Skin Lipid–Microbe Interplay Links Staphylococcus hominis to Barrier Control in Adult Atopic Dermatitis

BACKGROUND: Skin surface lipids and commensal microbes are essential for the epidermal barrier, but their mutual interactions remain poorly understood. METHODS: We conducted high-resolution shotgun lipidomics of tape strips from lesional and non-lesional atopic dermatitis (AD) skin and healthy controls. Lipidomic data were integrated with 16S amplicon sequencing to construct lipid-microbe interaction networks. RESULTS: AD skin showed disease-specific lipid-microbe correlations, with less diverse interactions in lesional compared to non-lesional and healthy skin. Staphylococcus hominis (S. hominis) negatively correlated with non-hydroxy-dehydrosphingosine (NdS) 18:0;2/24:0;0 and positively with diacylglycerol (DAG) 18:1;0_18:1;0 and DAG 16:0;0_18:1;0. In vitro co-cultures of reconstructed human epidermis (RHE) with AD skin-derived T cell supernatant (TCS) and S. hominis reduced RHE thickness, spongiosis, and NdS 18:0;2/24:0;0 levels. Furthermore, S. hominis directly lowered NdS 18:0;2/24:0;0 levels in lesional AD skin tape samples, and reversed type 2 inflammation and lipid metabolism gene expression in TCS-stimulated RHE. CONCLUSIONS: These findings identify S. hominis as a key regulator of lipid-microbe interactions in AD, influencing epidermal inflammation and differentiation.