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.
Highlights
The primary driver of bile aspiration in respiratory patients is a condition called gastro-oesophageal reflux disease (GERD)
In order to understand the mechanism involved in the chronic response of respiratory pathogens and host cells to aspirated bile, we undertook a systems based analysis, focusing initially on P. aeruginosa, the primary pathogen associated with morbidity and mortality in CF patients
Gene ontology and KEGG analysis of altered gene expression broadly revealed elevated levels of genes involved in energy production and metabolism, redox control, and cell envelope biogenesis, while those involved in intracellular trafficking and secretion as well as amino acid metabolism were suppressed in response to bile (Supplementary Table S1)
Summary
The primary driver of bile aspiration in respiratory patients is a condition called gastro-oesophageal reflux disease (GERD). Longitudinal analysis of the paediatric CF microbiome revealed characteristic aspirating and non-aspirating profiles, while phenotypic analysis of the isolates from these patients revealed a largely conserved response to physiologically relevant concentrations of bile, evidence of phenotypic heterogeneity was observed. These data suggest that bile acid signalling may play a previously unforeseen central role in disease progression and antibiotic tolerance in respiratory disease patients
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