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.