Maldigestion and –absorption, constipation and intestinal obstructive episodes (DIOS) are major health problems in cystic fibrosis patients. The defective Cl^– channel results in reduced fluidity and low pH of the pancreatic ducts and the gut lumen, which leads to ductal obstruction, maldigestion, mucus hyperviscosity, dysbiosis, mucosal inflammation, and slow intestinal transit.

In a strategic research center funded by the Cystic Fibrosis Trust the ability of three FDA-approved drugs against constipation-prone irritable bowel syndrome, i.e. the guanylyl cyclase and cGMP-linked agonist Linaclotide, and the prostaglandin E1 analogue Lubiprostone, and the NHE3-selective inhibitor Tenapanor, was tested for their ability to restore luminal fluidity and pH in CF mouse models. In parallel, the effect of these compounds on the activity of the NHE3 (SLC9A3) Na/H exchanger, the major intestinal sodium absorptive transporter and regulator of fluid absorption, was measured in stem cell-derived human intestinal organoids generated from ileal biopsies donated by homozygous F508del CF patients. Tenapanor was chosen for an intervention trial in CFTR null mice. Following retraction of their daily osmotic laxative, mice were gavaged twice daily with 30µg tenapanor or vehicle for 21 days, and carefully monitored for the occurrence of an intestinal obstruction. After the end of the intervention, or if a suspicion of an intestinal obstruction arose, the mice were sacrificed, the intestine excised, the microbial composition of the luminal contents and the mucosa-adherent mucus layer was analysed, and the mucosa was studied histologically. The results suggested that an intestine-specific inhibition of NHE3 results not only in an increase in gut fluidity and pH, but also reduces mucus hypersecretion and prevents intestinal obstruction.

A hallmark of inflammatory bowel disease (IBD) is chronic or recurrent “inflammatory diarrhea”. Reduced epithelial Na⁺ and fluid absorption is a prominent feature. Fluid absorption in the ileocolonic region is predominantly mediated by the Na⁺/H⁺ exchanger NHE3, the H⁺-short chain fatty acid (SCFA) cotransporter MCT1, the Cl^–/HCO₃-exchanger SLC26A3 (DRA), and the epithelial Na⁺ channel (ENaC). We asked the question whether the downregulation of specific absorptive ion transporters or a general defect in enterocyte differentiation correlates with the degree of diarrhea and inflammation. mRNA expression and/or protein abundance was systematically studied of a panel of genes that determine or correlate with the differentiation state of the colonic epithelium, including the transport genes named above, in the different segments of the ileocolon of healthy individuals and IBD patients with mildly, moderate-severely, or noninflamed colonic mucosa. Clinical scores for disease activity and diarrhea were obtained. The results from a comparison of the IBD and healthy control biopsies suggested that inflammation results in a dysregulation of differentiation, with an aberrant proliferative response, an elongation of the proliferative zone, and an incomplete differentiation of the surface enterocytes. This results in a dramatically reduced expression of the colonic absorptive transporters and an increased expression of the poreforming “leaky” claudin2, resulting in diarrhea. This dysregulation is reversible, and noninflamed IBD colon has the same differentiation pattern as that of healthy controls. Thus, anti-inflammatory treatment appears as the only option to improve inflammatory diarrhea.