Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin-18 downregulation and acid backflux

Aim: This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX).

Methods: We assessed the ability of CAIX-knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pH_i of exteriorized gastric mucosa in vivo using two-photon confocal laser scanning microscopy. Cytokines and claudin-18A2 expression was analysed by RT-PCR.

Results: CAIX-knockout gastric surface epithelial cells showed significantly faster pH_i decline after luminal acid load compared to WT. Increased gastric mucosal IL-1β and iNOS, but decreased claudin-18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin-18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL-11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin-18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL-1β. However, the treatment reduced the parietal cell loss in CAIX-KO mice in the subsequent months.

Conclusions: We propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO₂ and H₂ O, contributing to tight junction protection and gastric epithelial pH_i regulation. Lack of CAIX results in persistent acid backflux via claudin-18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.