Microbial Dysregulation of the Gut-Lung Axis in Bronchiectasis

• Published in: American journal of respiratory and critical care medicine Vol. 207; no. 7; pp. 908 - 920
• Main Authors: Narayana, Jayanth Kumar, Aliberti, Stefano, Mac Aogáin, Micheál, Jaggi, Tavleen Kaur, Ali, Nur A’tikah Binte Mohamed, Ivan, Fransiskus Xaverius, Cheng, Hong Sheng, Yip, Yun Sheng, Vos, Marcus Ivan Gerard, Low, Zun Siong, Lee, Jeannie Xue Ting, Amati, Francesco, Gramegna, Andrea, Wong, Sunny H., Sung, Joseph J. Y., Tan, Nguan Soon, Tsaneva-Atanasova, Krasimira, Blasi, Francesco, Chotirmall, Sanjay H.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.04.2023
• Subjects: Animals; Bronchiectasis - drug therapy; Digestive system; Lung - microbiology; Lung diseases; Medical research; Mice; Microbiota; Original; Patients; Prospective Studies; RNA, Ribosomal, 16S - genetics; mycobiome; gut-lung axis; bronchiectasis; microbiome; metagenomics
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.202205-0893OC

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.