The Longitudinal Microbial and Metabolic Landscape of infant Cystic Fibrosis: The gut-lung axis.

BACKGROUND AND AIM:: In cystic fibrosis (CF), gastrointestinal dysfunction and lower airway infection occur early and are independently associated with poorer outcomes in childhood. This study aimed to define the relationship between the microbiota at each niche during the first 2-years of life, its association with growth and airway inflammation, and explanatory features in the metabolome. MATERIALS AND METHODS:Sixty-seven bronchoalveolar lavage (BAL), 62 plasma and 105 stool samples were collected from 39 infants with CF between 0-24-months who were treated with prophylactic antibiotics. 16S rRNA amplicon and shotgun metagenomic sequencing were performed on BAL and stool respectively; metabolomic analyses were performed on all sample types. Sequencing data from healthy age-matched infants were used as controls. RESULTS:Bacterial diversity increased over the first 2-years in both BAL and stool, and microbial maturation was delayed in comparison to healthy controls from the RESONANCE cohort. Correlations between their respective abundances in both sites suggest stool may serve as a non-invasive alternative for detecting BAL Pseudomonas and Veillonella. Multi-site metabolomic analyses revealed age- and growth-related changes, associations with neutrophilic airway inflammation, and a set of core systemic metabolites. BAL Pseudomonas abundance was correlated with altered stool microbiome composition and systemic metabolite alterations, highlighting a complex gut-plasma-lung interplay and new targets with therapeutic potential. CONCLUSION:Exploration of the gut-lung microbiome and metabolome reveals diverse multi-site interactions in CF that emerge in early life. Gut-lung metabolomic links with airway inflammation and Pseudomonas abundance warrant further investigation for clinical utility, particularly in non-expectorating patients.