Lower Airway Dysbiosis in NTM+ Bronchiectasis is Associated with NET-Predominant Severe Phenotypes
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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 remain about the interplay between neutrophilic signatures and microbes in non-tuberculous 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
Evaluate the lower airway microbiota and neutrophilic traits in NTM- and 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 micro-aspiration 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 (e.g., Veillonella, Prevotella ). NET levels were higher in NTM+ BAL. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine micro-aspiration model, the combination of oral commensals and Mycobacterium led to a sustained pro-inflammatory immune response marked by an increase in Th17, γ8T cells, 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.
