Introduction
Cystic fibrosis (CF) patients develop intestinal obstructions, called “meconium ileus” in newborn and “distal intestinal obstructive syndrome” (DIOS) in juveniles and adults. Radiologic signs and clinical symptoms are that of mechanical ileus. Surgery is to be avoided, if at all possible, and conservative treatment consists of orally and rectally applied Gastrografin (meglumine diatrizoate), polyethylene glycol (PEG) lavage (20%), and oral laxatives and enemas (Houwen et al., 2010). Nevertheless, the need for surgery is high, the incidence of obstruction related segmental colectomies is increasing, with high morbidity and mortality (Hite et al., 2022; Sharma, Morton, Peckham & Jayne, 2012). Recent Cochrane analyses revealed a clear lack of evidence for preventive as well as therapeutic treatment strategies, and suggested that randomised controlled trials need to be conducted (Carroll, Green & Gilchrist, 2021; Gilchrist, Green & Carroll, 2021).
A recent survey revealed a high rate of abdominal complaints with a likely origin in the lower gut in CF patients not suffering from recurrent DIOS episodes (Hayee et al., 2019). Other studies demonstrated a correlation between abdominal symptoms and an increase of inflammatory markers in the stool (Beaufils et al., 2020; Jaudszus et al., 2022), undermining the hypothesis derived from CF animal models that inflammation, secondary to bacterial overgrowth, predisposes to obstructive episodes, disease severity, and abdominal complications (De Lisle, 2007; Dorsey & Gonska, 2017; Talebi et al., 2022). However, this hypothesis has not been validated in animal models or CF patients.
It has also been shown that the treatment with CF modulators and correctors reduces CF-associated inflammation (Tétard et al., 2020). Nevertheless, many of the patients having undergone surgery for DIOS were already on CF corrector therapy, which is also not available for all CF mutations. This suggests that additional intestine targeted therapies that improve the sequelae of CFTR dysfunction, namely the reduced gut fluidity, high luminal acidity, mucus hyper-viscosity, increased transit time, microbial dysbiosis and mucosal inflammation and thereby hopefully reduce obstructive episodes in the intestine, are urgently needed. Because it is obviously difficult to perform double-blind placebo controlled studies in this highly compromised group of patients, it is important to carefully test pharmacological strategies to alleviate CF related intestinal disease in suitable animal models.
All currently available CF animal models display a very high incidence of intestinal obstruction, leading to death unless prevented by surgical, genetic or pharmacological rescue (Borowitz & Gelfond, 2013; Clarke, Gawenis, Franklin & Harline, 1996; Rogers et al., 2008; Stoltz et al., 2013). Cftr -/- mice do not display pancreatic or pulmonary disease, but consistently develop intestinal obstructive episodes. Hence, we considered this model ideal to test intestine-targeted drug therapies that have been approved for the treatment of constipation-prone irritable bowel disease and are believed to increase epithelial fluid secretion, decrease fluid absorption, or both.
In a previous report, we had examined the efficacy of the guanylate cyclase 2C ligand linaclotide, prostaglandin E1 analogue lubiprostone, and intestine-specific Na+/H+exchanger isoform 3 (NHE3) inhibitor tenapanor on jejunal and colonic fluid balance and alkaline output in anesthetized bothCftr -/- mice and in F508del mutant micein vivo , titrating each drug to the minimal concentration that elicited a significant increase in gut fluidity and alkalinity (Tan et al., 2021). Although each of the drugs was able to increase jejunal alkaline output and reduce jejunal fluid absorption, linaclotide had no effect on the colon, and lubiprostone needed to be applied in much higher concentrations than were likely present in the gut lumen with the approved dosages for humans, suggesting that the anti-constipation effect may be due to an effect on motility rather than fluid balance. Tenapanor was able to decrease fluid absorption and increase alkaline output with similar efficacy in Cftr -/- andCftr +/+ mice, and did so in concentrations that were reasonably close to what can be expected in the gut lumen with the approved dosage for humans. We therefore chose tenapanor to test its efficacy to prevent obstructive episodes inCftr -/- mice when given by oral gavage for 21 days. We also aimed to explore the effect of tenapanor on the hallmarks of CF intestinal dysfunction, namely the reduced gut fluidity and alkalinity, mucus accumulation, cryptal hyperproliferation and villus elongation, slowed gastrointestinal transit time, and mucosal inflammation.