Microbial Dysregulation of the Gut-Lung Axis in Bronchiectasis
Narayana, JK; Aliberti, S; Mac Aogáin, M; et al.Jaggi, TK; Binte Mohamed Ali, NA; Xaverius Ivan, F; Cheng, HS; Yip, YS; Gerard Vos, MI; Low, ZS; Lee, JXT; Amati, F; Gramegna, A; Wong, SH; Sung, JJY; Tan, NS; Tsaneva-Atanasova, K; Blasi, F; Chotirmall, SH
Date: 26 October 2022
Article
Journal
American Journal of Respiratory and Critical Care Medicine
Publisher
American Thoracic Society
Publisher DOI
Abstract
Introduction: Emerging data supports the existence of a microbial ‘gut-lung’ axis that remains unexplored in bronchiectasis. Methods: Prospective and concurrent sampling of gut (stool) and lung (sputum) was performed in a cohort of n=57 individuals with bronchiectasis and subjected to bacteriome (16S rRNA) and mycobiome (18S ITS) ...
Introduction: Emerging data supports the existence of a microbial ‘gut-lung’ axis that remains unexplored in bronchiectasis. Methods: Prospective and concurrent sampling of gut (stool) and lung (sputum) was performed in a cohort of n=57 individuals with bronchiectasis and subjected to bacteriome (16S rRNA) and mycobiome (18S ITS) sequencing (total 228 microbiomes). Shotgun metagenomics was performed in a subset (n=15; 30 microbiomes). Data from gut and lung compartments were ‘integrated’ by weighted Similarity Network Fusion (wSNF), clustered and subjected to co-occurrence analysis to evaluate ‘gut-lung’ networks. Murine experiments were undertaken to validate specific Pseudomonas-driven ‘gut-lung’ interactions. Results: Microbial communities in stable bronchiectasis demonstrate significant ‘gut-lung’ interaction. Multi-biome integration followed by unsupervised clustering reveals two patient clusters, differing by ‘gut-lung’ interactions and with contrasting clinical phenotypes. A ‘high gut-lung interaction’ cluster characterized by lung Pseudomonas, gut Bacteroides and gut Saccharomyces associates with increased exacerbations, greater radiological and overall bronchiectasis severity while the ‘low gut-lung interaction’ cluster demonstrates an overrepresentation of lung commensals including Prevotella, Fusobacterium and Porphyromonas with gut Candida. The lung Pseudomonas-gut Bacteroides relationship, observed in the ‘high gut-lung interaction’ bronchiectasis cluster, was validated in a murine model of lung Pseudomonas aeruginosa (PAO1) infection. This interaction was abrogated following antibiotic (imipenem) pre-treatment in mice confirming the relevance and therapeutic potential of targeting the gut microbiome to influence the ‘gut-lung’ axis. Metagenomics in a subset of individuals with bronchiectasis corroborated our findings from targeted analyses. Conclusion: A dysregulated ‘gut-lung’ axis, driven by lung Pseudomonas, associates with poorer clinical outcomes in bronchiectasis.
Mathematics and Statistics
Faculty of Environment, Science and Economy
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