1 Department of Pediatrics and.
Am J Respir Crit Care Med. 2013 Nov 15;188(10):1193-201. doi: 10.1164/rccm.201304-0775OC.
The role of airway microbiome in corticosteroid response in asthma is unknown.
To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids.
16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation.
Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids.
A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.
气道微生物组在哮喘患者糖皮质激素反应中的作用尚不清楚。
检测糖皮质激素抵抗（CR）哮喘患者气道微生物组组成，并与糖皮质激素敏感（CS）哮喘患者和正常对照者进行比较，探讨哮喘患者气道中的细菌是否可能导致细胞对糖皮质激素反应的改变。
对 39 例哮喘患者和 12 例健康对照者的支气管肺泡灌洗液（BAL）样本进行 16S rRNA 基因测序。在哮喘患者中，对糖皮质激素反应性进行特征描述，用致病微生物和共生微生物刺激 BAL 巨噬细胞，并通过实时聚合酶链反应分析糖皮质激素调节基因和细胞 p38 丝裂原活化蛋白激酶（MAPK）的表达。
39 例哮喘患者中，29 例为 CR，10 例为 CS。CR 和 CS 哮喘患者 BAL 微生物组在丰富度、均匀度、多样性和门水平群落组成上无差异，但在属水平上存在差异，14 例 CR 哮喘患者有明显的属扩张。仅在 CR 哮喘气道中发现的独特扩张的潜在病原体流感嗜血杆菌（Haemophilus parainfluenzae）预先孵育哮喘气道巨噬细胞后，会导致 p38 MAPK 激活、IL-8 增加（P<0.01）、丝裂原激活蛋白激酶磷酸酶 1 mRNA 表达增加（P<0.01）和糖皮质激素反应抑制（P<0.05）。而接触共生菌普雷沃氏菌（Prevotella melaninogenica）则没有这种现象。MAPK 上游激活物转化生长因子-β相关激酶-1（TAK1）抑制剂，而非 p38 MAPK 抑制剂，可恢复细胞对糖皮质激素的敏感性。
CR 哮喘的亚组患者表现出特定革兰氏阴性细菌的气道扩张，这些细菌触发 TAK1/MAPK 激活并诱导糖皮质激素抵抗。TAK1 抑制恢复了细胞对糖皮质激素的敏感性。
