SLC26A3 (DRA, the Congenital Chloride Diarrhea Gene): A Novel Therapeutic Target for Diarrheal Diseases

Abstract

Diarrhea associated with enteric infections, gut inflammation, and genetic defects poses a major health burden and results in significant morbidity and mortality. Impaired fluid and electrolyte absorption or secretion in the intestine are the hallmark of diarrhea. Electroneutral NaCl absorption in the mammalian GI tract involves the coupling of Na⁺/H⁺ and Cl^-/HCO₃^- exchangers. SLC26A3 (Down Regulated in Adenoma, DRA) is the major anion exchanger involved in luminal Cl^- absorption and HCO₃^- secretion. Mutations in the SLC26A3 gene cause a severe disease called congenital chloride diarrhea (CLD). Multiple studies have shown that DRA function or expression is downregulated in infectious diarrheal disorders caused by EPEC, C rodentium, Salmonella, Clostridioides difficile and Cryptosporidium parvum infection. In addition, DRA levels are severely depleted in colonic mucosa of IBD patients and in mouse models of IBD (eg, DSS, TNBS, adoptive T-cell transfer, anti-CD-40, and IL-10 KO colitis). In addition, genetic defects exhibiting diarrhea including microvillus inclusion disease (MVID), keratin-8 depletion, knock-out mouse models of transcriptional factors (eg, CDX-2 and HNF1α/1β) also exhibit severe down regulation of DRA. Also, recent studies have shown that DRA is not only critical for chloride absorption but also plays a key role in maintaining gut epithelial barrier integrity, microbiome composition, and has now emerged as an IBD susceptibility gene. In this review, we provide strong evidence that DRA may serve as a novel therapeutic target with dual benefits in not only correcting diarrheal phenotype but also improving gut barrier integrity and inflammation in pathogen infection or IBD.

Keywords: Anion Transporter; Chloride/Bicarbonate exchanger; Electrolyte Absorption; Gut-Microbe Interactions; Infectious Diarrhea; Inflammatory Bowel Diseases.

Figure 1

Regulation of DRA expression or function with potential implications in diarrheal diseases. Down-regulation of DRA function or expression has been implicated in various diarrheal disorders, including enteric infections (EPEC, Salmonella, C difficile, C parvum, C rodentium); IBD (UC and CD); mouse models of IBD (DSS, TNBS, adoptive T-cell transfer, anti-CD-40, and IL10 KO colitis); genetic models of diarrhea: CLD, MVID, and keratin 8 KO; proinflammatory mediators: (IFNγ, TNFα, NF-κB, IL1β, H₂O₂, NO, ROS); loss of specific transcription factors (HNFs, CDX2, SATB2), and miRNAs (miR 494). Up-regulation of DRA function and expression by various agents may have antidiarrheal implications such as by vitamins and peptides (ATRA, GLP1, VIP, NPY); bioactive compounds (dexamethasone, LPA, S1P, butyrate); and probiotics (Lactobacilli and Bifidobacteria). Therefore, targeting DRA represents a potentially novel strategy for the development of therapeutic interventions to manage diarrheal disorders.

Figure 2

Auxiliary role(s) of DRA in dysbiosis, barrier integrity, and susceptibility to IBD. Single nucleotide polymorphisms (SNPs) or decreased DRA expression and/or function, resulting from inflammation or infection, may contribute to gut microbial dysbiosis; compromised mucus and epithelial barrier function; increased paracellular permeability leading to systemic dissemination of pathogens and toxins; and imbalanced immune response, ultimately increasing susceptibility to IBD.