Helicobacter pylori vaculating cytotoxin inhibits duodenal bicarbonate secretion by a histamine-dependent mechanism

Background & Aims: Helicobacter pylori (HP) infection reduces the secretory capacity of the duodenal mucosa for bicarbonate (Hogan et al. 1996), and CagAVacA positive H.p. extract strongly decreases murine duodenal HCO3- secretion in vitro within one hour (Tuo et al 2004). In this study, we investigated the effect of HP vacuolating cytotoxin (VacA) on duodenal mucosal bicarbonate secretion, and the underlying mechanisms for the VacA-induced reduction in HCO3- secretion.

Methods: Bicarbonate secretion by murine duodenal mucosa was examined in vitro in Ussing chambers. H.p. extracts from a VacA producing strain (P12) and an isogenic mutants lacking VacA (P12ΔvacA) were used (Gebert et al 2003).

Results: VacA-positive extract reduced PGE2-stimulated duodenal HCO3- secretion by 49% (P<0.0001), whereas the VacA-negative extract only slightly reduced PGE2-stimulated bicarbonate secretion by 17% (P>0.05). Preincubation with the H2-receptor antagonist ranitidine, but not with the H1 receptor antagonist diphenhydramine or the H3 receptor antagonist thioperamide, significantly attenuated the inhibitory effect of VacA-positive extract on PGE2-induced bicarbonate secretion partially. The VacA-positive H.p. extract stimulated duodenal mucosal histamine release concentration-dependently. After incubating for 15min with VacA-positive H.p. extract, duodenal mucosal histamine release markedly increased, it reached maximal levels at 45min, and this corresponded with the time course of development of the reduction in PGE2-mediated HCO3- secretion.

Conclusion: Hp VacA inhibits PGE2-stimulated duodenal epithelial bicarbonate secretion in part via the release of mucosal histamine, which in turn inhibits HCO3- secretion in an H2-receptor dependent mechanism. Hp VacA inhibition of duodenal bicarbonate secretion might therefore be an important pathogenic factor contributing to H.p. related duodenal mucosal injury.