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.