title: Bile signalling promotes chronic respiratory infections and antibiotic tolerance.
abstract: Despite 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.
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland.
authors.forename: F Jerry
authors.initials: FJ
authors.lastname: Reen
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Flynn
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland.
authors.forename: David F
authors.initials: DF
authors.lastname: Woods
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland.
authors.forename: Niall
authors.initials: N
authors.lastname: Dunphy
authors.affiliation: Paediatric Cystic Fibrosis Unit, Cork University Hospital, Cork, Ireland.
authors.forename: Muireann Ní
authors.initials: MN
authors.lastname: Chróinín
authors.affiliation: Paediatric Cystic Fibrosis Unit, Cork University Hospital, Cork, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Mullane
authors.affiliation: Telethon Kids Institute, Perth, Western Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Stick
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Adams
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland.|Telethon Kids Institute, Perth, Western Australia.|School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
authors.forename: Fergal
authors.initials: F
authors.lastname: O'Gara
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000378:metabolism / Q000494:pharmacology*; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000150:complications; D004361:Drug Tolerance / Q000235:genetics; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006801:Humans; D011552:Pseudomonas Infections / Q000150:complications / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012141:Respiratory Tract Infections / Q000150:complications / Q000382:microbiology*; D013183:Sputum / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid