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Bile Acids as a host trigger of Chronic infecting Pathogens in Respiratory Disease

A major cause of respiratory deterioration and disease progression in persistent lung conditions is the onset of acute exacerbations. Multiple factors may underpin the nature of these complications, but changes in the composition of the lung microbiota towards a pathogen-dominated community are frequently associated with these flare-up events. The pathogenesis of these complications still remains unknown.
Gastro-oesophageal reflux (GOR) is a highly prevalent condition in patients suffering with chronic respiratory disease. Intriguingly, in disorders influencing the respiratory tract, co-occurrence of GOR is associated with a higher number of hospital admissions and higher exacerbation rates. This suggests that intrinsic factors in the gastric refluxate may influence the prognosis of the disease.
We have observed that the presence of bile salts in the lungs of patients diagnosed with cystic fibrosis are positively associated with a reduction in the microbial diversity and an increase in respiratory pathogens and inflammatory markers. We also demonstrated that bile acids stimulate the formation of biofilms and antibiotic tolerance in typical airway pathogens such as Pseudomonas. Bile may therefore participate as an initial trigger of exacerbations and the downhill progression leading to chronic respiratory diseases.
This research programme aims to establish whether reduction of bile salts in the lungs is associated with a healthy lung microbiota, reduced inflammation and better disease outcomes. We will co-analyse bile acids and lung microbiota in the ongoing COMBAT-CF study, a placebo-controlled trial with azithromycin, an antibiotic known to also reduce GOR. The longitudinal nature of this study will provide a robust proof-of-concept for translation into other prevalent chronic disorder such as COPD. Using animal models, we will determine cause and effect mechanisms and validate innovative strategies for the prevention of chronic persistent fungal infections in respiratory disease.This research will add new clinical solutions to address the pathophysiology of chronic respiratory conditions.