Lower Airway Dysbiosis in NTM+ Bronchiectasis is Associated with NET-Predominant Severe Phenotypes.

[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 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 and Streptococcus). NET levels were higher in NTM+ BAL. 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 micro-aspiration model, the combination of oral commensals and Mycobacterium led to a sustained pro-inflammatory immune response marked by an increase in Th17, γδT 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.