Backround: 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.

Aim: 

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

Methods and Results: 

After pancreatic and biliary duct ligation, the proximal duodenum of anesthetized mice was perfused with saline and HCO₃^- concentration in the effluate determined by pH-stat titration. Pharmacological inhibition by the selective NHE3 inhibitor S1611, or genetic ablation of NHE3 resulted in a significantly higher basal HCO₃^- secretory rate in vivo, which was electroneutral and dependent on the presence of luminal Cl^-, and therefore due to an unmasking of apical Cl^-/HCO₃^- exchange activity. Accordingly, Slc26a6 ablation attenuated the S1611-induced J_HCO3- slightly, and Slc26a3 ablation virtually abolished it, indicating that Slc26a3 (DRA) is the predominant anion exchange protein coupled to NHE3 in the duodenum. Neither the deletion of Slc26a6 or Slc26a3 had major effect on the basal HCO₃^- secretory rate, although luminal Cl^- removal strongly reduced basal HCO₃^- secretion. This indicates that the Slc26 transporters may compensate for each other under certain conditions. Interestingly, the forskolin-stimulated HCO₃^- secretory response was almost unchanged in Slc26a6- as well as Slc26a3-deficient mice or in the absence of luminal Cl^-, but was almost abolished in the absence of CFTR. In the absence of CFTR, electroneutral NaCl absorptive rates were similar to wt rates, but S1611 induced virtually no increase in HCO₃^- secretion.

Conclusion: 

The data indicate 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. Slc26a3 is the predominant anion exchanger that couples to NHE3 in the duodenum for salt absorption, but is not essential for basal or forskolin-stimulated HCO₃^- secretion in vivo.