Loss of Airway Phylogenetic Diversity Is Associated with Clinical and Pathobiological Markers of Disease Development in Chronic Obstructive Pulmonary Disease.

<strong>Rationale:</strong> The airway microbiome has the potential to shape chronic obstructive pulmonary disease (COPD) pathogenesis, but its relationship to outcomes in milder disease is unestablished. <strong>Objectives:</strong> To identify sputum microbiome characteristics associated with markers of COPD in participants of the Subpopulations and Intermediate Outcome Measures of COPD Study (SPIROMICS). <strong>Methods:</strong> Sputum DNA from 877 participants was analyzed using 16S ribosomal RNA gene sequencing. Relationships between baseline airway microbiota composition and clinical, radiographic, and mucoinflammatory markers, including longitudinal lung function trajectory, were examined. <strong>Measurements and Main Results:</strong> Participant data represented predominantly milder disease (Global Initiative for Chronic Obstructive Lung Disease stage 0-2 obstruction in 732 of 877 participants). Phylogenetic diversity (i.e., range of different species within a sample) correlated positively with baseline lung function, decreased with higher Global Initiative for Chronic Obstructive Lung Disease stage, and correlated negatively with symptom burden, radiographic markers of airway disease, and total mucin concentrations (<em>P</em>&thinsp;&lt;&thinsp;0.001). In covariate-adjusted regression models, organisms robustly associated with better lung function included <em>Alloprevotella</em>, <em>Oribacterium</em>, and <em>Veillonella</em> species. Conversely, lower lung function, greater symptoms, and radiographic measures of small airway disease were associated with enrichment in members of <em>Streptococcus</em>, <em>Actinobacillus</em>, <em>Actinomyces</em>, and other genera. Baseline sputum microbiota features were also associated with lung function trajectory during SPIROMICS follow-up (stable/improved, decline, or rapid decline groups). The stable/improved group (slope of FEV₁ regression ⩾66th percentile) had greater bacterial diversity at baseline associated with enrichment in <em>Prevotella</em>, <em>Leptotrichia</em>, and <em>Neisseria</em> species. In contrast, the rapid decline group (FEV₁ slope ⩽33rd percentile) had significantly lower baseline diversity associated with enrichment in <em>Streptococcus</em> species. <strong>Conclusions:</strong> In SPIROMICS, baseline airway microbiota features demonstrate divergent associations with better or worse COPD-related outcomes.