Gnotobiotic transgenic mice reveal that transmission of Helicobacter pylori is facilitated by loss of acid-producing parietal cells in donors and recipients.

Helicobacter pylori is acquired during childhood, but its mode of transmission remains unclear. A genotyped H. pylori isolate (Hp1) that expresses two classes of adhesins was introduced into the stomachs of three types of germ-free FVB/N mice to model factors that may affect spread of H. pylori in humans. Normal mice represented human hosts with normal gastric acid production. Transgenic animals expressing human alpha-1,3/4-fucosyltransferase in their gastric pit cells represented humans with normal acid production and the commonly encountered Lewis(b) histo-blood group receptor for the bacterium's BabA adhesin. tox176 transgenic mice have a genetically engineered ablation of their acid-producing parietal cells and increased proliferation of gastric epithelial lineage progenitors that express sialylated glycan receptors for the bacterium's SabA adhesin. These mice mimic features encountered in humans with H. pylori-associated chronic atrophic gastritis (CAG). Different combinations and numbers of 6-week-old germ-free normal and transgenic mice were housed together. At least one donor mouse per cage was infected with a single gavage of 10(7) colony-forming units of Hp1. All cagemates were sacrificed 8 weeks later. Cultures of gastric and cecal contents, plus quantitative PCR assays of cecal contents harvested from donors and potential recipients, revealed that transmission only occurred between tox176 donors and tox176 recipients, and that the distribution of Hp1 along the gastrointestinal tract was significantly broader in mice without parietal cells (P < 0.001). Transmission between tox176 mice was not attributable to any significant difference in the density of Hp1 colonization of the stomachs of tox176 versus normal donors. Our findings lead to the testable hypothesis that the relative hypochlorhydria of young children, and conditions that promote reduced acid production in infected adults (e.g. CAG), represent risk factors for spread of H. pylori.

Correlation between cag pathogenicity island composition and Helicobacter pylori-associated gastroduodenal disease.

Helicobacter pylori infection is associated with a variety of outcomes ranging from seemingly asymptomatic coexistence to peptic ulcer disease and gastric cancer. The cag pathogenicity island (PAI) contains genes associated with a more aggressive phenotype and has been suggested to be a determinant of severe disease outcome. The cagA gene has served as a marker for the cag PAI. However, the presence of this single gene does not necessarily indicate the presence of a complete set of cag PAI genes. We have analyzed the composition of the cag PAI in 66 clinical isolates obtained from patients with duodenal ulcer, gastric cancer, and nonulcer dyspepsia. Hybridization of DNA to microarrays containing all the genes of the cag PAI showed that 76 and 9% of the strains contained all or none of the cag PAI genes, respectively. Partial deletions of the cag PAI were found in 10 isolates (15%), of which 3 were cagA negative. The ability to induce interleukin-8 (IL-8) production in AGS cells was correlated to the presence of a complete cag PAI. Strains carrying only parts of the island induced IL-8 at levels significantly lower than those induced by cag PAI-positive isolates. The presence of an intact cag PAI correlates with development of more severe pathology, and such strains were found more frequently in patients with severe gastroduodenal disease (odds ratio, 5.13; 95% confidence interval, 1.5 to 17.4). Partial deletions of the cag PAI appear to be sufficient to render the organism less pathogenic.

Colonization of germ-free transgenic mice with genotyped Helicobacter pylori strains from a case-control study of gastric cancer reveals a correlation between host responses and HsdS components of type I restriction-modification systems.

Helicobacter pylori infects the stomachs of half of all humans. It has a relatively benign relationship with most hosts but produces severe pathology, including gastric cancer, in others. Identifying the relative contributions of host, microbial, and environmental factors to the outcome of infection has been challenging. Here we describe one approach for identifying microbial genes that affect the magnitude of host responses to infection. Single colony purified H. pylori isolates were obtained from 25 cases and 71 controls in a Swedish case-control study of gastric cancer. Strains were first phenotyped based on their ability to produce adhesins that recognize two classes of human gastric epithelial receptors. Thirteen binding strains and two non-binding controls were then subjected to whole genome genotyping using H. pylori DNA microarrays. A cohort of "variable" genes was identified based on a microarray-determined call of "absent" in at least one member of the strain panel. Each strain was subsequently introduced into two types of germ-free transgenic mice, each programmed to express a different host factor postulated to pose increased risk for development of severe pathology. Expression of biomarkers of host defense was quantitated 4 weeks after inoculation, and the magnitude of the response correlated with bacterial genotype. The proportion of genes encoding HsdS homologs (specificity subunit of hetero-oligomeric type I restriction-modification systems) was significantly higher in the pool of 18 variable genes whose presence directly correlated with a robust host response than their proportion in the remaining 352 members of the variable gene pool. This suggests that the functions of these HsdS homologs may include control of expression of microbial determinants that affect the extent of gastric responses to this potentially virulent pathogen.