Inhibition of Na⁺/H⁺ exchanger isoform 3 improves gut fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator‐deficient and F508del mutant mice

Abstract

What is already known: Constipation, inflammation and intestinal obstructive episodes are major health problems in cystic fibrosis patients What this study adds: This study determines the ability of three FDA-approved drugs to increase gut fluidity and alkalinity in mice that express no CFTR protein or that express the F508del mutant protein and studies the mechanism of action. Clinical significance: These results pave the way for clinical trials to improve gut fluidity and reduce obstructive episodes in CF patients.

The Role of pHi in Intestinal Epithelial Proliferation–Transport Mechanisms, Regulatory Pathways, and Consequences

“…Employing an array of sophisticated methods, the group demonstrated an expression and functional activity of CFTR in murine ISCs, an alkaline intracellular pH i in Cftr −/− ISCs, accompanied by hyperproliferation in Cftr −/− organoids. These findings suggest that the Cftr −/− -associated crypt and villus elongations, which are also observed in the absence of inflammatory markers (Tan et al, 2020) and the hyperproliferation described in murine Cftr −/− intestinal epithelium (Gallagher and Gottlieb, 2001) may be partially a consequence of the lack of CFTR in ISCs. Crossbreeding of Cftr −/− and wt mice with transgenic mice which express a fluorophore (EGFP)-labeled WNT transducer Disheveled (Dsv) and the cell membrane-targeted, two-color fluorescent Cre-reporter Rosa TmT/mG enabled the group to study the proximity of Dsv to the membrane receptor Frizzled 7, which has been recognized as a key event in WNT signaling (Axelrod, 2001) in Cftr −/− and wt ISCs with live cell imaging.…”

The Role of Plasma Membrane Sodium/Hydrogen Exchangers in Gastrointestinal Functions: Proliferation and Differentiation, Fluid/Electrolyte Transport and Barrier Integrity

“…The fluid absorption rate in mid-distal colon of nhe2 −/− and wild type mice was similar. Only after application of the NHE3 specific inhibitor tenapanor ( Yu et al, 2019 ; Tan et al, 2021 ), we were able to show a minor involvement of NHE2 in colonic fluid absorption ( Nikolovska et al, 2022 ). Neither immunofluorescence analysis nor mRNA expression data showed an increase of NHE3 in the mid-distal colon of nhe2 −/− mice, albeit the NHE3 immunoreactivity area was extended more deeply into the cryptal mouth region in nhe2 −/− colon in contrast to wild type mid-distal colon ( Nikolovska et al, 2022 ).…”

“…Also in CF patients, tenapanor may be used to ameliorate constipation and reduce obstructive episodes. In CFTR null and F508 del mutant mouse intestine, direct NHE3 inhibition by tenapanor reduces the fluid absorptive rate and increases alkaline output ( Tan et al, 2021 ). As implied above, interfering with the molecular mechanisms regulating NHE3 activity can result in beneficial effects as well.…”

Upregulation of antimicrobial peptide expression in slc26a3-/- mice with colonic dysbiosis and barrier defect

“… 45 An increased fucosylation, as well as dysbiosis, was also observed in the small intestine of CFTR-deficient mice, 46 , 47 but in these mice, the small intestine has an acidic luminal mileau and is hyperabsorptive. 48 A recent review summarizes the data about microbiota alterations in different mouse models that are deficient in intestinal ion transport protein, and it becomes clear that there is yet a lot to be learned about the causal relationships. 49 …”