Background:

Duodenal defense strategies focus on pHi-regulation during gastric acidity in the lumen, while colonic mucosa counteracts damage by pathogens through the buildup of bacteria-free adherent mucus layer. HCO₃- transport is considered crucial for both duodenal defense against acid as well as the proper release of mucus, but the involved transport pathways are incompletely understood. Aim: To explore the cellular localization and physiological functions of the electroneutral Na⁺HCO₃^- cotransporter NBCn1 in duodenum and proximal-mid colon, the intestinal segments with high NBCn1 mRNA expression levels.

Methods and Results:

NBCn1 localized to the basolateral membrane of duodenal villous absorptive enterocytes, and of proximal-mid colonic goblet cells. Duodenal villus enterocyte pHi was studied before and during a luminal acid load by two photon microscopy in exteriorized, vascularly perfused, SNARF1-loaded duodenum of isoflurane-anesthetized systemic acid/base controlled mice, and acid-induced HCO₃^- secretion was measured by single pass perfusion and pH-stat titration. After a luminal acid load, NBCn1-deficient duodenocytes were unable to rapidly recover from intracellular acidification and could not adequately respond with a protective HCO₃- secretory response. In contrast, colonic crypt enterocyte pHi recovery from acidification was normal, but mucus layer build-up was delayed, which is consistent with the goblet-cell predominant expression of proximal-mid colonic NBCn1 and suggests that basolateral HCO₃^- uptake is essential for optimal mucus release.

Conclusions:

The electroneutral Na⁺HCO₃^- cotransporter NBCn1 displays a differential cellular distribution in the murine intestine and is essential for HCO₃^--dependent mucosal protective functions such as pHi-recovery and HCO₃^- secretion in the duodenum and mucus layer build-up in the colon.