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

Abstract

Background and purpose: Constipation and intestinal obstructive episodes are major health problems in cystic fibrosis (CF) patients. Three FDA-approved drugs against constipation-prone irritable bowel syndrome were tested for their ability to increase luminal fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator (CFTR) null (cftr^-/- ) and F508del mutant (F508del^mut/mut ) murine intestine.

Experimental approach: Guanylate cyclase C agonist linaclotide, PGE₁ analogue lubiprostone and intestine-specific NHE3 inhibitor tenapanor were perfused through a ~3 cm jejunal, proximal or mid-distal colonic segment in anaesthetized cftr^-/- , F508del^mut/mut and WT mice. Net fluid balance was determined gravimetrically and alkaline output by pH-stat back titration.

Key results: Basal jejunal fluid absorptive rates were significantly higher and basal HCO₃^- output was significantly lower in cftr^-/- and F508del^mut/mut compared to WT mice. In cftr^-/- and F508del^mut/mut mice, all three drugs significantly inhibited the fluid absorptive rate and increased alkaline output in the jejunum and tenapanor and lubiprostone, but not linaclotide, in the colon. After tenapanor pre-incubation, linaclotide elicited a robust fluid secretory response in WT jejunum, while no further change in absorptive rates was observed in cftr^-/- and F508del^mut/mut jejunum, suggesting that the increase in gut fluidity and alkalinity by linaclotide in CF gut is mediated via NHE3 inhibition. Lubiprostone also inhibited fluid absorption in cftr^-/- and F508del^mut/mut jejunum via NHE3 inhibition but had a residual NHE3-independent effect.

Conclusion and implications: Linaclotide, lubiprostone and tenapanor reduced fluid absorption and increased alkaline output in the CF gut. Their application may ameliorate constipation and reduce obstructive episodes in CF patients.

Keywords: DIOS; anion secretion; fluid secretion; intestinal fluid absorption; mucoviscidosis; sodium hydrogen exchange.