Marked depletion of non-canonical sphingolipids in atopic dermatitis reveals an understudied lipid class with potential roles in skin barrier function

Summary: Sphingoid bases, particularly long-chain free forms, are an underexplored lipid class, yet their dysregulation may underlie atopic dermatitis (AD), a chronic inflammatory disease characterized by barrier dysfunction, immune dysregulation, and microbial dysbiosis. This study examines the abundance and diversity of long-chain sphingoid bases (LCBs) in healthy and AD skin. Using D-Squame tape discs, we collected stratum corneum samples from five AD patients (lesional and non-lesional skin) and four healthy controls, followed by methanol-based lipid extraction and LC-MS/MS analysis. In healthy skin, these non-canonical LCBs were highly abundant, exceeding canonical species by over 90-fold (p < 0.01). These novel LCBs were predominantly free rather than intermediates in sphingolipid biosynthesis, unlike typical sphingoid bases, suggesting a distinct functional role. In AD, levels of these non-canonical LCBs were significantly reduced, with certain classes of free LCBs showing up to a sevenfold decrease in lesional skin compared to non-lesional skin (p < 0.05). These findings identify a previously understudied class of LCBs as a novel, abundant, and free lipid class in healthy skin, with marked depletion in AD lesions, highlighting their potential role in barrier integrity and expanding our understanding of AD pathogenesis. Matthew J. Kolar^{1, 2}, Tegan Nguyen¹, Richard L. Gallo², Christian Metallo¹ 1. Salk Institute for Biological Studies, La Jolla, CA, United States. 2. Department of Dermatology, University of California San Diego, La Jolla, CA, United States. Epidermal Structure and Barrier Function