Microbial Dysregulation of the Gut-Lung Axis in Bronchiectasis

<b>Rationale:</b> Emerging data support the existence of a microbial "gut-lung" axis that remains unexplored in bronchiectasis. <b>Methods:</b> Prospective and concurrent sampling of gut (stool) and lung (sputum) was performed in a cohort of <i>n</i> = 57 individuals with bronchiectasis and subjected to bacteriome (16S rRNA) and mycobiome (18S Internal Transcribed Spacer) sequencing (total, 228 microbiomes). Shotgun metagenomics was performed in a subset (<i>n</i> = 15; 30 microbiomes). Data from gut and lung compartments were integrated by weighted similarity network fusion, clustered, and subjected to co-occurrence analysis to evaluate gut-lung networks. Murine experiments were undertaken to validate specific <i>Pseudomonas-</i>driven gut-lung interactions. <b>Results:</b> Microbial communities in stable bronchiectasis demonstrate a significant gut-lung interaction. Multibiome 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 <i>Pseudomonas</i>, gut <i>Bacteroides</i>, and gut <i>Saccharomyces</i>, is associated with increased exacerbations and greater radiological and overall bronchiectasis severity, whereas the low gut-lung interaction cluster demonstrates an overrepresentation of lung commensals, including <i>Prevotella</i>, <i>Fusobacterium</i>, and <i>Porphyromonas</i> with gut <i>Candida</i>. The lung <i>Pseudomonas-</i>gut <i>Bacteroides</i> relationship, observed in the high gut-lung interaction bronchiectasis cluster, was validated in a murine model of lung <i>Pseudomonas aeruginosa</i> infection. This interaction was abrogated after antibiotic (imipenem) pretreatment 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. <b>Conclusions:</b> A dysregulated gut-lung axis, driven by lung <i>Pseudomonas</i>, associates with poorer clinical outcomes in bronchiectasis.