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CFTR modulator therapy drives microbiome restructuring through improved host physiology in cystic fibrosis: the IMMProveCF phase IV trial

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Argitaratua izan da:Nature Communications vol. 16, no. 1 (2025), p. 10111-10127
Egile nagusia: Knoll, Rebecca Luise
Beste egile batzuk: Brauny, Melanie Meihua, Robert, Evelyn, Cloos, Louisa, Waser, Lydia, Hilbert, Katja, Ulmer, Nina, Hillen, Barlo, Birkner, Till, Bartolomaeus, Theda Ulrike Patricia, Nitsche, Oliver, Jarquín-Díaz, Víctor Hugo, Lynch, Susan, Gehring, Stephan, Maier, Lisa, Poplawska, Krystyna, Forslund-Startceva, Sofia Kirke
Argitaratua:
Nature Publishing Group
Gaiak:
Physiology
Cystic fibrosis transmembrane conductance regulator
rRNA 16S
Longitudinal studies
Modulators
Mutation
Antibacterial activity
Species diversity
Gastrointestinal tract
Inflammation
Feces
Cystic fibrosis
Microbiomes
Intestinal microflora
Microorganisms
Lungs
Age
Sputum
Gene sequencing
Species richness
Antibiotics
Respiratory function
Dysbacteriosis
Gut microbiota
Genetic disorders
Digestive system
Escherichia
Staphylococcus
Environmental
Sarrera elektronikoa:Citation/Abstract
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Laburpena:Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene, leading to impaired CFTR function, mucus accumulation, chronic infections, and inflammation. The triple combination elexacaftor/tezacaftor/ivacaftor (ETI) has transformed CF treatment by restoring CFTR function. However, how ETI-induced physiological improvements affect long-standing dysbiosis and pathogen colonization across microbiome habitats remains poorly understood. In this prospective longitudinal study (DRKS00023862), we analyzed sputum, throat, and stool microbiomes of pwCF (n = 35) before and after ETI initiation, alongside healthy controls (n = 49). The primary endpoint was longitudinal change in diversity, species richness, and microbial composition in the respiratory and intestinal microbiome, profiled by 16S rRNA gene sequencing. Secondary endpoints included changes in lung function, systemic and gastrointestinal inflammation. We show how improved CFTR function and direct antibacterial effects of ETI create a niche disadvantage for Staphylococcus in the sputum microbiome. Respiratory microbiome shifts were immediate, while gut changes emerged gradually. Escherichia abundance in stool, initially elevated in pwCF, decreased post-ETI and correlated with lower fecal calprotectin. These findings demonstrate that ETI can partially reverse CF-associated dysbiosis through improved host physiology. They offer insights into host-microbiome dynamics under therapeutic modulation and emphasize the need for confounder-aware models in complex clinical populations.Here, in a clinical trial, the authors show that CFTR-modulator therapy reshapes the lung and gut microbiomes in cystic fibrosis, reducing bacteria such as Staphylococcus in the lungs and Escherichia in stool, and showing that microbiome dysbiosis can be partially reversed.
ISSN:2041-1723
DOI:10.1038/s41467-025-64218-z
Baliabidea:Health & Medical Collection