Background: 

CF patients suffer from a variety of gastrointestinal problems, which may all be directly or indirectly linked to the inability of the intestinal mucosa to secrete HCO3- and to inhibit Na⁺/H⁺ mediated fluid absorption and proton secretion. This has led to an intense search for alternative modes of intestinal anion transport, and expressions of a variety of potential alternative intestinal anion transporters have been reported.

Aim: 

To delineate the dependency of different modes of intestinal HCO₃^- secretion on CFTR expression.

Methods and Results: 

We studied acid-, agonist-, and HCO₃^- stimulated, as well as Cl^--dependent HCO₃^- secretion in the CFTRtm1cam and WT murine duodenum in vivo. NHE3 and Slc26a6-deficient mice were used for selected questions. Luminal acid, forskolin, heat-stable E. coli enterotoxin (STa), PGE2, carbachol, and an increase of blood HCO₃^- all stimulated duodenal HCO₃^- secretion in anesthetized WT but not in CFTRtm1cam mice. Pharmacological inhibition or genetic ablation of NHE3 resulted in a significantly higher basal HCO₃^- secretory rate, which was electroneutral and therefore due to an unmasking of apical Cl^-/ HCO₃^- exchange activity. Accordingly, Slc26a6 ablation attenuated S1611- induced J HCO₃^- Removal of luminal Cl^- reverted basal HCO₃^- secretion to H⁺ secretion, but surprisingly, forskolin was able to elicit a full HCO₃^- secretory response. In the absence of CFTR, electroneutral NaCl absorptive rates were similar to WT rates, but S1611 induced virtually no increase in HCO3^- secretion.

Conclusion: 

This indicates that the apical anion exchangers Slc26a6 and Slc26a3 need proton recycling via NHE3 to operate in the Cl^- absorptive mode, and Cl^- exit via CFTR to operate in the HCO₃^- secretory mode. In addition, Cl^- independent HCO₃^- secretion can be stimulated by cAMP increase, likely from the crypt region, which expresses high levels of CFTR but none of the anion exchangers.