Impact of CFTR modulation with Ivacaftor on Gut Microbiota and Intestinal Inflammation

Tanja Gonska,Laura Rossi,Millie Garg,Chee Y. Ooi,Bronwen Needham,Saad A. Syed,Julie Avolio,Kelsey Young,Michael G. Surette

doi:10.1038/s41598-018-36364-6

Abstract

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Next to progressive airway disease, CF is also associated with intestinal inflammation and dysbiosis. Ivacaftor, a CFTR potentiator, has improved pulmonary and nutritional status but its effects on the intestinal microbiota and inflammation are unclear. Hence, we assessed the changes on the intestinal microbial communities (16S rRNA variable 3 gene region) and inflammatory markers (calprotectin and M2-pyruvate kinase [M2-PK]) in 16 CF individuals (8 children and 8 adults) before and after (median 6.1 months) ivacaftor. Stool calprotectin significantly decreased following ivacaftor (median [IQR]: 154.4 [102.1–284.2] vs. 87.5 [19.5–190.2] mg/kg, P = 0.03). There was a significant increase in Akkermansia with ivacaftor. Increased abundance of Akkermansia was associated with normal stool M2-PK concentrations, and decreased abundances of Enterobacteriaceae correlated with decreased stool calprotectin concentrations. In summary, changes in the gut microbiome and decrease in intestinal inflammation was associated with Ivacaftor treatment among individuals with CF carrying at least one gating CFTR mutation. Thus, CFTR-modifying therapy may adequately improve the aberrant pathophysiology and milieu of the CF gut to favor a more healthy microbiota, which in turn reduces intestinal inflammation.

Highlights

Therapeutics in Cystic fibrosis (CF) have entered an exciting era with the availability of personalized small molecule therapies that target the basic defect(s) in the CFTR protein[19]
There was no association between stool calprotectin levels and Akkermansia and Anaerostipes (Fig. 3B,C). This is the first study to demonstrate that treatment with ivacaftor improves intestinal inflammation in individuals with CF carrying at least one gating CFTR mutation
In this prospective observational study, we found significant correlation between stool calprotectin levels and Enterobacteriaceae abundance, and that treatment with ivacaftor is associated with an increase in the relative abundance of Akkermansia

Summary

Introduction

Therapeutics in CF have entered an exciting era with the availability of personalized small molecule therapies that target the basic defect(s) in the CFTR protein[19]. A CFTR potentiator for CF patients carrying gating mutations such as G551D, has demonstrated impressive pulmonary outcomes, including reduction www.nature.com/scientificreports/. Ivacaftor was associated with substantial weight increase, which has been speculated to be related to improvements in gastrointestinal physiology rather than solely by improved pulmonary function[10,18,23,24,25]. The impact of such therapies on the gut microbiome and intestinal inflammation as biological markers of improved intestinal physiology in CF remains unclear. We hypothesize that improvements in gastrointestinal physiology following commencement of ivacaftor therapy, in patients with CF carrying at least one gating CFTR mutation, is associated with changes in the gut microbiome and inflammation. We evaluated the relationships between microbial profiles and gut inflammatory markers calprotectin and M2-PK

Methods

Results

Conclusion