Bile signalling promotes chronic respiratory infections and antibiotic tolerance

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dc.contributor.authorReen, F. Jerry
dc.contributor.authorFlynn, Stephanie
dc.contributor.authorWoods, David F.
dc.contributor.authorDunphy, Niall
dc.contributor.authorNí Chróinín, Muireann
dc.contributor.authorMullane, David
dc.contributor.authorStick, Stephen
dc.contributor.authorAdams, Claire
dc.contributor.authorO'Gara, Fergal
dc.contributor.funderEuropean Commission
dc.contributor.funderScience Foundation Ireland
dc.contributor.funderDepartment of Agriculture, Food and the Marine
dc.contributor.funderIrish Research Council for Science, Engineering and Technology
dc.contributor.funderHealth Research Board
dc.contributor.funderMarine Institute
dc.contributor.funderTeagasc
dc.contributor.funderIrish Thoracic Society
dc.date.accessioned2017-06-22T13:55:53Z
dc.date.available2017-06-22T13:55:53Z
dc.date.issued2016-07-19
dc.description.abstractDespite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease.en
dc.description.sponsorshipScience Foundation Ireland (SSPC-2, 12/RC/2275; 13/TIDA/B2625; 12/TIDA/B2411; 12/TIDA/B2405; 14/TIDA/2438); Department of Agriculture, Food and the Marine (FIRM/RSF/CoFoRD; FIRM 08/RDC/629; FIRM 1/F009/MabS; FIRM 13/F/516); Irish Research Council for Science, Engineering and Technology (PD/2011/2414; GOIPG/2014/647); Health Research Board/Irish Thoracic Society (MRCG-2014-6), Marine Institute (Beaufort award C2CRA 2007/082); Teagasc (Walsh Fellowship 2013).en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid29768
dc.identifier.citationReen, F. J., Flynn, S., Woods, D. F., Dunphy, N., Chróinín, M. N., Mullane, D., Stick, S., Adams, C. and O’Gara, F. (2016) 'Bile signalling promotes chronic respiratory infections and antibiotic tolerance', Scientific Reports, 6, 29768 (14pp). doi: 10.1038/srep29768en
dc.identifier.doi10.1038/srep29768
dc.identifier.endpage14
dc.identifier.issn2045-2322
dc.identifier.journaltitleScientific Reportsen
dc.identifier.startpage1
dc.identifier.urihttps://hdl.handle.net/10468/4167
dc.identifier.volume6
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/607786/EU/BluePharmTrain/BLUEPHARMTRAIN
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::KBBE/312184/EU/Increasing Value and Flow in the Marine Biodiscovery Pipeline/PHARMASEA
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::KBBE/311975/EU/Marine Microorganisms: Cultivation Methods for Improving their Biotechnological Applications/MACUMBA
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::KBBE/287589/EU/Marine Microbial Biodiversity, Bioinformatics and Biotechnology/MICRO B3
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/256596/EU/Dissecting the role of a novel transcriptional regulator in microbial-host interactomes./MEXT REGULATION
dc.relation.projectinfo:eu-repo/grantAgreement/EC/H2020::IA/634486/EU/Industrial Applications of Marine Enzymes: Innovative screening and expression platforms to discover and use the functional protein diversity from the sea/INMARE
dc.relation.urihttps://www.nature.com/articles/srep29768
dc.rights© 2016, Reen et al. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectInfectionen
dc.subjectPathogensen
dc.titleBile signalling promotes chronic respiratory infections and antibiotic toleranceen
dc.typeArticle (peer-reviewed)en
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