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

ABSTRACT 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.