Shotgun Metagenomics Reveals Skin Microbiome Composition and Function in Infant Atopic Disease

BACKGROUND: Atopic dermatitis (AD), food sensitization (FS), and food allergy (FA) frequently co-occur in infancy, but the factors underlying distinct atopic phenotypes remain unclear. Although FLG null mutations are major genetic risk factors for AD, they explain only part of disease heritability, suggesting a potential role for the skin microbiome. This study examined how early-life skin microbiome composition and its interaction with host genetics contribute to distinct atopic phenotypes in infancy. METHODS: We analyzed > 1000 skin swabs from 429 infants in the VITALITY cohort using deep shotgun metagenomic sequencing at 2-3 months (pre-diagnosis) and 12 months (post-diagnosis). Differential abundance, strain-level, and microbial genome-wide association analyses were performed to identify taxonomic and functional features associated with AD, FS, FA, their co-occurrence, and FLG mutation status. RESULTS: Within AD, microbial signatures differed by co-occurring FA or FS. At 12 months, Staphylococcus epidermidis was enriched in infants with AD alone, whereas infants with AD and FA showed decreased Staphylococcus hominis and Lactococcus species, and increased Dermacoccus nishinomiyaensis and Malassezia slooffiae. At 2-3 months, early skin dysbiosis characterized by enrichment of Staphylococcus species was associated with later development of AD with FS or FA, but not AD alone. Among infants with AD, FLG mutation carriers showed additional microbial shifts, including reduced Streptococcus species and increased M. slooffiae. Strain-level analyses revealed mother-infant sharing of AD-associated taxa, and microbial genome-wide association analyses identified species-specific genes linked to AD severity. CONCLUSIONS: Infant atopic phenotypes are associated with distinct, phenotype-specific skin microbiome features that emerge before and after disease onset, highlighting the microbiome as a potential target for early risk stratification.