Linaclotide, lubiprostone and tenapanor improve gut fluidity and alkalinity in CFTR-deficient and F508del mutant mice via NHE3 inhibition.

Background Constipation and intestinal obstructive episodes are major health problems in cystic fibrosis patients. Aim Three FDA-approved drugs against constipation-prone irritable bowel syndrome were tested for their ability to increase luminal fluidity and alkalinity in CFTR null (cftr-/- ) and F508del mutant (F508delmut/mut ) murine intestine, and the underlying mechanism of action was explored. Methods Guanylate cyclase C agonist linaclotide, prostaglandin E1 analogue lubiprostone, and intestine-specific NHE3 inhibitor tenapanor were perfused through a ~3 cm jejunal, proximal or mid-distal colonic segment in anesthetized cftr-/- , F508delmut/mut , and WT mice. Net fluid balance was determined gravimetrically and alkaline output by pH-stat back titration. Results Basal jejunal fluid absorptive rates were significantly higher, and basal HCO3 - output was significantly lower in cftr-/- and F508delmut/mut compared to WT mice. In cftr-/- and F508delmut/mut mice, all three agents significantly inhibited the fluid absorptive rate and increased alkaline output in the jejunum, and tenapanor and lubiprostone, but not linaclotide, also did so 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 F508delmut/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 F508delmut/mut jejunum via NHE3 inhibition, but had a residual NHE3-independent effect. Summary and conclusions 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.