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 α subunit of parietal cell H,K-ATPase (HKα). In AGS gastric epithelial cells, H pylori induces nuclear factor-κB (NF-κB) binding to and repression of transfected HKα promoter activity. This study sought to identify bacterial genes involved in HKα repression and to assess their impact on acid secretion.
Methods and results AGS cells transfected with an HKα promoter construct or human gastric body biopsies were infected with wild-type (wt) or isogenic mutant (IM) H pylori strains. AGS cell HKα promoter activity, and biopsy HKα mRNA, protein and H+ secretory activity were measured by luminometry, reverse transcription–PCR, immunoblotting and extracellular acidification, respectively. Wt H pylori and ΔvacA, ΔureA, Δslt and ΔflaA IM strains repressed HKα promoter activity by ∼50%, a ΔcagA IM strain repressed HKα by ∼33%, and ΔcagE, ΔcagM and ΔcagL IM strains elicited no HKα repression. Wt H pylori-infected biopsies had markedly reduced HKα 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 ΔcagL 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 HKα transcription. Further, acute H pylori infection of human gastric mucosa downregulates parietal cell H,K-ATPase expression, significantly inhibiting acid secretion.
- Acid secretion
- Helicobacter pylori
- proton pump inhibition
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