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.
Abstract Cystic fibrosis (CF) is a genetic disorder that leads to formation of thick epithelial secretions in affected organs. Chronic microbial infections associated with thick mucus secretions are the hallmarks of lung disease in CF. Despite similar conditions existing in the gastrointestinal tract, it is much less studied. We therefore examined the microbial communities within the gastrointestinal tract of children with and without CF (either pancreatic sufficient or insufficient) across a range of childhood ages (0.87–17 years). We observed a substantial reduction in the richness and diversity of gut bacteria associated with CF from early childhood (2 years) until late adolescence (17 years). A number of bacteria that establish themselves in the gut of healthy children were unable to do so in children with CF. In contrast, a few bacteria dominated the gut microbiota in children with CF and are unlikely to be beneficial for the metabolic function of the gut. A functioning pancreas (pancreatic sufficient) under a CF lifestyle showed little effect on microbial communities. Our results argue that any attempts to rectify the loss of bacterial diversity and provide normal bacterial function in the gut of CF patients should be conducted no later than early childhood.
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