcinoma or MALT lymphoma [1]
To study the effect of different gastric environments and gastric pH on Lewis antigen expression, we analyzed the LPS of five HPAG1 single-colony re-isolates obtained after one year of colonization of parietal cell-deficient tox176 mice (n = 2) and five HPAG1 single- colony re-isolates from wildtype mice (n = 4) [27]
In the normal group (n = 180), two out of nine individuals (Kx491 and Kx595) were colonized with H. pylori that were cagA negative and cag pathogenicity island (PAI) empty site positive, indicating deletion of the entire cag PAI. Another individual (Kx364) carried H. pylori isolates that were both cagA negative and cag PAI empty site negative, indicating that part of the cag PAI may still be present in these isolates, the cagA gene is deleted
Summary
Helicobacter pylori colonization leads to gastritis in virtually all infected hosts, and a subset progresses to peptic ulcer, gastric adenocarcinoma or MALT lymphoma [1]. The gastric environment changes and the infecting H. pylori strains must adapt to persist in a gastric habitat with increased pH, a new gastric cell composition and invasion of intestinal microbes. H. pylori encodes several virulence factors, the most well-described being the cag pathogenicity island (PAI), which encodes a type IV secretion system and the effector protein CagA, and the vacuolating cytotoxin VacA, which induces morphogenic changes of the host cell [3,4,5]. H. pylori possesses the ability to phase-vary genes encoding outer membrane proteins as well as genes involved in lipopolysaccharide (LPS) biosynthesis, which enables adaptation to varying gastric conditions [6,7,8,9]
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