Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: Potential contributors to IBD-associated diarrhea

Background: One of the most common symptoms among patients with inflammatory bowel disease (IBD) is diarrhea, which is thought to be contributed by changes in electrolyte transport associated with intestinal inflammation. This study was designed to test the hypothesis that intestinal Na⁺-related transporters/channels and their regulatory proteins may be downregulated as a potential contributor to IBD-associated diarrhea. Methods: SDS-PAGE and Western blotting and/or confocal immunomicroscopy were used to examine the expression of Na⁺/H⁺-exchangers 1-3 (NHE1-3), epithelial Na⁺ channel (ENaC), Na⁺K⁺-ATPase, the intracellular Cl^- channel 5 (ClC-5), and NHE3 regulatory factors (NHERF1,2) in ileal and colonic pinch biopsies from IBD patients and noninflammatory controls, as well as from colonic mucosa of dextran sodium sulfate (DSS)- and TNBS-induced acute murine IBD models. Results: NHE1,3 (but not NHE2), β-ENaC, Na⁺/K⁺-ATPase-α, ClC-5, and NHERF1 were all downregulated in sigmoid mucosal biopsies from most cases of active UC and/or CD compared to controls. NHE3 was also decreased in ileal mucosal biopsies of active CD, as well as in ≈50% of sigmoid biopsies from inactive UC or CD. Importantly, similar downregulation of NHE1,3, β-ENaC, and NHERF1,2 was also observed in the mouse colon (but not ileum) of DSS- and TNBS-induced colitis. Conclusions: IBD-associated diarrhea may be due to a coordinated downregulation of multiple Na⁺ transporter and related regulatory proteins, including NHE1,3, Na⁺/K⁺- ATPase, and ENaC, as well as NHERF1,2, and ClC-5, all of which are involved directly or indirectly in intestinal Na⁺ absorption.