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RATIONALE: Progressive lung function loss is recognized in COPD; however, no study concurrently evaluates how accelerated lung function decline relates to mucus properties and the microbiome in COPD. OBJECTIVE: Longitudinal assessment of mucus and microbiome changes accompanying accelerated lung function decline in COPD patients. METHODS: Prospective, longitudinal assessment of the London COPD cohort exhibiting the greatest FEV1 decline (n=30; "accelerated decline"; 156 mL/year FEV1 loss) and with no FEV1 decline (n=28; "non-decline"; 49 mL/year FEV1 gain) over time. Lung microbiomes from "paired" sputum (total 116 specimens) were assessed by shotgun metagenomics and corresponding mucus profiles evaluated for biochemical and biophysical properties. RESULTS: Biochemical and biophysical mucus properties are significantly altered in the accelerated decline group. Unsupervised principal component analysis showed clear separation, with mucus biochemistry associated with accelerated decline, while biophysical mucus characteristics contributed to inter-individual variability. When mucus and microbes are considered together, an accelerated decline mucus-microbiome association emerges, characterized by increased mucin (MUC5AC and MUC5B) concentration and the presence of Achromobacter and Klebsiella. As COPD progresses, mucus-microbiome shifts occur, initially characterized by low mucin concentration and transition from viscous to elastic dominance accompanied by the commensals Veillonella, Gemella, Rothia and Prevotella (GOLD A and B) before transition to increased mucus viscosity, mucins, and DNA concentration along with the emergence of pathogenic microorganisms including Haemophilus, Moraxella and Pseudomonas (GOLD E). CONCLUSION: Mucus-microbiome associations evolve over time with accelerated lung function decline, symptom progression and exacerbations affording fresh therapeutic opportunities for early intervention. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Rationale: Chronic infection and inflammation shapes the airway microbiome in bronchiectasis. Utilizing whole-genome shotgun metagenomics to analyze the airway resistome provides insight into interplay between microbes, resistance genes, and clinical outcomes. Objectives: To apply whole-genome shotgun metagenomics to the airway microbiome in bronchiectasis to highlight a diverse pool of antimicrobial resistance genes: the "resistome," the clinical significance of which remains unclear. Methods: Individuals with bronchiectasis were prospectively recruited into cross-sectional and longitudinal cohorts (n = 280), including the international multicenter cross-sectional Cohort of Asian and Matched European Bronchiectasis 2 (CAMEB 2) study (n = 251) and two independent cohorts, one describing patients experiencing acute exacerbation and a further cohort of patients undergoing Pseudomonas aeruginosa eradication treatment. Sputum was subjected to metagenomic sequencing, and the bronchiectasis resistome was evaluated in association with clinical outcomes and underlying host microbiomes. Measurements and Main Results: The bronchiectasis resistome features a unique resistance gene profile and increased counts of aminoglycoside, bicyclomycin, phenicol, triclosan, and multidrug resistance genes. Longitudinally, it exhibits within-patient stability over time and during exacerbations despite between-patient heterogeneity. Proportional differences in baseline resistome profiles, including increased macrolide and multidrug resistance genes, associate with shorter intervals to the next exacerbation, whereas distinct resistome archetypes associate with frequent exacerbations, poorer lung function, geographic origin, and the host microbiome. Unsupervised analysis of resistome profiles identified two clinically relevant "resistotypes," RT1 and RT2, the latter characterized by poor clinical outcomes, increased multidrug resistance, and P. aeruginosa. Successful targeted eradication in P. aeruginosa-colonized individuals mediated reversion from RT2 to RT1, a more clinically favorable resistome profile demonstrating reduced resistance gene diversity. Conclusions: The bronchiectasis resistome associates with clinical outcomes, geographic origin, and the underlying host microbiome. Bronchiectasis resistotypes link to clinical disease and are modifiable through targeted antimicrobial therapy.