Helicobacter pylori infection is associated with gastric adenocarcinoma in some humans, especially those that develop an antecedent condition, chronic atrophic gastritis (ChAG). Gastric epithelial progenitors (GEPs) in transgenic gnotobiotic mice with a ChAG-like phenotype harbor intracellular collections of H. pylori. To characterize H. pylori adaptations to ChAG, we sequenced the genomes of 24 isolates obtained from 6 individuals, each sampled over a 4-year interval, as they did or did not progress from normal gastric histology to ChAG and/or adenocarcinoma. H. pylori populations within study participants were largely clonal and remarkably stable regardless of disease state. GeneChip studies of the responses of a cultured mouse gastric stem cell-like line (mGEPs) to infection with sequenced strains yielded a 695-member dataset of transcripts that are (i) differentially expressed after infection with ChAG-associated isolates, but not with a "normal" or a heat-killed ChAG isolate, and (ii) enriched in genes and gene functions associated with tumorigenesis in general and gastric carcinogenesis in specific cases. Transcriptional profiling of a ChAG strain during mGEP infection disclosed a set of responses, including up-regulation of hopZ, an adhesin belonging to a family of outer membrane proteins. Expression profiles of wild-type and DeltahopZ strains revealed a number of pH-regulated genes modulated by HopZ, including hopP, which binds sialylated glycans produced by GEPs in vivo. Genetic inactivation of hopZ produced a fitness defect in the stomachs of gnotobiotic transgenic mice but not in wild-type littermates. This study illustrates an approach for identifying GEP responses specific to ChAG-associated H. Pylori strains and bacterial genes important for survival in a model of the ChAG gastric ecosystem.