Lung Allograft Dysbiosis Associates with Immune Response and Primary Graft Dysfunction

Lower airway enrichment with oral commensals has been previously associated with grade 3 severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades, including milder forms, and whether it is...

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Published in:	The Journal of heart and lung transplantation
Main Authors:	Nelson, Nathaniel C., Wong, Kendrew K., Mahoney, Ian J., Malik, Tahir, Rudym, Darya, Lesko, Melissa B., Qayum, Seema, Lewis, Tyler C., Chang, Stephanie H., Chan, Justin C.Y., Geraci, Travis C., Li, Yonghua, Pamar, Prerna, Schnier, Joseph, Singh, Rajbir, Collazo, Destiny, Chang, Miao, Kyeremateng, Yaa, McCormick, Colin, Borghi, Sara, Patel, Shrey, Darawshi, Fares, Barnett, Clea R., Sulaiman, Imran, Kugler, Matthias C., Brosnahan, Shari B., Singh, Shivani, Tsay, Jun-Chieh J., Wu, Benjamin G., Pass, Harvey I., Angel, Luis F., Segal, Leopoldo N., Natalini, Jake G.
Format:	Journal Article
Language:	English
Published:	Elsevier Inc 17-11-2024
Subjects:	host transcriptome Lung transplantation microbiome primary graft dysfunction microbiome primary graft dysfunction Lung transplantation host transcriptome
Online Access:	Get full text
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Summary:	Lower airway enrichment with oral commensals has been previously associated with grade 3 severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades, including milder forms, and whether it is associated with a distinct host inflammatory endotype. Lower airway samples from 96 LT recipients with varying degrees of PGD 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. Differential analyses demonstrated lower airway enrichment with supraglottic-predominant taxa (SPT) in both moderate and severe PGD. Dirichlet Multinomial Mixtures (DMM) modeling identified two distinct microbial clusters. A greater percentage of subjects with moderate-severe PGD were identified within the dysbiotic cluster (C-SPT) than within the no PGD group (48 and 29%, respectively) though this difference 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, microbial 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 (PAI-1), MPO, and MMP1 genes and upregulation of MAPK pathways, suggesting that dysbiosis regulates host signaling to promote neutrophilic inflammation. Lower airway dysbiosis within the lung allograft is associated with a neutrophilic inflammatory endotype, an immune profile commonly recognized as the hallmark for PGD pathogenesis. This data highlights a putative role for lower airway microbial dysbiosis in the pathogenesis of this syndrome.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1053-2498 1557-3117 1557-3117
DOI:	10.1016/j.healun.2024.11.006