Impact of CFTR Modulation on Intestinal pH, Motility, and Clinical Outcomes in Patients With Cystic Fibrosis and the G551D Mutation

Abstract

Objectives:A defect in bicarbonate secretion contributes to the pathophysiology of gastrointestinal complications in patients with cystic fibrosis (CF). We measured gastrointestinal pH, clinical outcomes, and intestinal transit profiles in patients with the G551D mutation before and after treatment with ivacaftor, a CF transmembrane regulator channel (CFTR) potentiator.Methods:Observational studies of ivacaftor effectiveness were conducted in the United States and Canada. A subset of subjects ingested a wireless motility capsule (n=10) that measures in vivo pH, both before therapy with ivacaftor and 1 month after treatment; values obtained were compared for mean pH and area under the pH curve, and regional intestinal motility. We also queried subjects about abdominal pain and recorded body weight before and after treatment.Results:One month after administering ivacaftor, a significant increase in mean pH was observed after gastric emptying (P<0.05). Area under the pH curve analyses indicate increased bicarbonate mass (P<0.05 for select 5 min intervals and all segments >30 min); mean weight gain was 1.1 kg (P=0.08). No difference in abdominal pain or regional transit times was seen.Conclusions:CFTR modulation improves the proximal small intestinal pH profile in patients with the G551D CFTR mutation and we observed clinically relevant, contemporaneous weight gain, although it did not reach statistical significance. These data provide in vivo evidence that CFTR is an important regulator of bicarbonate secretion, which may be a translational link between CFTR function and clinical improvement.

EPC/HPSG evidence-based guidelines for the management of pediatric pancreatitis

“…Increased gastrointestinal acidity has been reported in people with CF due to several factors originating from a dysfunctional CFTR, an ion channel involved in the transport of bicarbonate in pancreatic/biliary ducts, duodenal Brunner glands and others 148,149 . This can lead to inactivation of pancreatic enzymes in the gut and impair fat digestion.…”

The Pulmonary Microbiome in Cystic Fibrosis

“…Secondly, the restoration of CFTR activity could result in a dramatic change in the local pulmonary microenvironment, turning a previously favourable environmental niche into an inhospitable one for resident microbiota. There is evidence to support a similar effect in the GI tract, where CFTR modulation with ivacaftor was associated with improved proximal small intestinal pH, likely secondary to improved bicarbonate secretion [63]. Thirdly, a direct bactericidal effect of ivacaftor itself has been postulated given that its chemical structure contains a quinolone ring and many quinolone derivatives have antimicrobial properties [64].…”

Growth and Nutrition in Cystic Fibrosis

“…Gelfond et al have shown that despite changes in pH after short-term CFTR potentiator use, there was no association with symptoms or changes in overall transit time. 92 As motility evaluation in gastroenterology becomes more commonplace, more will undoubtedly be learned about GI transit in CF.…”