BACKGROUND Lower airway enrichment with oral commensals has been previously associated with severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades and whether it is associated with a distinct host inflammatory endotype. METHODS Lower airway samples from 96 LT recipients were used to evaluate the lung allograft microbiota via 16S rRNA gene sequencing. Bronchoalveolar lavage (BAL) cytokine concentrations and cell differential percentages were compared across PGD grades. In a subset of samples, we evaluated the lower airway host transcriptome using RNA sequencing methods. RESULTS Differential analyses demonstrated lower airway enrichment with supraglottic-predominant taxa (SPT) in moderate and severe PGD. Dirichlet multinomial mixtures modeling identified 2 distinct microbial clusters. A greater percentage of subjects with moderate-severe PGD than no PGD were identified within the dysbiotic cluster (C-SPT, 48% and 29%, respectively) though this did not reach statistical significance (p = 0.06). PGD severity associated with increased BAL neutrophil concentration (p = 0.03) and correlated with BAL concentrations of MCP-1/CCL2, IP-10/CXCL10, IL-10, and TNF-α (p < 0.05). Furthermore, signatures of dysbiosis correlated with neutrophils, MCP-1/CCL-2, IL-10, and TNF-α (p < 0.05). C-SPT exhibited differential expression of TNF, SERPINE1, MPO, and MMP1 genes and upregulation of MAPK pathways, host signling associated with neutrophilic inflammation. CONCLUSIONS Lower airway dysbiosis within the lung allograft is associated with a neutrophilic inflammatory endotype, an immune profile commonly recognized as the hallmark for PGD. These data highlight a putative role of lower airway microbial dysbiosis in the pathogenesis of this syndrome.

中文翻译：

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肺同种异体移植物生态失调与免疫反应和原发性移植物功能障碍有关。


背景 口服共生物的下气道富集以前与肺移植 （LT） 后严重的原发性移植物功能障碍 （PGD） 有关。我们旨在确定这种菌群异常特征是否存在于所有 PGD 严重程度等级中，以及它是否与不同的宿主炎症内型有关。方法 使用 96 例 LT 受者的下气道样本，通过 16S rRNA 基因测序评估肺同种异体移植微生物群。比较不同 PGD 等级的支气管肺泡灌洗液 （BAL） 细胞因子浓度和细胞差异百分比。在样本子集中，我们使用 RNA 测序方法评估了下气道宿主转录组。结果 差异分析显示，在中度和重度 PGD 中，声门上为主分类群 （SPT） 的气道富集较低。狄利克雷多项混合物建模确定了 2 个不同的微生物簇。在菌群中发现患有中重度 PGD 的受试者比例高于无 PGD 的受试者 （C-SPT，分别为 48% 和 29%），尽管这没有达到统计学意义 （p = 0.06）。PGD 严重程度与 BAL 中性粒细胞浓度升高相关 （p = 0.03），并与 MCP-1/CCL2、IP-10/CXCL10、IL-10 和 TNF-α 的 BAL 浓度相关 （p < 0.05）。此外，生态失调特征与中性粒细胞、 MCP-1/CCL-2、IL-10 和 TNF-α 相关 （p < 0.05）。C-SPT 表现出 TNF 、 SERPINE1 、 MPO 和 MMP1 基因的差异表达以及 MAPK 通路的上调，与中性粒细胞炎症相关的宿主签名。结论 肺同种异体移植物内的下气道菌群失调与中性粒细胞炎性内型有关，这种免疫特征通常被认为是 PGD 的标志。 这些数据强调了下气道微生物群落失调在该综合征发病机制中的假定作用。