BACKGROUND Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood. OBJECTIVE We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity. METHODS We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases-funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures. RESULTS S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C16:0→C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S aureus abundance and ELOVL6 expression by day 21. CONCLUSION CERS1 is a unique molecular biomarker of S aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter-chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6.

中文翻译：

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CERS1 是金黄色葡萄球菌丰度和特应性皮炎严重程度的生物标志物。


背景 特应性皮炎 （AD） 是一种炎症性皮肤病，其特征是皮肤金黄色葡萄球菌数量变化很大，导致疾病严重并对 2 型免疫阻断（即 dupilumab）有快速反应。调节 AD 受试者之间金黄色葡萄球菌水平的分子机制仍然知之甚少。目的 我们研究了可能预测金黄色葡萄球菌丰度并与 AD 严重程度相对应的宿主基因。方法 我们研究了来自美国国立卫生研究院/国家过敏和传染病研究所资助 （NCT03389893 [ADRN-09]） 的随机、双盲、安慰剂对照多中心研究的数据，该研究在成人 （n = 71 名受试者） 中度至重度 AD 中。将皮肤活检样本 （n = 57 个病灶，55 个非病灶） 的大量 RNA 测序与表皮金黄色葡萄球菌丰度、脂质组学和 AD 临床测量进行比较。结果金黄色葡萄球菌丰度和神经酰胺合酶 1 （CERS1） 表达在非病变 （r = 0.29， P = .030） 和病变 （r = 0.41， P = .0015） 皮肤中呈正相关。病变 CERS1 表达也与 AD 严重程度 （即 SCORAD r = 0.44，P = .0006） 和皮肤屏障功能障碍 （曲线下经表皮失水面积 r = 0.31，P = .025） 呈正相关。CERS1 表达（C18：0 鞘脂形式）与超长链脂肪酸的伸长呈负相关 （ELOVL6;C16：0→C18：0） 表达，并与较短的链长鞘脂组成相对应。Dupilumab 迅速降低 CERS1 表达（第 7 天），并在第 21 天消融与金黄色葡萄球菌丰度和 ELOVL6 表达的关系。 结论 CERS1 是金黄色葡萄球菌丰度和 AD 严重程度的独特分子生物标志物，可能通过脂肪酸隔离作为对减少的 ELOVL6 的适应不良代偿反应，导致皮肤屏障功能障碍和短链鞘脂组成。