Microbiome and metabolome patterns after lung transplantation reflect underlying disease and chronic lung allograft dysfunction.

IF 13.8 1区 生物学 Q1 MICROBIOLOGY
Christian Martin, Kathleen S Mahan, Talia D Wiggen, Adam J Gilbertsen, Marshall I Hertz, Ryan C Hunter, Robert A Quinn
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引用次数: 0

Abstract

Background: Progression of chronic lung disease may lead to the requirement for lung transplant (LTx). Despite improvements in short-term survival after LTx, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the molecular and microbial relationships between underlying lung disease and the development of CLAD in bronchoalveolar lavage fluid (BALF) from subjects post-LTx, which is crucial for tailoring treatment strategies specific to allograft dysfunctions.

Methods: Paired 16S rRNA gene amplicon sequencing and untargeted LC-MS/MS metabolomics were performed on 856 BALF samples collected over 10 years from LTx recipients (n = 195) with alpha-1-antitrypsin disease (AATD, n = 23), cystic fibrosis (CF, n = 47), chronic obstructive pulmonary disease (COPD, n = 78), or pulmonary fibrosis (PF, n = 47). Data were analyzed using random forest (RF) machine learning and multivariate statistics for associations with underlying disease and CLAD development.

Results: The BALF microbiome and metabolome after LTx differed significantly according to the underlying disease state (PERMANOVA, p = 0.001), with CF and AATD demonstrating distinct microbiome and metabolome profiles, respectively. Uniqueness in CF was mainly driven by Pseudomonas abundance and its metabolites, whereas AATD had elevated levels of phenylalanine and a lack of shared metabolites with the other underlying diseases. BALF microbiome and metabolome composition were also distinct between those who did or did not develop CLAD during the sample collection period (PERMANOVA, p = 0.001). An increase in the average abundance of Veillonella (AATD, COPD) and Streptococcus (CF, PF) was associated with CLAD development, and decreases in the abundance of phenylalanine-derivative alkaloids (CF, COPD) and glycerophosphorylcholines (CF, COPD, PF) were signatures of the CLAD metabolome. Although the relative abundance of Pseudomonas was not associated with CLAD, the abundance of its virulence metabolites, including siderophores, quorum-sensing quinolones, and phenazines, were elevated in those with CF who developed CLAD. There was a positive correlation between the abundance of these molecules and the abundance of Pseudomonas in the microbiome, but there was no correlation between their abundance and the time in which BALF samples were collected post-LTx.

Conclusions: The BALF microbiome and metabolome after LTx are particularly distinct in those with underlying CF and AATD. These data reflect those who developed CLAD, with increased virulence metabolite production from Pseudomonas, an aspect of CF CLAD cases. These findings shed light on disease-specific microbial and metabolic signatures in LTx recipients, offering valuable insights into the underlying causes of allograft rejection. Video Abstract.

肺移植后的微生物组和代谢组模式反映了潜在的疾病和慢性肺异体移植功能障碍。
背景:慢性肺部疾病的恶化可能导致需要进行肺移植(LTx)。尽管肺移植术后的短期存活率有所提高,但慢性肺移植功能障碍(CLAD)仍是长期存活的关键挑战。本研究调查了肺移植术后受试者支气管肺泡灌洗液(BALF)中潜在肺部疾病与 CLAD 发生之间的分子和微生物关系,这对于定制针对异体移植功能障碍的治疗策略至关重要:方法: 对10年来从患有α-1-抗胰蛋白酶病(AATD,n = 23)、囊性纤维化(CF,n = 47)、慢性阻塞性肺病(COPD,n = 78)或肺纤维化(PF,n = 47)的LTx受者(n = 195)处收集的856份BALF样本进行了配对16S rRNA基因扩增片测序和非靶向LC-MS/MS代谢组学研究。使用随机森林(RF)机器学习和多变量统计对数据进行分析,以确定与潜在疾病和CLAD发展之间的关联:结果:LTx后的BALF微生物组和代谢组随基础疾病状态的不同而有显著差异(PERMANOVA,p = 0.001),CF和AATD分别显示出不同的微生物组和代谢组特征。CF的独特性主要是由假单胞菌的丰度及其代谢物造成的,而AATD的苯丙氨酸水平升高,缺乏与其他基础疾病共享的代谢物。在样本采集期间,CLAD 患者与未患者的 BALF 微生物组和代谢组组成也有所不同(PERMANOVA,p = 0.001)。Veillonella(AATD、COPD)和链球菌(CF、PF)平均丰度的增加与 CLAD 的发展有关,苯丙氨酸衍生物生物碱(CF、COPD)和甘油磷酸胆碱(CF、COPD、PF)丰度的降低是 CLAD 代谢组的特征。虽然假单胞菌的相对丰度与CLAD无关,但其毒力代谢物,包括嗜苷酸类、定量感应喹诺酮类和吩嗪类的丰度在发展为CLAD的CF患者中有所升高。这些分子的丰度与假单胞菌在微生物组中的丰度呈正相关,但其丰度与LTx后采集BALF样本的时间没有相关性:LTx后的BALF微生物组和代谢组在有潜在CF和AATD的患者中尤其不同。这些数据反映了CF CLAD病例中假单胞菌毒力代谢物产生增加的情况。这些发现揭示了LTx受者的疾病特异性微生物和代谢特征,为了解异体移植排斥反应的根本原因提供了宝贵的见解。视频摘要。
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来源期刊
Microbiome
Microbiome MICROBIOLOGY-
CiteScore
21.90
自引率
2.60%
发文量
198
审稿时长
4 weeks
期刊介绍: Microbiome is a journal that focuses on studies of microbiomes in humans, animals, plants, and the environment. It covers both natural and manipulated microbiomes, such as those in agriculture. The journal is interested in research that uses meta-omics approaches or novel bioinformatics tools and emphasizes the community/host interaction and structure-function relationship within the microbiome. Studies that go beyond descriptive omics surveys and include experimental or theoretical approaches will be considered for publication. The journal also encourages research that establishes cause and effect relationships and supports proposed microbiome functions. However, studies of individual microbial isolates/species without exploring their impact on the host or the complex microbiome structures and functions will not be considered for publication. Microbiome is indexed in BIOSIS, Current Contents, DOAJ, Embase, MEDLINE, PubMed, PubMed Central, and Science Citations Index Expanded.
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