Deciphering the Lung Microbiome During Pulmonary Exacerbations and Clinical Stability in Bronchiectasis

Abstract Background: Bronchiectasis is characterized by cycles of inflammation and chronic infection. Pulmonary exacerbations are defined by periods of worsening symptoms and dropping lung function. Traditional dogma suggests this is due to overgrowth of canonical bacterial pathogens; however recent studies have shown this to not fully represent all events. The cause(s) of exacerbations are currently unknown, representing a knowledge gap. The central hypothesis of this research project is different endotypes exist in bronchiectasis, are unique to the individual, and can be used for future applications to delineate appropriate clinical therapy. Methodology: Unique at the University of Calgary, we maintain a prospectively collected sputum from all patients, including those with bronchiectasis, who submitted samples from 1980 to present (>20,000 sputum samples and associated metadata). In this study, we sought to identify sputum samples at periods of clinical stability and acute exacerbation within our retrospective cohort. Long-read DNA sequencing was performed using the MinION (Oxford Nanopore). For alpha-diversity analyses, rarefaction curves and diversity indices of observed species richness Chao1, and Shannon were measured followed by Kruskal-Wallis test (p-value < = 0.05). For Beta-Diversity analysis and to visualize overall community structure PCoA plots based on Bray-Curtis dissimilarities are generated and PERMANOVA to measure differences between the microbial community profiles. Preliminary Findings: Our preliminary data evaluates 162 samples from 69 patients at different timepoints. Interim analysis demonstrates that the majority (13/16, 81%) had no clear etiology and was deemed idiopathic. Sequencing data demonstrated majority of microbes were classified as expected pathogens within bronchiectasis including Pseudomonas followed by Staphylococcus and Escherichia. Anaerobic genera were present including Prevotella, Gemella and Veillonella. Not surprisingly, we observed varying degree of inter and intra patient variability and heterogeneity with some patients demonstrating relative stability during altered clinical periods and others showing considerable temporal variation. The constrained coordination plot reveals dissimilarities between the community composition at species level and stronger effect of constraint (different time points) on the ordination. No significant changes in the alpha diversity were observed in any of the timepoints across all subjects and PERMANOVA analysis did not reveal any community-wide differences (p=0.20). Conclusions: Our preliminary data suggests cohorts of patients with bronchiectasis that experience temporal change during periods of exacerbations, whereas others do not. This suggests endotypes exist and may be used to personalize therapeutic approaches. Expansion into our cohort across more subjects will be required as next steps to validate our initial findings and delineate clinical associations.

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