A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung.
A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung.
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DOI：
10.1016/j.jcf.2021.11.003
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发表时间：
2022-11
影响因子：
5.2
通讯作者：
Quinn, Robert A.
中科院分区：
文献类型：
--
作者：
Sosinski, Lo M.;Martin, Christian H.;Neugebauer, Kerri A.;Ghuneim, Lydia-Ann J.;Guzior, Douglas, V;Castillo-Bahena, Alicia;Mielke, Jenna;Thomas, Ryan;McClelland, Marc;Conrad, Doug;Quinn, Robert A.
Elexacaftor-Tezacaftor-Ivacaftor （ETI）疗法在治疗囊性纤维化（CF）方面显示出有希望的疗效，并且自最近FDA批准以来正变得越来越广泛。然而，人们对这些药物如何影响肺部感染知之甚少，肺部感染是CF （pwCF）患者发病和死亡的主要原因。我们使用16S rRNA基因测序和非靶向代谢组学分析了pwCF （n=24）在ETI治疗前后的痰微生物组和代谢组数据。治疗前后患者的痰菌群多样性，尤其是均匀性有所提高（p=0.036），且治疗前后个体间的菌群谱存在差异（PERMANOVA F=1.92, p=0.044）。尽管有这些变化，个体内的微生物组仍然比整个样本群体更相似。治疗前后没有特定微生物类群的相对丰度差异，但经典CF病原体与厌氧菌的集体对数比显著降低（p=0.013）。痰代谢组也显示与ETI相关的变化（PERMANOVA F=4.22, p=0.002），并且在治疗期间，受试者之间的差异更大。代谢组的变化是由多肽、氨基酸和犬尿氨酸途径代谢物的减少所驱动的，这与CF病原体的减少有关。组成ETI的三种小分子的代谢是广泛的，包括以前未表征的结构修饰。ETI治疗与气道粘液中微生物组和代谢组的变化有关。这种作用在痰生化上更强，这可能反映了随着药物作用的发生，肺粘液中微生物栖息空间的变化。
Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy is showing promising efficacy for treatment of cystic fibrosis (CF) and is becoming more widely available since recent FDA approval. However, little is known about how these drugs will affect lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF). We analyzed sputum microbiome and metabolome data from pwCF (n=24) before and after ETI therapy using 16S rRNA gene sequencing and untargeted metabolomics. The sputum microbiome diversity, particularly its evenness, was increased (p=0.036) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes remained more similar within an individual than across the sampled population. No specific microbial taxa differed in relative abundance before and after therapy, but the collective log-ratio of classic CF pathogens to anaerobes significantly decreased (p=0.013). The sputum metabolome also showed changes associated with ETI (PERMANOVA F=4.22, p=0.002) and was characterized by greater variation across subjects while on treatment. Changes in the metabolome were driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway, which were associated with a decrease in CF pathogens. Metabolism of the three small molecules that make up ETI was extensive, including previously uncharacterized structural modifications. ETI therapy is associated with a changing microbiome and metabolome in airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche space for microbial residency in lung mucus as the drug’s effects take hold.
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影响因子：
168.9
作者：
Heijerman, Harry G. M.;McKone, Edward F.;Mccoy, Karen S.
通讯作者：
Mccoy, Karen S.
在囊性纤维化中，跨年龄和疾病阶段的肺微生物群。
影响因子：
4.6
作者：
Coburn B;Wang PW;Diaz Caballero J;Clark ST;Brahma V;Donaldson S;Zhang Y;Surendra A;Gong Y;Elizabeth Tullis D;Yau YC;Waters VJ;Hwang DM;Guttman DS
通讯作者：
Guttman DS
影响因子：
6.7
作者：
Flynn, Jeffrey M.;Niccum, David;Hunter, Ryan C.
通讯作者：
Hunter, Ryan C.
影响因子：
3
作者：
Barth, AL;Pitt, TL
通讯作者：
Pitt, TL
影响因子：
5.2
作者：
Manzenreiter, Reinhard;Kienberger, Ferry;Hart, Dominik
通讯作者：
Hart, Dominik