慢性阻塞性肺疾病（COPD）与高发病率、死亡率和医疗费用密切相关。虽然吸烟是诱发因素，但并非所有重度吸烟者都会患上COPD。微生物定植和感染是COPD进展的促进因素，尤其在晚期疾病中。在这里，我们调查了轻度至中度COPD患者是否存在下呼吸道菌群失调，并分析其对COPD发病机制的可能贡献。我们招募了57名吸烟史大于10包年的患者：其中26名存在COPD的生理证据，31名肺功能正常（吸烟者对照组）。支气管镜样本采集了上呼吸道（UA）、下呼吸道（BAL）和环境背景（BKG）。样本通过16S rRNA基因测序、全基因组、RNA转录组和宿主RNA转录组进行分析。使用临床前小鼠模型评估了吸烟和菌群失调对下呼吸道炎症损伤的贡献。与吸烟者对照组相比，微生物组分析显示COPD患者的下呼吸道富集了常见的口腔共生菌群。下呼吸道宿主转录组分析表明，轻度至中度COPD中有炎症和肿瘤生成标志物的差异，如IL-17、IL-6、ERK/MAPK、PI3K、MUC1和MUC4的上调。最后，在暴露于烟雾的临床前小鼠模型中，常见口腔共生菌群引起下呼吸道菌群失调，加剧炎症损伤，表现出与人类COPD患者相似的转录组特征。烟雾暴露下的下呼吸道菌群失调早期对COPD的炎症损伤起到贡献作用。针对下呼吸道菌群治疗结合戒烟可能具有潜在的治疗意义。

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality and health care 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 advance stages.Here we investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis.We recruited 57 patients with >10 pack year smoking history: 26 had physiological evidence of COPD, 31 had normal lung function (smoker controls). Bronchoscopy sampled the upper airways (UA), lower airways (BAL) and environmental background (BKG). 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.Compared with smoker controls, 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 pre-clinical 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 COPD subjects.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.