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Functional studies of how early-life interventions shape the airway microbiome remain scarce. Here, we performed metagenomic sequencing of 704 longitudinal nasal swabs from infants with and without cystic fibrosis (CF) to construct and characterize a non-redundant gene atlas of the infant nasal microbiome. We aimed to determine how the nasal microbiome is perturbed by early therapies, as CF is commonly treated with inhaled hypertonic saline to improve mucociliary clearance. We found functional and compositional microbiome changes linked to inhalation therapy, including an expansion of salt-associated transporter genes and a community shift toward CF-associated microbial opportunists, including Haemophilus influenzae and fungi, carrying the identified salt-associated transporter genes with high sequence and structural identity. Hypertonic, compared with isotonic, saline accelerates H. influenzae growth and induces efflux pumps linked to antibiotic tolerance in vitro. This study establishes a reference framework for functional airway microbiome research, enabling the examination of therapeutic perturbations and their impact on microbial adaptation.