Loss of downregulated in adenoma (DRA) impairs mucosal HCO 3 − secretion in murine ileocolonic inflammation

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 HCO   3 −secretory rate (J   HCO3   −). Disturbances in J   HCO3   −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. HCO   3 −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 J   HCO3   −observed in WT ileal and mid‐colonic mucosa were luminal Cl − ‐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 + /HCO   3 −cotransporter (NBC), and epithelial sodium channel (ENaC) expression was not significantly altered. This indicates that the severe defect in ileocolonic J   HCO3   −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 HCO   3 −secretion, which may contribute to alterations in surface pH, intestinal flora, and mucus barrier properties. (Inflamm Bowel Dis 2011;)