支气管扩张气道变形菌门的丰度和多样性及其临床意义

Bronchiectasis has been a common respiratory disease in China. The vicious cycle, consisting of bacterial infection, airway inflammation and airway destruction, has been a well recognized drive in the pathogenesis of bronchiectasis, in which bacteria play a pivotal role. Proteobacteria comprise various clinically pathogenic genus, including Pseudomonas aeruginosa and Hemophilus spp. While routine sputum culture identifies a limited number of pathogenic microorganisms, 16srRNA pyrosequencing may comprehensively characterize the airway bacterial spectrum, particularly regarding the microbiota taxa and genus. In this study, the 16srRNA pyrosenquencing will be utilized to characterize the abundance and diversity of airway proteobacteria in bronchiectasis patients with positive or negative sputum cultures and to investigate their associations with airway and systemic inflammatory markers, matrix metalloproteinase, lung function and disease severity indices. Apart from the delineation of the variations in the abundance and diversity of airway proteobacteria when clinically stable, during acute exacerbations and convalescence phase following regular antibiotics therapy, an emphasis will also be positioned on the characteristics of proteobacteria in severe bronchiectasis, in particular, subjects who have repetitively negative culture findings. These are expected to offer a critical rationale for assessment of disease management and prognosis leading to the utilization of optimized and personalized antibiotics. Our study may also provide a novel approach for the treatment of airway infection and destruction.

支气管扩张（支扩）是国内较常见的呼吸科疾病之一，细菌感染、气道炎症、气道结构破坏这一恶性循环贯穿支扩发病过程，其中细菌感染扮演重要角色。变形菌门是细菌含多种临床常见的致病菌（如铜绿假单胞菌、嗜血杆菌）。常规痰培养只能鉴别部分致病菌，16srRNA测序则可全面评估气道细菌谱。本研究拟利用16srRNA测序了解变形菌门的丰度及多样性在痰培养阳性及阴性的稳定期支扩患者中的特点，探讨其与气道、系统性炎症、金属基质蛋白酶、肺功能及支扩严重程度的相关性，对比稳定期、支扩急性加重经过规范、系统性抗生素治疗后变形菌门丰度、种属及多样性的改变，并重点研究重度支扩（特别是反复痰培养阴性）患者气道中变形菌门的特征。本研究将可能为疾病病情和预后评估提重要参考，从新的视野优化抗生素个体化选用，此外为干预气道感染和破坏提供新的切入点。

支气管扩张（支扩）是慢性气道感染性疾病，但变形菌门在支扩发病中的作用仍不甚明确。本研究对稳定期、急性加重期、恢复期支扩患者、正常人进行痰液采集，对比支扩患者与正常人变形菌门相对丰度与多样性的差异；根据痰培养结果、支扩严重程度指数（BSI）对支扩患者进行分组，对比稳定期支扩患者痰液细菌群落构成的差异，探讨BSI与变形菌门（特别是假单胞菌属）相对丰度与多样性的相关性；分析常规痰培养结果与16srRNA测序结果的一致性；按照常规痰培养与痰脓性评分对稳定期支扩患者进行分组，分析痰脓性与变形菌门群落结构的相关性。该研究发现：1）支扩患者最常见的是变形菌门，其次是拟杆菌门；2）铜绿假单胞菌组变形菌门、假单胞菌属相对丰度显著增高，其它机会致病菌组其次，培养阴性组最低；假单胞菌属仅仅在铜绿假单胞菌组中的贡献度最大；3）变形菌门（特别是假单胞菌属）为中度、重度支扩的优势菌群，其相对丰度与多样性与BSI密切相关；4）支扩急性加重期各组的变形菌门相对丰度与多样性均较稳定期无显著差异；5）重度支扩患者变形菌门（特别是假单胞菌属）扩增尤为显著；6）痰脓性在一定程度上反映了气道细菌结构的变化，但是脓性痰仍存在较大的异质性，培养阳性组变形菌门（特别是假单胞菌属）的相对丰度显著增高。这系列研究发现的意义在于：1）说明临床医生需要重视支扩患者下气道菌群失调的现象，意味着气道内变形菌门、假单胞菌属扩增，伴随的是其它菌群的缩减（菌群失调更为显著）；2）变形菌门（特别是假单胞菌属）对推动支扩病情发展的作用，其为反映支扩病情的标记物之一；3）临床医师要联合根据痰脓性以及常规培养结果判断，这样可以在未行16srRNA测序的情况下大致判断气道菌群失调的程度。