Aspiration of Conjugated Bile Acids Predicts Adverse Lung Transplant Outcomes and Correlates with Airway Lipid and Cytokine Dysregulation

Introduction: Duodeno-gastroesophageal reflux aspiration is associated with chronic lung allograft dysfunction (CLAD). Reflux aspirate can contain bile acids (BA), functional molecules in the gastro-intestinal tract with emulsifying properties. We sought to determine and quantify the various BA species in airways of the lung transplant recipients to better understand the various effects of aspirated BA that contribute to post-transplantation outcomes. Methods: Bronchial washings (BW) were prospectively collected from lung transplant recipients and subsequently assayed by liquid chromatography-mass spectrometry for 13 BA and 25 lipid families. Patients were monitored for CLAD, rejection, inflammation and airway infections. Results: Detectable BA were present in 45/50 patients (90%) at 3 months after transplant. Elevated BA and predominance of conjugated species were independent predictors of CLAD (hazard ratio 7.9; 95% confidence interval 2.7-23.6; p < 0.001 and 7.3; 2.4-22; p < 0.001, respectively) and mortality (hazard ratio 4.4; 1.5-12.7; p = 0.007 and 4.8; 1.4-15.8; p = 0.01, respectively). High BA associated with increased positive bacterial cultures (60% vs 25%, p = 0.02). Primary conjugated species independently correlated with the rate of bacterial cultures during the first-year post-transplant (Beta coefficient: 0.77; 0.28-1.26; p = 0.003) and changes in airway lipidome and cytokines. Conclusions: Higher BA levels and predominance of conjugated BA are independent predictors of chronic lung allograft dysfunction, mortality and bacterial infections. Primary conjugated BA are related to distinct changes in airway lipidome and inflammatory cytokines. This elucidates novel evidence into the mechanism following BA aspiration and proposes novel markers for prediction of adverse post-transplant outcomes.