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Shotgun metagenomics was performed in a subset (n\u2009=\u200915; 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 Pseudomonas-driven gut-lung interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 Pseudomonas, gut Bacteroides, and gut Saccharomyces, 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 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 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A dysregulated gut-lung axis, driven by lung Pseudomonas, associates with poorer clinical outcomes in bronchiectasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202205-0893oc","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T13:55:16Z","timestamp":1666792516000},"page":"908-920","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":121,"title":["Microbial Dysregulation of the Gut-Lung Axis in Bronchiectasis"],"prefix":"10.1093","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8794-9048","authenticated-orcid":false,"given":"Jayanth Kumar","family":"Narayana","sequence":"first","affiliation":[{"name":"Lee Kong Chian School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Aliberti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy"},{"name":"Respiratory Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1726-7700","authenticated-orcid":false,"given":"Miche\u00e1l","family":"Mac Aog\u00e1in","sequence":"additional","affiliation":[{"name":"Biochemical Genetics Laboratory, Department of Biochemistry, St. James\u2019s Hospital, Dublin, Ireland"},{"name":"Clinical Biochemistry Unit, School of Medicine, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tavleen Kaur","family":"Jaggi","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur A\u2019tikah Binte Mohamed","family":"Ali","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fransiskus Xaverius","family":"Ivan","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong Sheng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun Sheng","family":"Yip","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus Ivan Gerard","family":"Vos","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zun Siong","family":"Low","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannie Xue Ting","family":"Lee","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Amati","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy"},{"name":"Respiratory Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gramegna","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Respiratory Unit and Cystic Fibrosis Adult Center, Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny H.","family":"Wong","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine and"},{"name":"Department of Gastroenterology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J. 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