Towards an integrated understanding of bronchiectasis : pathogens, microbiome, host metabolomics, and clinical characterization

Background Bronchiectasis is a chronic respiratory disease characterized by irreversible bronchial dilation, persistent microbial infection, and chronic inflammation that drive progressive lung damage through a self-perpetuating pathological cycle. While airway infections are recognized as key drivers of disease progression, critical gaps remain in understanding the complete microbial ecosystem - including bacteria, fungi, and viruses - and its ecological dynamics within the airways. Furthermore, the metabolic consequences of host-microbe interactions and their role in sustaining inflammation remain poorly characterized. The pathophysiological mechanisms governing the transition from stable chronic infection to acute exacerbations are particularly unclear, largely due to the current inability to capture these transitional events in real time.

Aim This study seeks to establish an integrated understanding of bronchiectasis by systematically characterizing airway microbial ecology, host-microbe interactions, and developing a tool to monitor transitional phases between disease states, thereby addressing the challenges associated with infection- driven disease progression.

Study I conducted a global systematic review and meta-analysis of 98 studies (54,384 participants) to evaluate microbial patterns in bronchiectasis. Culture- based data revealed Pseudomonas aeruginosa as the most prevalent pathogen across all disease stages (stable: 26%; exacerbation: 23%), while Haemophilus influenzae and Streptococcus pneumoniae were more common in stable phases. Fungal isolations highlighted Aspergillus spp. (stable: 15%) and Candida spp. (exacerbation: 11%). Sequencing-based microbiota analysis revealed reduced bacterial diversity and increased fungal diversity during exacerbations, characterized by dominance of Pseudomonas and Candida, respectively. Intriguingly, viral detection rates were generally higher in sputum than nasopharyngeal samples, with most of the viruses showing disease stage- independent prevalence.

Study II performed shotgun metagenomic sequencing on sputum, saliva, and throat swabs from 46 stable bronchiectasis patients and 43 healthy controls. Dirichlet Multinomial Mixtures (DMM) modeling stratified patients into two clusters: DMM1 (mild disease, microbiome resembling healthy controls) and DMM2 (severe disease, enriched with P. aeruginosa and depleted oral commensals like Streptococcus spp.). Notably, rare environmental fungi (Eremothecium gossypii, Trichoderma breve) correlated with disease severity. Inter-site microbial correlations revealed stronger saliva-sputum than throat-sputum associations, suggesting oral microbiota as a potential modulator of lung ecology.

Study III analyzed serum metabolomes from the same participants as Study II, identifying significant perturbations in bronchiectasis patients versus controls. Key findings included dysregulation of membrane lipid metabolism pathways (e.g., ABC transporters, linoleic acid metabolism), particularly in severe patients (DMM2), which were closely linked to microbial biofilm formation. Altered levels of Steroid hormones (e.g., pregnanediol, corticosterone), suggested impaired anti- inflammatory responses and potential sex-related differences in disease pathogenesis. Diagnostic models using sorbitol (AUC = 0.965) and betaine (AUC = 0.945) showed high accuracy.

Study IV transculturally adapted and validated the Wisconsin Upper Respiratory Symptom Survey (WURSS-24) for Chinese populations (n = 300). The 4-domain structure (activity/function, systemic, nasal, and throat symptoms) demonstrated excellent reliability (Cronbach's a = 0.940) and validity (strong correlation with SF- 8 health scores). Nasal congestion, fatigue, and poor sleep were the most common symptoms, with Minimally Important Differences (MIDs) ranging from 0.41-1.14. The tool's responsiveness to clinical change supports its utility in exacerbation monitoring.

Conclusions This work establishes bronchiectasis as a disease of microbial dysbiosis, where P. aeruginosa dominance and loss of oral commensal taxa drive severity, pointing toward a potential dysregulated oral-lung microbial translocation. Metabolomic profiling revealed disrupted membrane lipid metabolism reflecting microbial biofilm-mediated host interactions, and dysregulated steroid hormone pathways potentially underlying sex-specific disease manifestations. The validated WURSS-24-C addresses unmet needs in patient-reported monitoring of exacerbations.

List of scientific papers

I. Yuanyuan Wang, Jingmin Xiao, Xiaolin Yang, Yanmin Liu, Juan Du, Apostolos Bossios, Xi Zhang, Guobin Su, Lei Wu, Zhongde Zhang and Cecilia Stålsby Lundborg. Pulmonary microbiology and microbiota in adults with non-cystic fibrosis bronchiectasis: a systematic review and meta-analysis. Respiratory Research. 2025;26(1):77. https://doi.org/10.1186/s12931-025-03140-w

II. Yuanyuan Wang, Chengrui Wang, Yanmin Liu, Xiaolin Yang, Apostolos Bossios, Guobin Su, Zhongde Zhang, Cecilia Stålsby Lundborg and Juan Du. The airway microbiomes in patients with stable bronchiectasis: A cross-sectional observational study [Manuscript]

III. Yanmin Liu, Yuanyuan Wang, Chengrui Wang, Xiaolin Yang, Apostolos Bossios, Guobin Su, Zhongde Zhang, Juan Du and Cecilia Stålsby Lundborg. Serum metabolomic profiling reveals disease heterogeneity in bronchiectasis patients stratified by airway microbiome [Manuscript]

IV. Yuanyuan Wang, Zehui He, Simin Chen, Yuntao Liu, Fang Li, Bruce Barrett, Zhongde Zhang, Guobin Su & Cecilia Stålsby Lundborg. Validation of the Wisconsin upper respiratory symptom survey-24, Chinese version. Annals of Medicine. 2022;54(1):655-665. https://doi.org/10.1080/07853890.2022.2043559