依列卡福妥/替扎卡福妥/依伐卡托对囊性纤维化青少年口咽微生物组的纵向影响。

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

作者信息

Steinberg Ruth, Moeller Alexander, Gisler Amanda, Mostacci Nadja, Hilty Markus, Usemann Jakob

机构信息

Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern-Bern Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern-Bern Switzerland; University Children's Hospital Basel UKBB Switzerland.

Department of Respiratory Medicine, University Children's Hospital Zurich, University of Zurich-Zurich Switzerland.

出版信息

J Cyst Fibros. 2025 May;24(3):562-570. doi: 10.1016/j.jcf.2024.10.001. Epub 2024 Oct 15.

DOI:10.1016/j.jcf.2024.10.001

PMID:39406574

Abstract

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.

摘要

背景

三联调节剂疗法依列卡福/替扎卡福/依伐卡托（ETI）可改善肺功能，并对患有晚期肺部疾病的囊性纤维化患者（pwCF）的呼吸道微生物群产生影响。然而，患有囊性纤维化（CF）的青少年相比成年pwCF，其细菌病原体定植较少，但他们的微生物群已经与健康个体有所不同。本研究的目的是纵向分析ETI对主要患有轻度CF肺部疾病的青少年呼吸道宏基因组的影响。

方法

在这项前瞻性观察性研究中，我们纳入了年龄在12 - 20岁、至少有一个F508del突变的pwCF，他们在ETI治疗开始前和开始后，每周两次至每两周一次，持续三个月，采集口咽拭子。我们进行了全宏基因组鸟枪法测序，随后进行宿主DNA过滤和分类分析。我们使用线性和加性混合效应模型，对已知混杂因素进行调整，并对多重检验进行校正，以研究微生物群的纵向发展。我们分析了细菌多样性、丰度和菌株水平的系统发育。

结果

我们分析了20名pwCF的297份拭子的宏基因组数据。ETI治疗开始后，微生物群组成发生了变化。我们观察到随着时间的推移，微生物群略有多样化（逆辛普森指数，系数0.085，95%置信区间0.003，0.17，p = 0.04）。菌株水平分析和聚类表明，即使在ETI治疗期间，最常见细菌种类的菌株保留也是主要的。