Microbial Dysregulation of the Gut-Lung Axis in Bronchiectasis.

Emerging data support the existence of a microbial "gut-lung" axis that remains unexplored in bronchiectasis. Prospective and concurrent sampling of gut (stool) and lung (sputum) was performed in a cohort of  = 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 ( = 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 driven gut-lung interactions. 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 , gut , and gut , 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 , , and with gut . The lung gut relationship, observed in the high gut-lung interaction bronchiectasis cluster, was validated in a murine model of lung 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. A dysregulated gut-lung axis, driven by lung , associates with poorer clinical outcomes in bronchiectasis.