Rationale: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages. Objectives: We investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. Methods: We recruited 57 patients with a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome, and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. Measurements and Main Results: Compared with smoker control subjects, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis, such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1, and MUC4 in mild-to-moderate COPD. Finally, in a preclinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury, revealing transcriptomic signatures similar to those observed in human subjects with COPD. Conclusions: Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.

中文翻译：

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下气道生态失调会加重轻至中度慢性阻塞性肺疾病的肺部炎症损伤。

理由：慢性阻塞性肺疾病 (COPD) 与高发病率、死亡率和医疗费用有关。香烟烟雾是一个致病因素；然而，并非所有重度吸烟者都会患慢性阻塞性肺病。微生物定植和感染是晚期疾病进展的促成因素。目的：我们调查了轻至中度 COPD 是否发生下气道生态失调，并分析了 COPD 发病机制的可能机制。方法：我们招募了 57 名吸烟史 > 10 包年的患者：26 名有慢性阻塞性肺病 (COPD) 的生理证据，31 名肺功能正常（吸烟者对照受试者）。支气管镜检查对上呼吸道、下呼吸道和环境背景进行了采样。通过 16S rRNA 基因测序、全基因组、RNA 宏转录组和宿主 RNA 转录组对样本进行分析。使用临床前小鼠模型来评估香烟烟雾和生态失调对下呼吸道炎症损伤的影响。测量和主要结果：与吸烟者对照受试者相比，微生物组分析表明，慢性阻塞性肺病受试者的下呼吸道富含常见的口腔共生菌。下气道宿主转录组学显示炎症和肿瘤发生标志物的差异，例如轻至中度 COPD 中 IL-17、IL-6、ERK/MAPK、PI3K、MUC1 和 MUC4 的上调。最后，在暴露于香烟烟雾的临床前小鼠模型中，常见口腔共生菌的下气道生态失调加剧了炎症损伤，揭示了与慢性阻塞性肺病人类受试者中观察到的转录组特征相似的转录组特征。结论：烟雾暴露环境下的下气道生态失调导致 COPD 早期炎症损伤。针对下呼吸道微生物群与戒烟相结合可能具有潜在的治疗意义。