Mechanisms Underlying Dysregulation of Electrolyte Absorption in Inflammatory Bowel Disease-Associated Diarrhea

Abstract

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.

Figure 1. Ion transporters and channels involved in Na⁺ and Cl⁻ transport in intestinal epithelial cells

Various ion transporters and channels work in conjunction to orchestrate electrolyte transport in the intestinal tract. Electroneutral NaCl absorption takes place by coupled operation of Na⁺/H⁺ exchanger 3 (NHE3) and Down Regulated in Adenoma (DRA) expressed apically at the luminal membrane of enterocytes. Epithelial sodium channel (ENaC) located at the apical membrane (predominantly in distal intestine) is involved in Na⁺ transport that is electrogenic in nature and is energized by Na⁺/K⁺ ATPase. Na⁺/K⁺ ATPase is a plasma membrane protein localized to the basolateral membrane of the enterocyte that sets up a Na⁺ gradient, which is necessary for several forms of secondary active transport in the intestine. Transepithelial chloride secretion is also electrogenic and is made up of several transmembrane transport pathways including cystic fibrosis transmembrane conductance regulator (CFTR) a cAMP-activated, apical Cl⁻ channel, which plays the major role in chloride movement across the apical membrane and the basolateral Na⁺/K⁺/2Cl⁻ cotransport system (NKCC1) that takes up Cl⁻ from the serosal side in an electroneutral manner. K⁺ taken up by NKCC1 is recycled back to the basolateral side by K⁺ channels localized to the basolateral membrane. The expression and/or function of these transporters and channels (except for those involved in chloride secretion) is diminished in inflammatory disorders of the gut such as IBD resulting in associated diarrhea.