Background Ileocolonic luminal pH has been reported to be abnormally low in inflammatory bowel disease (IBD) patients, and one of the causative factors may be reduced epithelial HCO3− secretory rate (JHCO3−). Disturbances in JHCO3− may occur due to inflammation-induced changes in the crypt and villous architecture, or due to the effect of proinflammatory cytokines on epithelial ion transporters. Methods To discriminate between these possibilities, the tumor necrosis factor alpha (TNF-α) overexpressing (TNF+/ΔARE) mouse model was chosen, which displays high proinflammatory cytokine levels in both ileum and colon, but develops only mild colonic histopathology and diarrhea. HCO3− secretion, mRNA expression, immunohistochemistry, and fluid absorptive capacity were measured in ileal and mid-colonic mucosa of TNF+/ΔARE and wildtype (WT) (TNF+/+) mice in Ussing chambers, and in anesthetized mice in vivo. Results The high basal JHCO3− observed in WT ileal and mid-colonic mucosa were luminal C1−-dependent and strongly decreased in TNF+/ΔARE mice. Downregulated in adenoma (DRA) mRNA and protein expression was strongly decreased in TNF+/ΔARE ileocolon, whereas cystic fibrosis transmembrane conductance regulator (CFTR), Na+/H+ exchanger 3 (NHE3), Na+/HCO3− cotransporter (NBC), and epithelial sodium channel (ENaC) expression was not significantly altered. This indicates that the severe defect in ileocolonic JHCO3− was due to DRA downregulation. Fluid absorption was severely depressed in the ileum but only mildly affected in the mid-distal colon, preventing the development of overt diarrhea. Conclusions Even mild ileocolonic inflammation may result in a decrease of epithelial HCO3− secretion, which may contribute to alterations in surface pH, intestinal flora, and mucus barrier properties.

Electrolyte transporters located in the basolateral membrane of the colonic epithelium are increasingly appreciated as elaborately regulated components of specific transport functions and cellular homeostasis: During electrolyte absorption, Na(+) /K(+) ATPase, Cl⁻ conductance, Cl⁻/HCO₃⁻ exchange, K(+) /Cl⁻ cotransport and K(+) channels are candidates for basolateral Na(+) , Cl⁻ and K(+) extrusion. The process of colonic anion secretion involves basolateral Na(+) /K(+) /2Cl⁻ , and probably also Na(+) /HCO₃⁻ cotransport, as well as Na(+) /K(+) ATPase and K(+) channels to supply substrate, stabilize the membrane potential and generate driving force respectively. Together with a multitude of additional transport systems, Na(+) /H(+) exchange and Na(+) /HCO₃⁻ cotransport have been implicated in colonocyte pH(i) and volume homeostasis. The purpose of this article is to summarize recently gathered information on the molecular identity, function and regulation of the involved basolateral transport systems in native tissue. Furthermore, we discuss how these findings can help to integrate these systems into the transport function and the cellular homoeostasis of colonic epithelial cells. Finally, disturbances of basolateral electrolyte transport during disease states such as mucosal inflammation will be reviewed.

Key points• In the upper intestinal tract, luminal acidity due to intermittent release of gastric juice needs to be counteracted by basolateral HCO 3 − import. In the lower gastrointestinal tract, the build-up of a thick mucus layer is a major defence mechanism against pathogens, and HCO 3 − is of the utmost importance for this process. The pathways for HCO 3 − transport that play a role in these mucosal defence strategies are, however, unknown.• We recently identified the electroneutral Na + -HCO 3 − cotransporter NBCn1 as a major regulator of intracellular pH in duodenal villous enterocytes. The present study shows that the murine duodenocytes, whose intracellular pH was monitored by in vivo two-photon confocal microscopy in anaesthetized NBCn1 knock-out mice, are unable to recover rapidly from intracellular acidification imposed by a short pulse of low-pH solution in the duodenal lumen. Likewise, they are not able to respond to contact of the surface with low pH by a protective HCO 3 − secretory response.• The cotransporter NBCn1 is also expressed in the basolateral membrane of colonic crypt cells, many of which stain positive for mucin granules. We found only a minor role for NBCn1 in colonic epithelial HCO 3 − secretion, but the build-up of a mucus layer, measured in the exteriorized colon of anaesthetized mice by in vivo microscopy, was significantly delayed in the absence of NBCn1 expression.• Therefore, NBCn1 plays major but different roles in mucosal protective functions in the upper and lower intestine.Abstract Duodenal epithelial cells need efficient defence strategies during gastric acidification of the lumen, while colonic mucosa counteracts damage by pathogens by building up a bacteria-free adherent mucus layer. Transport of HCO 3 − is considered crucial for duodenal defence against acid as well as for mucus release and expansion, but the transport pathways involved are incompletely understood. This study investigated the significance of the electroneutral Na + -HCO 3 − cotransporter NBCn1 for duodenal defence against acid and colonic mucus release. NBCn1 was localized to the basolateral membrane of duodenal villous enterocytes and of colonic crypt cells, with predominant expression in goblet cells. Duodenal villous enterocyte intracellular pH was studied before and during a luminal acid load by two-photon microscopy A. K. Singh and W. Xia contributed equally to this work. in exteriorized, vascularly perfused, indicator (SNARF-1 AM)-loaded duodenum of isoflurane-anaesthetized, systemic acid-base-controlled mice. Acid-induced HCO 3 − secretion was measured in vivo by single-pass perfusion and pH-stat titration. After a luminal acid load, NBCn1-deficient duodenocytes were unable to recover rapidly from intracellular acidification and could not respond adequately with protective HCO 3 − secretion. In the colon, build-up of the mucus layer was delayed, and a decreased thickness of the adherent mucus layer was observed, suggesting that basolateral HCO 3 − uptake is essential for optimal release of mucus...

Inflammation during TNF-α overexpression leads to increased epithelial permeability in murine proximal colon, decreased tight junctional cation selectivity, and increased HCO(3)(-) loss into the lumen. Inflammation-associated colonic HCO(3)(-) loss may occur through leaky tight junctions rather than through HCO(3)(-) secreting ion transporters.

BackgroundDuodenal mucosa needs efficient defence strategies against gastric acidity, while colonic mucosa counteracts damage by pathogens through the build‐up of an adherent mucus layer.AimThis study delineates the significance of the electroneutral Na+HCO3− cotransporter NBCn1 (Slc4a7) for duodenal defence against acid and for colonic mucus release.Methods and ResultsNBCn1 was localised to the basolateral membrane of duodenal villous enterocytes and of colonic crypt cells. Duodenal villous enterocyte pHi was studied before and during a luminal acid load by two‐photon microscopy in exteriorised, vascularly perfused, pH indicator‐loaded duodenum of anaesthetised mice. Acid‐induced HCO3− secretion was measured in vivo 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. Colonic mucus layer build‐up was delayed, and a decreased thickness of the adherent mucus layer was observed, suggesting that basolateral HCO3− uptake is essential for optimal colonic mucus release.ConclusionsThe electroneutral Na+HCO3− cotransporter NBCn1 is essential for intestinal mucosal protective functions, such as pHi‐recovery and HCO3− secretion after an acid load in the duodenum, as well as mucus secretion in the colon.