Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are chronic relapsing inflammatory disorders of the gastrointestinal tract. Chronic inflammation of the intestine affects the normal fluid and electrolyte absorption leading to diarrhea, the hallmark symptom of IBD. The management of IBD-associated diarrhea still remains to be a challenge, and extensive studies over the last 2 decades have focused on investigating the molecular mechanisms underlying IBD-associated diarrhea. These studies have shown that the predominant mechanism of diarrhea in IBD involves impairment of electroneutral NaCl absorption, with very little role if any played by anion secretion. The electroneutral NaCl absorption involves coupled operation of Na+/H+ exchanger 3 (NHE3 or SLC9A3) and Cl−/HCO3 − exchanger DRA (Down Regulated in Adenoma, or SLC26A3). Increasing evidence now supports the critical role of a marked decrease in NHE3 and DRA function and/or expression in IBD-associated diarrhea. This review provides a detailed analysis of the current knowledge related to alterations in NHE3 and DRA function and expression in IBD including the mechanisms underlying these observations and highlights the potential of these transporters as important and novel therapeutic targets.
Article first published online 24 August 2015.
*Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and
†Jesse Brown VA Medical Center, Chicago, Illinois.
Reprints: Pradeep K. Dudeja, PhD, Jesse Brown VA Medical Centre, University of Illionois at Chicago, Medical Research Service (600/151), 820 South Damen Avenue, Chicago, IL 60612 (e-mail: firstname.lastname@example.org).
Supported by Department of Veterans Affairs Merit Award No. BX002011 (P.K.D.), Merit Award No. BX000152 (W.A.A.), and a Senior Research Career Scientist Award (P.K.D.), and the NIDDK Grants DK54016, DK81858, and DK92441 (P.K.D.), DK96254 (S.S.), DK 98170 (R.K.G.), and DK 71596 (W.A.A.).
The authors have no conflicts of interest to disclose.
S. Priyamvada and R. Gomes contributed equally to this work.
Received April 20, 2015
Accepted May 11, 2015