Redefining the Skin Barrier: A Microbiome‐Integrated Multilayered Defense Model

ABSTRACT The skin constitutes a dynamic interface orchestrating a sophisticated multilayered defense system comprising physical, chemical, immune, and microbial barriers. This review synthesizes current understanding of the structural and functional integration of these barriers, emphasizing their synergistic interactions in maintaining cutaneous homeostasis. The physical barrier, anchored by the stratum corneum and tight junctions, provides structural integrity, whereas the chemical barrier employs an acidic pH gradient, antimicrobial peptides (AMPs), and microbiota‐derived metabolites to create a hostile microenvironment for pathogens. Specialized epidermal immune cells, including Langerhans cells, tissue‐resident memory T‐cells (TRM), and γδ T‐cells, mediate immune surveillance and rapid response to breaches. Concurrently, the microbial barrier, governed by commensal organisms, reinforces host defense through colonization resistance or varied metabo‐/immunomodulation. Crucially, these barriers exhibit extensive crosstalk, wherein dysregulation in one system triggers cascading disruptions across others, contributing to barrier pathologies. By delineating the integrative mechanisms of skin barrier function, this review highlights the necessity for holistic approaches in managing cutaneous disorders and restoring barrier integrity.