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.