Lung allograft dysbiosis associates with immune response and primary graft dysfunction

Nathaniel C Nelson¹, Kendrew K Wong¹, Ian J Mahoney¹, Tahir Malik¹, Darya Rudym², Melissa B Lesko², Seema Qayum², Tyler C Lewis³, Stephanie H Chang⁴, Justin C Y Chan⁴, Travis C Geraci⁴, Yonghua Li¹, Prerna Pamar¹, Joseph Schnier¹, Rajbir Singh¹, Destiny Collazo¹, Miao Chang¹, Yaa Kyeremateng¹, Colin McCormick¹, Sara Borghi⁵, Shrey Patel¹, Fares Darawshy⁶, Clea R Barnett¹, Imran Sulaiman⁷, Matthias C Kugler¹, Shari B Brosnahan¹, Shivani Singh¹, Jun-Chieh J Tsay⁸, Benjamin G Wu⁸, Harvey I Pass⁹, Luis F Angel², Leopoldo N Segal¹, Jake G Natalini¹⁰

Affiliations

¹ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York.
² Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; NYU Langone Transplant Institute, NYU Langone Health, New York, New York.
³ NYU Langone Transplant Institute, NYU Langone Health, New York, New York.
⁴ NYU Langone Transplant Institute, NYU Langone Health, New York, New York; Department of Cardiothoracic Surgery, New York University Grossman School of Medicine, New York, New York.
⁵ Department of Pathology, New York University Grossman School of Medicine, New York, New York.
⁶ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; The Institute of Pulmonology, Hadassah Medical Center, Jerusalem, Israel; Department of Medicine, The Faculty of Medicine at the Hebrew University of Jerusalem, Jerusalem, Israel.
⁷ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; Department of Respiratory Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Respiratory Medicine, Beaumont Hospital, Dublin, Ireland.
⁸ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, VA New York Harbor Healthcare System, New York, New York.
⁹ Department of Cardiothoracic Surgery, New York University Grossman School of Medicine, New York, New York.
¹⁰ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; NYU Langone Transplant Institute, NYU Langone Health, New York, New York. Electronic address: jake.natalini@nyulangone.org.

PMID: 39561864
PMCID: PMC11956144 (available on 2026-03-01)
DOI: 10.1016/j.healun.2024.11.006

Lung allograft dysbiosis associates with immune response and primary graft dysfunction

Nathaniel C Nelson et al. J Heart Lung Transplant. 2025 Mar.

. 2025 Mar;44(3):422-434.

doi: 10.1016/j.healun.2024.11.006. Epub 2024 Nov 17.

Authors

Affiliations

¹ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York.
² Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; NYU Langone Transplant Institute, NYU Langone Health, New York, New York.
³ NYU Langone Transplant Institute, NYU Langone Health, New York, New York.
⁴ NYU Langone Transplant Institute, NYU Langone Health, New York, New York; Department of Cardiothoracic Surgery, New York University Grossman School of Medicine, New York, New York.
⁵ Department of Pathology, New York University Grossman School of Medicine, New York, New York.
⁶ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; The Institute of Pulmonology, Hadassah Medical Center, Jerusalem, Israel; Department of Medicine, The Faculty of Medicine at the Hebrew University of Jerusalem, Jerusalem, Israel.
⁷ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; Department of Respiratory Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Respiratory Medicine, Beaumont Hospital, Dublin, Ireland.
⁸ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, VA New York Harbor Healthcare System, New York, New York.
⁹ Department of Cardiothoracic Surgery, New York University Grossman School of Medicine, New York, New York.
¹⁰ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York; NYU Langone Transplant Institute, NYU Langone Health, New York, New York. Electronic address: jake.natalini@nyulangone.org.

PMID: 39561864
PMCID: PMC11956144 (available on 2026-03-01)
DOI: 10.1016/j.healun.2024.11.006

Abstract

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.

Keywords: dysbiosis; host transcriptome; lung transplantation; microbiome; primary graft dysfunction.

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References

1. Snell GI, et al. Report of the ISHLT working group on primary lung graft dysfunction, part I: definition and grading-a 2016 consensus group statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2017;36:1097–103. - PubMed
1. Cantu E, et al. Quantitative evidence for revising the definition of primary graft dysfunction after lung transplant. Am J Respir Crit Care Med 2018;197:235–43. - PMC - PubMed
1. Kreisel D, et al. Short- and long-term outcomes of 1000 adult lung transplant recipients at a single center. J Thorac Cardiovasc Surg 2011;141:215–22. - PubMed
1. Daud SA, et al. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2007;175:507–13. - PubMed
1. Diamond JM, et al. Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit care Med 2013;187:527–34. - PMC - PubMed

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Lung allograft dysbiosis associates with immune response and primary graft dysfunction

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Lung allograft dysbiosis associates with immune response and primary graft dysfunction

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