Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa

Background and aims Helicobacter pylori infection of gastric mucosa causes gastritis and transient hypochlorhydria, which may provoke emergence of a mucosal precancer phenotype; H pylori strains containing a cag pathogenicity island (PAI) augment cancer risk. Acid secretion is mediated by the catalytic a subunit of parietal cell H, K-ATPase (HK alpha). In AGS gastric epithelial cells, H pylori induces nuclear factor-kappa B (NF-kappa B) binding to and repression of transfected HK alpha promoter activity. This study sought to identify bacterial genes involved in HK alpha repression and to assess their impact on acid secretion. Methods and results AGS cells transfected with an HK alpha promoter construct or human gastric body biopsies were infected with wild-type (wt) or isogenic mutant (IM) H pylori strains. AGS cell HK alpha promoter activity, and biopsy HK alpha mRNA, protein and H+ secretory activity were measured by luminometry, reverse transcriptione-PCR, immunoblotting and extracellular acidification, respectively. Wt H pylori and Delta vacA, Delta ureA, Delta slt and Delta flaA IM strains repressed HK alpha promoter activity by similar to 50%, a Delta cagA IM strain repressed HK alpha by similar to 33%, and Delta cagE, Delta cagM and Delta cagL IM strains elicited no HK alpha repression. Wt H pylori-infected biopsies had markedly reduced HK alpha mRNA and protein compared with IM strain infections or mock-infected controls. Histamine-stimulated, SCH28080-sensitive biopsy acid secretion was significantly inhibited by wt but not by Delta cagL IM H pylori infection compared with vehicle-only controls. Conclusions It is concluded that H pylori cag PAI gene products CagE, CagM, CagL and, possibly, CagA are mechanistically involved in repression of HK alpha transcription. Further, acute H pylori infection of human gastric mucosa downregulates parietal cell H, K-ATPase expression, significantly inhibiting acid secretion.