Functional and Compositional Shifts in Lung and Gut Microbiota after One Year of Treatment with Highly Effective CFTR Modulators in Cystic Fibrosis

BACKGROUND: Highly effective CFTR modulator therapy with elexacaftor-tezacaftor-ivacaftor (ETI) has revolutionized clinical outcomes in cystic fibrosis (CF), yet its effects on gut and lung microbiota, especially at the functional level, are poorly understood. METHODS: In a 12-month prospective study, we enrolled 35 clinically stable CF patients initiating ETI. Paired fecal and sputum samples, collected at baseline and after 12 months, were analyzed using shotgun metagenomics, metaproteomics, and short-chain fatty acid (SCFA) quantification. Multi-omics data were integrated with clinical parameters assessing lung, hepatic, pancreatic, and intestinal function. Microbiota composition showed limited shifts: alpha diversity was stable, and beta diversity changes accounted for only small variance in both compartments. However, butyrate-producing genera enriched in feces, while oropharyngeal taxa increased in sputum. Metaproteomics revealed broad downregulation of host neutrophil-driven inflammatory proteins; sputum additionally showed increased abundance of extracellular matrix-related proteins. Microbial proteins linked to carbohydrate/lipid metabolism, particularly butanoate pathways, increased in feces alongside a trend for higher butyrate. In sputum, formaldehyde dehydrogenase enzymes rose, indicating enhanced oxidative microbial metabolism. CONCLUSIONS: ETI is associated with minimal compositional but substantial functional reprogramming in CF microbiota. These changes are accompanied by an increase in butyrate-producing taxa, attenuation of host pro-inflammatory pathways, and a shift in lung metabolism toward oxidation. Despite ongoing pathogenic colonization, these changes suggest CFTR modulation is associated with a less inflammatory, more stable host-microbiota ecosystem.