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Abstract：
BACKGROUND: Our understanding of airway dysbiosis in chronic obstructive pulmonary disease (COPD) remains incomplete, which may be improved by unraveling the complexity in microbial interactome.
OBJECTIVE: To characterize reproducible features of airway bacterial interactome in COPD at clinical stability and during exacerbation, and evaluate their associations with disease phenotypes.
METHODS: We performed weighted ensemble-based co-occurrence network analysis of 1742 sputum microbiomes from published and new microbiome datasets, comprising two case-control studies of stable COPD versus healthy control, two studies of COPD stability versus exacerbation, and one study with exacerbation-recovery time series data.
RESULTS: Patients with COPD had reproducibly lower degree of negative bacterial interactions, i.e. total number of negative interactions as a proportion of total interactions, in their airway microbiome compared with healthy controls. Evaluation of the Haemophilus interactome showed that the antagonistic interaction networks of this established pathogen rather than its abundance consistently changed in COPD. Interactome dynamic analysis revealed reproducibly reduced antagonistic interactions but not diversity loss during COPD exacerbation, which recovered after treatment. In phenotypic analysis, unsupervised network clustering showed that loss of antagonistic interactions was associated with worse clinical symptoms (dyspnea), poorer lung function, exaggerated neutrophilic inflammation, and higher exacerbation risk. Furthermore, the frequent exacerbators (≥ 2 exacerbations per year) had significantly reduced antagonistic bacterial interactions while exhibiting subtle compositional changes in their airway microbiota.
CONCLUSIONS: Bacterial interactome disturbance characterized by reduced antagonistic interactions, rather than change in pathogen abundance or diversity, is a reproducible feature of airway dysbiosis in COPD clinical stability and exacerbations, which suggests that we may target interactome rather than pathogen alone for disease treatment.
OBJECTIVE: To characterize reproducible features of airway bacterial interactome in COPD at clinical stability and during exacerbation, and evaluate their associations with disease phenotypes.
METHODS: We performed weighted ensemble-based co-occurrence network analysis of 1742 sputum microbiomes from published and new microbiome datasets, comprising two case-control studies of stable COPD versus healthy control, two studies of COPD stability versus exacerbation, and one study with exacerbation-recovery time series data.
RESULTS: Patients with COPD had reproducibly lower degree of negative bacterial interactions, i.e. total number of negative interactions as a proportion of total interactions, in their airway microbiome compared with healthy controls. Evaluation of the Haemophilus interactome showed that the antagonistic interaction networks of this established pathogen rather than its abundance consistently changed in COPD. Interactome dynamic analysis revealed reproducibly reduced antagonistic interactions but not diversity loss during COPD exacerbation, which recovered after treatment. In phenotypic analysis, unsupervised network clustering showed that loss of antagonistic interactions was associated with worse clinical symptoms (dyspnea), poorer lung function, exaggerated neutrophilic inflammation, and higher exacerbation risk. Furthermore, the frequent exacerbators (≥ 2 exacerbations per year) had significantly reduced antagonistic bacterial interactions while exhibiting subtle compositional changes in their airway microbiota.
CONCLUSIONS: Bacterial interactome disturbance characterized by reduced antagonistic interactions, rather than change in pathogen abundance or diversity, is a reproducible feature of airway dysbiosis in COPD clinical stability and exacerbations, which suggests that we may target interactome rather than pathogen alone for disease treatment.
摘要：
背景：我们对慢性阻塞性肺疾病（COPD）的气道菌群失调的理解仍然不完整，这可以通过揭示微生物相互作用的复杂性来改善。
目的：为了表征COPD在临床稳定和恶化期间气道细菌相互作用的可重复特征，并评估它们与疾病表型的关联。
方法：我们对来自已发布和新的微生物组数据集的1742个痰微生物组进行了基于加权集合的共现网络分析，包括两项稳定期COPD与健康对照的病例对照研究，两项COPD稳定性与加重的研究，和一项具有恶化-恢复时间序列数据的研究。
结果：COPD患者的阴性细菌相互作用程度降低，即消极互动的总数占总互动的比例，与健康对照组相比，他们的气道微生物组。对嗜血杆菌相互作用组的评估表明，在COPD中，这种已建立的病原体的拮抗相互作用网络而不是其丰度不断变化。相互作用组动态分析显示，在COPD加重期间，拮抗相互作用可重复减少，但多样性丧失。治疗后恢复。在表型分析中，无监督网络聚类表明，拮抗相互作用的丧失与更差的临床症状（呼吸困难）有关，肺功能较差，过度的嗜中性炎症，和更高的恶化风险。此外，频繁发作(每年加重≥2次)的患者显著减少了拮抗细菌的相互作用,同时其气道微生物群出现细微的组成变化.
结论：以拮抗相互作用减少为特征的细菌相互作用紊乱，而不是病原体丰度或多样性的变化，是COPD临床稳定性和恶化中气道菌群失调的可再现特征，这表明我们可以针对相互作用组，而不是单独的病原体来治疗疾病。
目的：为了表征COPD在临床稳定和恶化期间气道细菌相互作用的可重复特征，并评估它们与疾病表型的关联。
方法：我们对来自已发布和新的微生物组数据集的1742个痰微生物组进行了基于加权集合的共现网络分析，包括两项稳定期COPD与健康对照的病例对照研究，两项COPD稳定性与加重的研究，和一项具有恶化-恢复时间序列数据的研究。
结果：COPD患者的阴性细菌相互作用程度降低，即消极互动的总数占总互动的比例，与健康对照组相比，他们的气道微生物组。对嗜血杆菌相互作用组的评估表明，在COPD中，这种已建立的病原体的拮抗相互作用网络而不是其丰度不断变化。相互作用组动态分析显示，在COPD加重期间，拮抗相互作用可重复减少，但多样性丧失。治疗后恢复。在表型分析中，无监督网络聚类表明，拮抗相互作用的丧失与更差的临床症状（呼吸困难）有关，肺功能较差，过度的嗜中性炎症，和更高的恶化风险。此外，频繁发作(每年加重≥2次)的患者显著减少了拮抗细菌的相互作用,同时其气道微生物群出现细微的组成变化.
结论：以拮抗相互作用减少为特征的细菌相互作用紊乱，而不是病原体丰度或多样性的变化，是COPD临床稳定性和恶化中气道菌群失调的可再现特征，这表明我们可以针对相互作用组，而不是单独的病原体来治疗疾病。
