Pathophysiology of IBD associated diarrhea

Abstract

Inflammatory bowel diseases broadly categorized into Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gastrointestinal tract with increasing prevalence worldwide. The etiology of the disease is complex and involves a combination of genetic, environmental, immunological and gut microbial factors. Recurring and bloody diarrhea is the most prevalent and debilitating symptom in IBD. The pathogenesis of IBD-associated diarrhea is multifactorial and is essentially an outcome of mucosal damage caused by persistent inflammation resulting in dysregulated intestinal ion transport, impaired epithelial barrier function and increased accessibility of the pathogens to the intestinal mucosa. Altered expression and/or function of epithelial ion transporters and channels is the principle cause of electrolyte retention and water accumulation in the intestinal lumen leading to diarrhea in IBD. Aberrant barrier function further contributes to diarrhea via leak-flux mechanism. Mucosal penetration of enteric pathogens promotes dysbiosis and exacerbates the underlying immune system further perpetuating IBD associated-tissue damage and diarrhea. Here, we review the mechanisms of impaired ion transport and loss of epithelial barrier function contributing to diarrhea associated with IBD.

Keywords: DRA; Diarrhea; ENaC; NHE3; Na+/K+-ATPase; NaCl absorption; barrier function; inflammatory bowel diseases; ion transport; tight junctions.

Figure 1.

Schematic of electrolyte transporters and junctional proteins in IECs: Ion transporters, channels, physical and chemical barriers are compromised in IBD leading to diarrhea. The transepithelial pathway of solutes and ions is mediated by ion/solute transporters and channels. As depicted in the figure, in steady state, apical transporters, NHE3 (Na⁺/H⁺ exchanger 3) and DRA (Down Regulated in Adenoma) work in conjunction to mediate electroneutral NaCl absorption. Electrogenic mode of Na⁺ absorption occurs in the distal part of colon via ENaC (Epithelial sodium channel). Intracellular Na⁺ gradient essential for sodium dependent transport processes is generated by the action of Na⁺/K⁺-ATPase present at the basolateral membrane. Cl⁻ secretion across the membrane is facilitated by apical Cl⁻ channel CFTR (cystic fibrosis transmembrane conductance regulator). Basolateral NKCC1 (Na⁺/K⁺/2Cl⁻ cotransport system) is involved in uptake of Cl⁻ from the serosal side. K⁺ taken up by NKCC1 and Na⁺/K⁺-ATPase is recycled back to the basolateral side by K⁺ channels localized to the basolateral membrane. Predominant mechanism of diarrhea in IBD involves impairment of electroneutral NaCl absorption accompanied with dysfunctional ENaC and Na⁺/K⁺-ATPase, with very little role if any played by anion secretion. Negative sign indicates the downregulation in function and/or expression of NHE3, DRA, ENaC and Na⁺/K⁺-ATPase in IBD. The mucus layers serves as a barrier and prevents the direct contact of gut microbes with the underlying epithelium. Adjacent intestinal epithelial cells are sealed together via an intricate network of junctional proteins including the tight junction (TJ) proteins (claudins, occludin, JAM and ZO-1), adherens junction (AJ, E-cadherin) and desmosomes. The optimal expression and function of tight and adherens junction proteins regulate the paracellular flux under physiological conditions. Negative sign indicates the downregulation in function and/or expression of TJ and AJ proteins in IBD. Breakdown of barrier function in IBD results in diarrhea via leak-flux mechanism. As summarized in the review, understanding of the mechanisms underlying loss of barrier function and defective ion absorption in IBD is essential for development of better treatment strategies for IBD and associated diarrhea.