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

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 gut inflammation and dysbiosis. CFTR-targeted treatment with ivacaftor has shown significant improvement in pulmonary and nutritional status. However, its impact on the gut microbiota and intestinal inflammation remains unclear. Hence, we examined the changes on gut microbial communities (16S rRNA variable 3 gene region) and biomarkers of gut inflammation (calprotectin and M2-pyruvate kinase [M2-PK]) in 16 CF patients (8 children and 8 adults) before and after (median 6.1 months) ivacaftor. There was significant reduction in stool calprotectin levels following ivacaftor (median [IQR]: 154.4 [102.1-284.2] vs. 87.5 [19.5-190.2] mg/kg, P=0.03). Akkermansia significantly increased following ivacaftor. Reduced abundances of Enterobacteriaceae was associated with decreased stool calprotectin levels, and increased abundance of Akkermansia correlated with normal stool M2-PK levels. In conclusion, Ivacaftor therapy was associated with alterations in the gut microbiome and reduction in intestinal inflammation in CF patients carrying at least one gating CFTR mutation. Thus, CFTR-modifying therapy may sufficiently improve the abnormal pathophysiology of the CF gut to favor a more healthy gut microbiota, which in turn leads to a reduction in gut inflammation.