Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on the oropharyngeal metagenome in adolescents with cystic fibrosis.

BACKGROUND

Triple modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and impacts upon the respiratory microbiome in people with Cystic fibrosis (pwCF) with advanced lung disease. However, adolescents with cystic fibrosis (CF) are less colonized with bacterial pathogens than adult pwCF but their microbiota already differs from healthy individuals. The aim of this study was to longitudinally analyze the impact of ETI on the respiratory metagenome in adolescents with predominantly mild CF lung disease.

METHODS

In this prospective observational study, we included pwCF aged 12-20 years with at least one F508del mutation, who collected oropharyngeal swabs before and after initiation of ETI therapy twice per week to biweekly over three months. We performed whole metagenome shotgun sequencing, followed by host DNA filtering and taxonomic profiling. We used linear and additive mixed effects models adjusted for known confounders and corrected for multiple testing to study longitudinal development of the microbiome. We analyzed bacterial diversity, abundance, and strain-level phylogeny.

RESULTS

We analyzed the metagenomic data of 297 swabs of 20 pwCF. Microbiome composition changed after initiation of ETI therapy. We observed a slight diversification of the microbiome over time (Inv Simpson, Coef 0.085, 95 %CI 0.003, 0.17, p = 0.04). Strain-level analysis and clustering showed that strain retention of the most frequent bacterial species is predominant even during ETI therapy.

CONCLUSIONS

During three months of ETI therapy, commensal bacteria increased, which may help to prevent overgrowth of bacterial pathogens.

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander Moeller reports financial support was provided by Vertex Pharmaceuticals Incorporated. Jakob Usemann reports a relationship with Swiss Lung Foundation that includes: funding grants. Jakob Usemann reports a relationship with Palatin Foundation that includes: funding grants. Jakob Usemann reports a relationship with Swiss Group for Clinical Cancer Research that includes: funding grants. Jakob Usemann reports a relationship with Vertex Pharmaceuticals Incorporated that includes: speaking and lecture fees and travel reimbursement. Jakob Usemann reports a relationship with LUNGE ZURICH that includes: funding grants and speaking and lecture fees. Ruth Steinberg reports a relationship with Cystic Fibrosis Switzerland that includes: funding grants. Ruth Steinberg reports a relationship with Swiss National Science Foundation that includes: funding grants. Ruth Steinberg reports a relationship with Society of Paediatric Pneumology (GPP) that includes: funding grants & travel reimbursement. Ruth Steinberg reports a relationship with Vertex Pharmaceuticals Incorporated that includes: speaking and lecture fees and travel reimbursement. Markus Hilty reports a relationship with Lindenhof Bern Foundation that includes: funding grants. Markus Hilty reports a relationship with Cystic Fibrosis Switzerland that includes: funding grants. Markus Hilty reports a relationship with Swiss Lung Foundation that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.