Lower airway dysbiosis in nontuberculous mycobacteria-positive bronchiectasis is associated with neutrophil extracellular trap-predominant severe phenotypes

TY - JOUR

T1 - Lower airway dysbiosis in nontuberculous mycobacteria-positive bronchiectasis is associated with neutrophil extracellular trap-predominant severe phenotypes

AU - Singh, Shivani

AU - Darawshy, Fares

AU - Erlandson, Kirby

AU - Narayana, Jayanth Kumar

AU - Li, Qingsheng

AU - Li, Yonghua

AU - Atandi, Isabella

AU - Krolikowski, Kelsey

AU - Patel, Shrey

AU - Collazo, Destiny

AU - Mac Aogáin, Micheál

AU - Gilmour, Amy

AU - Long, Merete

AU - Chang, Miao

AU - Hoque, Afshana

AU - Schluger, Rosemary

AU - Kumar, Sanjan

AU - Chung, Cecilia J

AU - Wong, Kendrew

AU - Porter, Gabriella

AU - Feng, Yicheng

AU - Czachor, Anna

AU - McCormick, Colin

AU - Clementi, Emily

AU - Kyeremateng, Yaa

AU - Lukovnikova, Alena

AU - Harris, Danielle

AU - Gomez, Sebastian

AU - Kain, Taylor

AU - Kocak, Ibrahim

AU - Singh, Rajbir

AU - Rodriguez, Claudia

AU - Kwok, Benjamin

AU - Barnett, Clea

AU - Kugler, Matthias

AU - Weiden, Michael D

AU - Nelson, Nathaniel

AU - Natalini, Jake G

AU - Luglio, David

AU - Desvignes, Ludovic

AU - Gautam, Samir

AU - McGuire, Erin

AU - Gordon, Terry

AU - Sulaiman, Imran

AU - Tsay, Jun-Chieh J

AU - Basavaraj, Ashwin

AU - Wu, Benjamin G

AU - Kamelhar, David

AU - Addrizzo-Harris, Doreen

AU - Chalmers, James D

AU - Chotirmall, Sanjay H

AU - Wu, Benjamin G

AU - Kamelhar, David

AU - Addrizzo-Harris, Doreen

AU - Segal, Leopoldo N.

N1 - Publisher Copyright: Published by Oxford University Press on behalf of the American Thoracic Society 2026.

PY - 2026/5/1

Y1 - 2026/5/1

N2 - RATIONALE: The discoveries of neutrophilic inflammation and Pseudomonas-dominant pulmonary dysbiosis have helped pave the way for host-directed therapy in bronchiectasis. Substantial knowledge gaps still remain about the interplay between neutrophilic signatures and microbes in nontuberculous mycobacterial lung disease (NTM-LD), a phenotypically diverse lung infection that is increasingly prevalent in the United States and other parts of the world. OBJECTIVES: To evaluate the lower airway microbiota and neutrophilic traits in NTM-negative (NTM-) and NTM-positive (NTM+) bronchiectasis. METHODS: 16S rRNA gene sequencing, cell counts, and neutrophil extracellular trap (NET) immunoassays were performed on bronchoscopic lower airway samples in 200 bronchiectasis subjects (108 NTM-, 92 NTM+). A preclinical model of oral commensal microaspiration and NTM infection was used to profile the murine lower airways with flow cytometry and a NET assay. MEASUREMENTS AND MAIN RESULTS: Lower airways of NTM+ bronchiectasis patients were enriched with Mycobacterium and oral commensals (eg, Veillonella, Prevotella, and Streptococcus). NET levels were higher in NTM+ BAL fluid. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa were associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine microaspiration model, the combination of oral commensals and Mycobacterium led to a sustained proinflammatory immune response marked by an increase in Th17 cells, γδT cells, and PD-1+ T lymphocytes as well as higher NET levels. CONCLUSIONS: Our analyses showed that distinct microbiome features beyond the primary pathogen can contribute to neutrophilic inflammation and severe disease phenotypes in bronchiectasis/NTM-LD.

AB - RATIONALE: The discoveries of neutrophilic inflammation and Pseudomonas-dominant pulmonary dysbiosis have helped pave the way for host-directed therapy in bronchiectasis. Substantial knowledge gaps still remain about the interplay between neutrophilic signatures and microbes in nontuberculous mycobacterial lung disease (NTM-LD), a phenotypically diverse lung infection that is increasingly prevalent in the United States and other parts of the world. OBJECTIVES: To evaluate the lower airway microbiota and neutrophilic traits in NTM-negative (NTM-) and NTM-positive (NTM+) bronchiectasis. METHODS: 16S rRNA gene sequencing, cell counts, and neutrophil extracellular trap (NET) immunoassays were performed on bronchoscopic lower airway samples in 200 bronchiectasis subjects (108 NTM-, 92 NTM+). A preclinical model of oral commensal microaspiration and NTM infection was used to profile the murine lower airways with flow cytometry and a NET assay. MEASUREMENTS AND MAIN RESULTS: Lower airways of NTM+ bronchiectasis patients were enriched with Mycobacterium and oral commensals (eg, Veillonella, Prevotella, and Streptococcus). NET levels were higher in NTM+ BAL fluid. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa were associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine microaspiration model, the combination of oral commensals and Mycobacterium led to a sustained proinflammatory immune response marked by an increase in Th17 cells, γδT cells, and PD-1+ T lymphocytes as well as higher NET levels. CONCLUSIONS: Our analyses showed that distinct microbiome features beyond the primary pathogen can contribute to neutrophilic inflammation and severe disease phenotypes in bronchiectasis/NTM-LD.

KW - Non-tuberculous mycobacteria

KW - microbiome

KW - neutrophil extracellular trap

KW - nontuberculous mycobacteria

U2 - 10.1093/ajrccm/aamag015

DO - 10.1093/ajrccm/aamag015

M3 - Article

C2 - 41738242

SN - 1073-449X

VL - 212

SP - 936

EP - 951

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 5

ER -