Na<sup>+</sup>/H<sup>+</sup> exchanger-3 (NHE3) is crucial for intestinal Na<sup>+</sup> absorption, and its reduction has been implicated in infectious and inflammatory bowel diseases (IBD)-associated diarrhea.
Reduced NHE3 expression or function has been implicated in the pathogenesis of diarrhea associated with inflammatory bowel disease (IBD) or enteric infections.
Intestinal epithelial Na<sup>+</sup>/H<sup>+</sup> exchange facilitated by the apical NHE3 (Slc9a3) is a highly regulated process inhibited by intestinal pathogens and in inflammatory bowel diseases.
SLC9A3 encodes Na/H antiporter 3, the major intestinal brush border Na/H exchanger, and a downstream target of GC-C. A number of patients with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease.
This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients.