Bacterial communities co-develop with respiratory immunity early in life, linking dysbiosis to systemic monocyte signature and wheezing

Early microbial colonization influences respiratory disease risk, yet mechanisms remain unclear. In a prospective birth cohort of 256 infants, we profiled bacterial, fungal, and viral communities in the upper airway and assessed local immune gene expression longitudinally, and systemic gene expression at one year. Bacterial populations, not fungal or viral, correlated most strongly with immune development during the first three months, coinciding with composition shifts and immune-related gene expression changes, including interferon and adaptive immunity pathways. In contrast, the mycobiome and resident viruses showed no significant co-evolution with host immunity. By one year, infants who previously wheezed displayed an upper airway microbiota enriched in Haemophilus influenzae and Moraxella, accompanied by a distinct local and systemic immune gene signature featuring elevated classical monocyte-related genes. These
findings reveal a specific link between early-life bacterial dysbiosis, monocyte-related immunity, and wheezing onset, suggesting potential targets for early intervention in respiratory disease.