The host response to the lung microbiome in Chromic Obstructive Pulmonary Disease

Rationale: The relatively sparse but diverse microbiome in human lungs may become less diverse in chronic obstructive pulmonary disease (COPD). This article examines the relationship of this microbiome to emphysematous tissue destruction, number of terminal bronchioles, infiltrating inflammatory cells, and host gene expression. Methods: Culture-independent pyrosequencing microbiome analysis was used to examine the V3–V5 regions of bacterial 16S ribosomal DNA in 40 samples of lung from 5 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 4) and 28 samples from 4 donors (controls). A second protocol based on the V1–V3 regions was used to verify the bacterial microbiome results. Within lung tissue samples the microbiome was compared with results of micro–computed tomography, infiltrating inflammatory cells measured by quantitative histology, and host gene expression. Measurements and Main Results: Ten operational taxonomic units (OTUs) was found sufficient to discriminate between control and GOLD stage 4 lung tissue, which included known pathogens such as Haemophilus influenzae. We also observed a decline in microbial diversity that was associated with emphysematous destruction, remodeling of the bronchiolar and alveolar tissue, and the infiltration of the tissue by CD4+ T cells. Specific OTUs were also associated with neutrophils, eosinophils, and B-cell infiltration (P < 0.05). The expression profiles of 859 genes and 235 genes were associated with either enrichment or reductions of Firmicutes and Proteobacteria, respectively, at a false discovery rate cutoff of less than 0.1. Conclusions: These results support the hypothesis that there is a host immune response to microorganisms within the lung microbiome that appears to contribute to the pathogenesis of COPD.

研究背景：人体肺部微生物组（microbiome）虽相对稀疏但具有多样性，而慢性阻塞性肺疾病（chronic obstructive pulmonary disease, COPD）患者的肺部微生物组多样性可能会下降。本研究探讨了该肺部微生物组与肺气肿性组织破坏、终末细支气管数量、浸润性炎症细胞以及宿主基因表达之间的关联。
研究方法：本研究采用非培养焦磷酸测序微生物组分析技术，对5例慢性阻塞性肺疾病（全球慢性阻塞性肺疾病倡议[GOLD] 4级）患者的40份肺部样本以及4名健康供体的28份肺部对照样本中的细菌16S核糖体DNA的V3–V5区进行检测。同时采用基于V1–V3区的第二套实验方案对细菌微生物组的检测结果进行验证。在肺部组织样本中，将微生物组检测结果与微型计算机断层扫描（micro–computed tomography）结果、通过定量组织学检测得到的浸润性炎症细胞水平以及宿主基因表达情况进行对比分析。
检测指标与主要结果：研究发现，仅需10个操作分类单元（operational taxonomic units, OTUs）即可区分对照样本与GOLD 4级慢性阻塞性肺疾病患者的肺部组织样本，其中包含流感嗜血杆菌（Haemophilus influenzae）等已知致病菌。同时观察到微生物组多样性下降与肺气肿性组织破坏、细支气管及肺泡组织重塑以及CD4+ T细胞浸润组织存在关联。特定的操作分类单元还与中性粒细胞、嗜酸性粒细胞浸润以及B细胞浸润显著相关（P < 0.05）。在错误发现率阈值小于0.1的条件下，分别有859个基因和235个基因的表达谱与厚壁菌门（Firmicutes）和变形菌门（Proteobacteria）的丰度升高或降低相关。
研究结论：本研究结果支持如下假说：宿主会对肺部微生物组中的微生物产生免疫应答，该应答可能参与了慢性阻塞性肺疾病的发病机制。