“It has long been thought that chronic bacterial infection of the airways could play a role in driving the pathogenesis of COPD,” explains Yvonne J. Huang, MD, ATSF. “However, past studies mostly looked at patients with more advanced disease or with frequent exacerbations, where it is difficult to disentangle if microbial changes are due to more severe disease and/or cumulative effects of treatments. Earlier studies also used culture or specific molecular methods geared more toward identifying specific species in samples such as sputum, which is less intrusive to obtain. Bronchoscopy studies in COPD are rare, particularly in patients who have milder disease or who do not have COPD by current diagnostic criteria but are at risk based on smoking history.”

Dr. Huang says it is now known that the composition of airway microbes is more complex, especially in chronic inflammatory lung diseases. “This complexity is reflected in not just the number and different types of organisms present, but also in their functions, which can shape their host milieu. In this study, we addressed some outstanding questions and limitations of prior studies, through analysis of microbial and metabolite data generated from bronchoalveolar lavage fluid that was obtained from subjects in this multicenter study (SPIROMICS) with earlier stage COPD.”

The Lung Environment Is a Complex Ecological Habitat

For a study published in the American Journal of Respiratory and Critical Care Medicine, Dr. Huang and colleagues identified elements of the lung microbiome and metabolome linked with clinical markers in milder stage COPD. The study team conducted integrated analyses of paired lung microbiome and metabolomic data from 137 participants, looking at COPD status (ever-smokers with or without the diagnosis), measures of lung function and respiratory symptom burden, and exacerbation events. They performed an analysis to first filter and select for the microbiota members and metabolite features most strongly linked with each outcome. The selection step was repeated numerous times, and the features that remained most strongly linked with the outcome were then used in a specific type of regression model called elastic net regression. This approach is advantageous when the input data (predictors) are high-dimensional and also highly correlated, which is common is multi-‘omic’ data. These models included covariates such as age, sex, smoking status, and use of inhaled steroid therapy or antibiotics

“Our overall finding was that the lung environment is essentially a complex ecological habitat,” Dr. Huang notes. “Components of this habitat, like any microbiome, are constantly interacting and shaping host responses. This web of interactions may support different clinical trajectories or phenotypes in COPD.”

Certain Lung Bacteria & Metabolites Pathways Align With Worse Lung Function

The study team observed patterns of co-associated lung bacteria and metabolites from pathways that together strongly aligned with worse lung function, more symptoms, and greater likelihood of having been diagnosed with COPD. “Conversely, combinations of other lung bacteria and other types of metabolites correlated with better lung function, no diagnosis of COPD, and/or fewer symptoms among some ever-smokers in this cohort,” Dr. Huang says. “There was not one dominant species or metabolic pathway implicated, as we observed signals that involved multiple bacterial lineages and metabolite classes co-associated with each outcome. This suggests that ecological interactions in the lung in earlier stage COPD pathogenesis differ from those found in more advanced disease.

Lung microbiota and metabolite components were able to predict outcome classifications for nearly all the clinical measures modeled, Dr. Huang notes. “This is indicative of the collective contribution of lung microbiota and metabolites to pathophysiologic mechanisms underlying these outcomes, such as lung function (Figure).”

Inhaled Steroids or Antibiotics Can Alter Lung Environment

These findings support the recognition that multiple factors play a role in COPD pathogenesis beyond the clinical variables already known, according to Dr. Huang. “Specifically, the lung microbial and metabolic milieu, though complex, may explain why some smokers do or do not develop COPD, a long-standing question and clinical observation,” she says. “We also believe this milieu is sensitive to exposures that can perturb its dynamics. Therefore, recognizing that prescribed therapies—such as inhaled steroids or antibiotics without clear indication—could further alter the lung environment in ways beyond what is currently understood is a first step.”

Dr. Huang and colleagues concur that more mechanistic research is needed, particularly in how exactly lung microbiota may functionally interact or contribute to specific metabolic pathways. “Additional studies in other COPD cohorts would be useful, particularly if similar types of data and clinical groups are available, so that it can be determined whether our findings are unique to this cohort,” Dr. Huang says.