背景：痤疮是一种常见的慢性炎症性皮肤病，可引起患者不适、损容，更可产生焦虑、抑郁等不良心理社会负担。目前研究已明确，皮脂分泌过多和皮肤菌群失调参与痤疮的发生发展，但皮肤表面脂质（skin surface lipids, SSLs）与皮肤微生物之间的相互作用研究较少。在临床治疗方面，口服异维A酸推荐用于治疗重度痤疮及其他常规治疗无效的患者，其治疗能够显著减少皮脂分泌并间接抑制痤疮丙酸杆菌生长，但其对SSLs和微生物的影响尚有待研究。

目的：本研究旨在通过多组学联合分析，探讨中重度寻常痤疮患者皮肤表面脂质及微生物组的特征及其相互作用、脂质异常与微生物失调在痤疮发病机制中的作用，评估异维A酸治疗对皮肤脂质和菌群的调控效果，为揭示痤疮发病机制及优化治疗策略提供理论依据。

方法：纳入21例中重度痤疮患者和20例健康对照，通过超高效液相色谱-串联质谱进行SSLs绝对定量脂质组学分析，同时应用16S rRNA基因测序技术分析皮肤微生物组。中重度痤疮患者口服异维A酸治疗8周后，对比性研究其治疗前后SSLs、微生物及临床指标的变化。采用主成分分析、正交偏最小二乘法判别分析、Metastats、线性判别分析与Spearman相关性分析，筛选差异脂质、菌群，并评估其相关性。

结果：脂质组学分析结果显示，痤疮患者与对照组相比，神经酰胺（Cer）、甘油二酯（DG）、磷脂酰乙醇胺（PE）和甘油三酯（TG）较健康对照者显著升高。其中，Cer、DG和PE仅在女性痤疮患者中显著升高，而TG仅在男性患者中显著升高。微生物组研究结果显示，痤疮组差异菌属包括葡萄球菌属（Staphylococcus）、拟杆菌属（Bacteroides）、瘤胃球菌属（Ruminococcus）、异杆菌属（Allobaculum）和副普雷沃菌属（Paraprevotella）等显著升高。皮肤脂质变化与微生物变化的相关性分析显示，痤疮患者的拟杆菌属和瘤胃球菌属与Cer (d18:2/16:0(2OH))和Cer (t18:0/24:1(2OH))呈正相关，而在对照组中呈负相关。葡萄球菌属在健康对照中与多种脂质显著相关，但在痤疮患者中未观察到类似关联。共20例中重度患者完成异维A酸治疗8周随访，脂质组学分析结果显示，SSLs总量显著降低约67%，TG、DG、游离脂肪酸（FFA）、胆固醇脂（CE）等显著减少，磷脂酰丝氨酸（PS）等显著上调，Cer(d18:2/40:2(2OH))的含量正常化。微生物组研究结果显示，微生物α多样性显著提升，皮肤杆菌属（Cutibacterium）、拟杆菌属、罗尔斯通菌属（Ralstonia）等丰度降低，链球菌属（Streptococcus）、芬戈尔德菌属（Finegoldia）、嗜胨菌属（Peptoniphilus）和卟啉单胞菌属（Porphyromonas）等丰度增加，异杆菌属和副普雷沃菌属恢复至正常水平。异维A酸治疗后SSLs变化与微生物变化之间的相关性分析揭示，芬戈尔德菌属与DG正相关，嗜胨菌属、卟啉单胞菌属和罗尔斯通菌属均与TG正相关。

结论：本研究通过多组学联合分析证明脂质代谢紊乱与微生物失调在痤疮发病机制中发挥关键作用。与对照组相比，痤疮组的Cer、DG、PE及TG显著升高，拟杆菌属、瘤胃球菌属等菌群丰度升高且与特定神经酰胺分子呈正相关。异维A酸治疗可重塑SSLs组成和皮肤微生物组成，下调TG、DG、FFA、CE等脂质，并通过调控皮肤杆菌属等关键菌群恢复微生物多样性，为痤疮精准治疗提供了新的思路与依据。

Background: Acne is a common chronic inflammatory skin disease that can cause discomfort and cosmetic damage to patients, as well as lead to adverse psychosocial burdens such as anxiety and depression. Current research has confirmed that excessive sebum production and skin microbiota dysbiosis are involved in the pathogenesis of acne. However, there remains a knowledge gap regarding the interaction between skin surface lipids (SSLs) and skin microorganisms. Clinically, oral isotretinoin is recommended for severe acne and patients who do not respond to conventional therapies. It significantly reduces sebum secretion and indirectly inhibits the growth of Cutibacterium acnes, but the exact mechanism of its therapeutic effect on acne remains unclear.

Objective: Acne vulgaris is a common inflammatory skin disease with a multifactorial pathogenesis involving excessive sebum production and skin dysbiosis. This study aimed to characterize SSLs and microbiome profiles in patients with moderate-to-severe acne through multi-omics analysis, investigate the roles of lipid abnormalities and microbial dysbiosis in acne pathogenesis, and evaluate the regulatory effects of isotretinoin treatment on skin lipids and microbiota, thereby providing a theoretical basis for elucidating acne mechanisms and optimizing therapeutic strategies.

Methods: A total of 21 patients with moderate-to-severe acne and 20 healthy controls were enrolled. Absolute quantitative lipidomics of SSLs was performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), while skin microbiome composition was analyzed using 16S rRNA gene sequencing. Changes in SSLs, microbiota, and clinical parameters before and after 8 weeks of oral isotretinoin treatment in patients with moderate-to-severe acne were comparatively studied. Principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), KEGG pathway enrichment, and Spearman correlation analysis were employed to identify differential lipids, microbiota, and their interactions.

Results: Acne patients exhibited significant alterations in lipid composition, with elevated levels of ceramide (Cer), diacylglycerol (DG), phosphatidylethanolamine (PE), and triglyceride (TG) compared to healthy controls. Cer, DG, and PE were significantly increased only in female acne patients, whereas TG was elevated only in male patients. Differential microbial taxa in acne patients included increased Staphylococcus, Bacteroides, Ruminococcus, Allobaculum, and Paraprevotella. The correlation analysis of skin lipid alterations with the microbiome showed that in acne patients, Bacteroides and Ruminococcus were positively correlated with Cer (d18:2/16:0(2OH)) and Cer (t18:0/24:1(2OH)) while in the control group, they showed a negative correlation. Staphylococcus exhibited a significant correlation with several lipids in healthy controls but not in acne patients. A total of 20 patients with moderate-to-severe acne completed the 8-week follow-up of isotretinoin treatment. Lipidomics analysis revealed that the total amount of SSLs was significantly reduced by approximately 67%, with significant reductions in TG, DG, free fatty acids (FFA), and cholesteryl esters (CE), while phosphatidylserine (PS) increased. The content of Cer(d18:2/40:2(2OH)) was normalized. Microbial α-diversity significantly improved. The relative abundance of Cutibacterium, Bacteroides, and Ralstonia decreased significantly, while that of Streptococcus, Finegoldia, Peptoniphilus, and Porphyromonas showed a significant increase. The relative abundances of Allobaculum and Paraprevotella was normalized. Correlation analysis revealed significant positive associations of Finegoldia with DG, and of Cutibacterium, Peptoniphilus, Porphyromonas and Ralstonia with TG.

Conclusion: This study revealed the abnormal characteristics of skin surface lipids and the microbiome and their correlations in patients with moderate to severe acne through a combined analysis of multi-omics. It demonstrated that lipid metabolic disorders and microbial dysregulation play a key role in the pathogenesis of acne. Compared with the control group, the levels of Cer, DG, PE, and TG in the acne group were significantly elevated. The abundances of bacterial groups such as Bacteroides and Ruminococcus increased and were positively correlated with specific ceramide molecules. Isotretinoin treatment can reshape the composition of SSLs and the skin microbiome, downregulate lipids such as TG, DG, FFA, and CE, and restore microbial diversity by regulating key bacterial groups such as Cutibacterium, providing new targets and a theoretical basis for the precision treatment of acne.