2026/03/10 by Ulrich M. Zissler, Andreas Rembert Koczulla · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Cystic Fibrosis Research Advances #Gut microbiota and health #Neonatal Respiratory Health Research
paper · doi:10.1093/ajrccm/aamag117
openalex publication_date 2026/03/10 · openalex created_date 2026/03/17 · openalex updated_date 2026/06/19
Neutrophil extracellular traps (NETs) play a dual role in nontuberculous mycobacterial (NTM) bronchiectasis, acting as antimicrobial defenses while driving excessive inflammation and disease severity.1 In this context, NETs are associated with dysbiosis, positive NTM, and poor outcomes, positioning them as biomarkers and therapeutic targets. The study by Singh et al.2 in the current American Journal of Respiratory and Critical Care Medicine sheds light on this through bronchoscopic profiling in bronchiectasis patients and a preclinical microaspiration model, revealing how oral commensals amplify Mycobacterium-induced NET formation to perpetuate severe phenotypes (Figure 1). Conceptual model of a nontuberculous mycobacterial (NTM)–associated, neutrophil extracellular trap (NET)–dominated endotype in bronchiectasis. Lower airway dysbiosis with nontuberculous mycobacteria and oral commensals in the distal bronchiole lumen promotes recruitment and activation of neutrophils and formation of dense NET clusters. Th17 cells and γ/δ T cells in the bronchial wall amplify this neutrophil–NET response, driving chronic inflammation, structural airway damage with high NECTAR scores, and a clinically severe phenotype characterized by increased exacerbations. In a precisely phenotyped cohort of 200 patients with noncystic fibrosis–associated bronchiectasis, nearly half with American Thoracic Society criteria for NTM-lung disease (NTM-LD), bronchoscopic sampling of the most severely affected segments was combined with radiologic assessment (NECTAR score), exacerbation history, and cavitation status.2 This anchors microbiome and NET measurements in clinically severe, NTM-enriched bronchiectasis rather than in convenience sputum collections. Bronchiectasis embodies airway dilation, recurrent infections, and neutrophilic inflammation, with microbial dysbiosis as a hallmark of progression shaping exacerbations, hospitalizations, and mortality.3,4 Lower airway studies highlight Pseudomonas dominance and reduced diversity as predictors of lung function decline,5 yet globally rising NTM-LD remains underexplored amid microbiome heterogeneity. Neutrophil extracellular traps, DNA-histone scaffolds with elastase, and myeloperoxidase ensnare pathogens like Mycobacterium avium complex to limit dissemination.6 In NTM-LD, Mycobacterium-triggered NETosis aids macrophage killing, but low BAL loads evade 16S detection despite cultures, while M. abscessus biofilms exploit NET scaffolds for persistence. Excess NETs, however, drive pathogenesis by tissue injury, mucus plugs, and cytokine cascades via AIM2 inflammasome activation.7 Neutrophil extracellular traps were elevated in NTM+ BAL, correlating with bacterial burden, neutrophils, and oral taxa like Veillonella and Prevotella, distinct from Pseudomonas antagonism in NTM- cases.2 Dirichlet multinomial mixture modeling identified 3 lower airway metacommunities: low-biomass background, oral-commensal–enriched, and pathogen-dominant (Pseudomonas and classic respiratory pathogens). In NTM- patients, NETs peaked in pathogen-dominant clusters with Pseudomonas-driven neutrophilia. In NTM+ disease, NETs aligned with Mycobacterium/oral commensals in oral-enriched clusters, plus severe phenotypes like cavitation and frequent exacerbations. The parallel NTM+ MOC (mixed oral commensals) mouse model recapitulated an oral-commensal/Mycobacterium-driven metacommunity with sustained Th17/γδ T-cell influx, programmed cell death–1 upregulation, and persistent NET formation. These signatures stratify severity as NETs surge in cavitators (high NECTAR scores) and exacerbators, surpassing FACED indices, with multicohort validation tying NETs to mortality/low diversity.8 The NET-high, cavitating, frequently exacerbating NTM+ cluster aligns with the “frequent exacerbator” endotype, triggering preventive long-term antibiotics/macrolides in bronchiectasis.9 Characterizing this NET-high subgroup, including endotype stability and responses to macrolides, inhaled antibiotics, and dideptidyl peptidase–1 (DPP-1) inhibition, would link microbiome-host signatures to risk-stratified algorithms. In NTM+, Mycobacterium/commensals synchronize with NETs, highlighting microaspiration.10 Several strengths of this study need to be emphasized. Bronchoscopic sampling in the clinical cohort provides precise lower airway microenvironment views, avoiding sputum limitations of prior studies, while excluding confounders like recent antibiotics and validating robustness in untreated NTM subgroups. Murine assays innovatively link co-occurrence and causality in microbiome-host dynamics. Building on Pseudomonas-NET links,11 it pioneers NTM-specific endotypes, nominating NETs for trials. Conceptually, it expands bronchiectasis beyond Pseudomonas dominance to 2 NET-linked endotypes, a classic Pseudomonas/low-diversity state and an NTM+/oral-commensal state with distinct community structure and immunophenotype, crucial for biomarker-guided, host-directed interventions over blanket neutrophil suppression. Nevertheless, the study has key limitations framing its interpretation. Its cross-sectional nature prevents assessing longitudinal microbiome/NET dynamics during NTM therapy initiation, exacerbations, or host-directed treatments. Multicohort data link higher NETs to poor outcomes/impaired antibiotic responses in bronchiectasis but do not clarify NETosis evolution under infection changes, immunomodulation, or rehabilitation. Longitudinal sampling across NTM treatment, exacerbations, macrolide/DPP-1 inhibitor initiation/withdrawal is essential to determine if NET-high endotypes are fixed traits or modifiable states per 2025 European Respiratory Society (ERS) guidelines.9 Second, 16S rRNA V4 sequencing offers only genus-level resolution, unable to differentiate pathogenic vs nonpathogenic strains or resistance determinants, leaving strain-level ecology questions unanswered. Third, single-center recruitment at a tertiary NTM referral site, enriched for bronchoscopically/radiologically severe cases, limits generalizability to milder/sputum-diagnosed disease in routine practice. Fourth, the BALB/c NTM + MOC model covers only 1-2 months of infection, incompletely reflecting chronic human NTM-LD trajectories where immune responses plateau beyond 9 weeks. It has already been shown that NET modulation with macrolide antibiotics alleviates bronchiectasis.12 A further unresolved dimension pertains to the impact of background anti-inflammatory and antimicrobial regimens on the lower airway microbiome–NET axis. The 2025 ERS bronchiectasis guidelines strongly recommend chronic macrolide therapy for patients at high exacerbation risk.9 This therapy not only reduces exacerbations but also modulates neutrophil serine protease activity and NET formation. This suggests that NET-high endotypes may be differentially shaped by long-term macrolide exposure. Conversely, guidelines advise against routine long-term inhaled corticosteroids (absent asthma/chronic obstructive pulmonary disease [COPD]) due to pneumonia, NTM, and dysbiosis risks.9 Cumulative effects of systemic corticosteroids on NETosis/dysbiosis in NTM-enriched bronchiectasis remain unexplored, warranting longitudinal/interventional trials. In addition, brensocatib inhibits specific NET proteases, reducing exacerbations without infection risk.13 These findings intersect a rapidly evolving therapeutic landscape. The recent ERS bronchiectasis guideline frames NET-driven inflammation within broader treatable traits such as vaccination status, smoking, comorbidities, physical activity, and airway clearance. Recommendations stress up-to-date respiratory pathogen immunizations, systematic management of cardiovascular disease, osteoporosis, anxiety/depression, and aggressive smoking cessation, which modulate exacerbation risk, dysbiosis, and neutrophil activation indirectly. Airway clearance techniques and pulmonary rehabilitation improve sputum mobilization and alleviate symptoms and may disrupt microenvironments sustainingNETosis in Pseudomonas- and NTM-driven bronchiectasis. The study highlights increased physical activity and clearance devices. Macrolides and DPP-1 inhibitors like brensocatib selectively attenuate neutrophil serine protease activity, cutting exacerbations without impairing antibacterial defense. Neutrophil extracellular trap–high/NTM+ endotypes are prime candidates for future DPP-1 trials, with vigilant mycobacterial monitoring. Proximal NET dismantlers (DNase/PAD4 inhibition) risk narrower windows in NTM-LD, where NETs aid mycobacterial containment or biofilm organization.14 From a biomarker perspective, Singh et al.2 show that NET levels in bronchoalveolar lavage (BAL) scale with bacterial burden, specific taxa, and radiologic severity, including NECTAR score, cavitation, and exacerbation status. Future translational studies must address whether NETs/related signatures can be detected noninvasively such as induced sputum or exhaled biomarkers to stratify patients for DPP-1 inhibition, antimicroaspiration, or intensified NTM therapy. By entwining commensals with Mycobacterium in NET webs, Singh et al. 2 redefine bronchiectasis as a disease of interacting communities and host programs rather than single pathogens.2 Their findings prompt key questions: should future DPP-1 trials include NTM+, NET-high patients to assess host-directed benefits, and how do biologics used for overlapping asthma, allergic bronchopulmonary aspergillosis, or eosinophilic phenotypes affect NET biology and the airway microbiome? Although ERS guidelines note frequent comorbid asthma, COPD, or allergic bronchopulmonary aspergillosis (ABPA), data on effects of biologics on NET formation, NTM behavior, or community structure remain scarce.9 Future bronchiectasis and NTM-LD cohorts should systematically capture biologic exposure and mechanistic NET data to bridge precision immunomodulation with microbiome-host dynamics. Further priorities include testing whether mitigating microaspiration and oral dysbiosis modulates NET-driven inflammation and applying strain-resolved multiomics to refine endotypes. Clinically, an NTM+ oral-commensal signature may indicate a highly inflammatory, destructive phenotype; scientifically, it outlines an integrative roadmap linking microbiome, immunity, and targeted therapy. Supplementary material is available at American Journal of Respiratory and Critical Care Medicine online. Prof. Dr. Zissler reports an endowed professorship of the Max Aicher Foundation for the Technology Transfer Center for Building Biology, Indoor Health and Building Material Recycling in Berchtesgadener Land, grants and personal fees from the German Center for Lung Research (DZL), grants and personal fees from the Federal Ministry of Education and Research, grants and personal fees from the Bavarian State Ministry of Sciences and Arts, grants and personal fees from CFi-aktiv e. V. Mukoviszidose Selbsthilfe Suedbayern outside the submitted work. Prof. Dr. Koczulla states grants from the German Center for Lung Research (DZL). Please see the ICMJE disclosure forms, which have been provided as supplementary material.