Early life elevations of methionine oxidation and ornithine track and predict cystic fibrosis structural lung disease.

Introduction: Early cystic fibrosis (CF) lung disease monitoring is crucial for understanding responses to therapy and preventing progressive pulmonary decline. Structural lung disease (SLD) is a major cause of pulmonary decline in CF. We aimed to identify metabolites in CF bronchoalveolar lavage (BAL) associated with and predictive of SLD. Methods: We applied untargeted metabolomics to 84 BAL samples from a cross-sectional cohort of 67 clinically stable children with CF aged 1-5 years across two sites. We used a linear mixed-effects model to select metabolites associated with SLD, BAL neutrophils, and myeloperoxidase (MPO) and neutrophil elastase (NE) activities. An independent longitudinal cohort of infants who either did or did not exhibit bronchiectasis by age 9 years was analysed to determine whether metabolites associated with SLD could also predict future lung disease. Results: In the cross-sectional cohort, 10 BAL metabolites, including methionine sulfoxide (MetO), ornithine and Conclusions: We identified BAL metabolites associated with SLD, MPO and NE, detectable in the earliest stages of CF. MetO, %OxMet, NAcMet and ornithine predicted bronchiectasis development, outperforming established biomarkers. These metabolites reflect oxidising, proteolytic and other enzymatic activities of neutrophils, highlighting potential therapeutic avenues.