AbstractAtopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored.

摘要特应性皮炎（AD）是一种慢性炎症性皮肤病，影响全球数千万人。代谢物与AD病理之间的因果关系尚未正式指出，代谢物影响AD的介导机制尚未探索。

This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD.

本研究旨在确定代谢物与AD之间的遗传关系，并确定氨基酸代谢物影响AD的途径。荟萃分析使用METAL软件整合了多个GWAS分析的结果。使用双向双样本孟德尔随机化（MR），我们分析了代谢物与AD之间的因果关系。

The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity.

因果效应的主要MR检验是使用逆方差加权回归进行的，我们使用反向MR分析来排除反向因果关系。我们还进行了MR-PRESSO测试以检测和校正可能的多效性，并使用Cochran Q测试来评估异质性。

Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells.

两步MR用于分析氨基酸代谢物与AD发病之间的介导因素。使用edgeR和GSVA软件包分析介导因素（炎性蛋白S100A12）与免疫细胞浸润之间的相关性。使用来自AD患者皮肤组织的单细胞测序数据，我们研究了S100A12基因在免疫细胞中的调节作用。

Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically as.

使用多个药物数据库和大分子对接来搜索S100A12靶向药物。双向双样本MR分析表明，22种代谢物和1种炎症蛋白（S100A12）与AD发病机制显着相关。S100A12是氨基酸代谢物（N6-甲基赖氨酸；N2-乙酰基，N6，N6-二甲基赖氨酸和N6，N6-二甲基赖氨酸）的介质，其在遗传上是as。

IntroductionAD is a common, chronic inflammatory skin disease, and patients with AD typically exhibit recurrent eczema and severe itching of the skin1. In the United States, approximately one-quarter of adults with AD develop symptoms in adulthood2. The pathogenesis of AD is quite elusive and complex.

引言AD是一种常见的慢性炎症性皮肤病，AD患者通常表现出复发性湿疹和严重的皮肤瘙痒1。在美国，大约四分之一的AD成年人在成年后出现症状2。AD的发病机制非常难以捉摸和复杂。

Some suspect that this may be caused by a combination of genetic and environmental factors that lead to skin barrier dysfunction and abnormal immune responses3,4. Metabolites are intermediates or end products of metabolic reactions that affect disease pathogenesis. Recent studies have shown that AD may be associated with metabolic disorders, including central obesity, diabetes, dyslipidemia and hypertension5,6.Amino acid metabolites are related to the onset of AD.

一些人怀疑这可能是由遗传和环境因素共同导致的，这些因素导致皮肤屏障功能障碍和异常免疫反应3,4。代谢物是影响疾病发病机制的代谢反应的中间体或终产物。最近的研究表明，AD可能与代谢紊乱有关，包括中枢性肥胖，糖尿病，血脂异常和高血压5,6。氨基酸代谢物与AD的发病有关。

Tryptophan metabolites facilitate the resolution of skin inflammation in AD by restoring the barrier function of the epithelium and regulating immune and inflammatory responses by modulating the activation, survival, proliferation and differentiation of immune cells7. Bifidobacterium longum-mediated tryptophan metabolism relieves AD symptoms by activating the AHR-driven immune response8.Metabolites often play a role in the immune response by affecting related inflammatory factors and inflammatory proteins.

色氨酸代谢物通过恢复上皮的屏障功能并通过调节免疫细胞的活化，存活，增殖和分化来调节免疫和炎症反应，从而促进AD中皮肤炎症的消退7。长双歧杆菌介导的色氨酸代谢通过激活AHR驱动的免疫应答来缓解AD症状8。代谢物通常通过影响相关的炎症因子和炎症蛋白在免疫应答中发挥作用。

An association between metabolism and immunity has been reported since the 1960s9. In recent years, some studies have further demonstrated the interaction between metabolic pathways and the immune response10. For example, glutamate participates in multiple immune responses by promoting the polarization of macrophages in response to IL-4 stimulation11.Circulating inflammatory proteins participate in the pathogenesis of various diseases such as autoimmune diseases by mediating abnormal inflammatory responses.

自20世纪60年代以来，已经报道了代谢与免疫之间的关联9。近年来，一些研究进一步证明了代谢途径与免疫反应之间的相互作用10。例如，谷氨酸通过促进巨噬细胞对IL-4刺激的极化来参与多种免疫反应11。循环炎症蛋白通过介导异常炎症反应参与各种疾病如自身免疫性疾病的发病机制。

The.

的。

Data availability

数据可用性

The data used in this study are all publicly available. The FinnGen dataset (https://www.finngen.fi/en). The UK Biobank (http://www.nealelab.is/blog/2017/7/19/rapid-gwas-of-thousands-of-phenotypes-for-337000-samples-in-the-uk-biobank). The genetic variants for 91 circulating inflammatory proteins were obtained from the EBI GWAS Catalog (Accession Numbers GCST90274758–GCST90274848).

这项研究中使用的数据都是公开的。FinnGen数据集(https://www.finngen.fi/en)。英国生物库(http://www.nealelab.is/blog/2017/7/19/rapid-gwas-of-thousands-of-phenotypes-for-337000-samples-in-the-uk-biobank)。91种循环炎症蛋白的遗传变异来自EBI GWAS目录（登录号GCST90274758–GCST90274848）。

The summary data of GWAS of the plasma metabolome were obtained from EBI GWAS Catalog (accession numbers GCST90199621-90201020). The transcriptome sequencing data of AD from the GSE193309 dataset. The other data is provided within the manuscript or supplementary information files..

血浆代谢组的GWAS汇总数据来自EBI GWAS目录（登录号GCST90199621-90201020）。来自GSE193309数据集的AD转录组测序数据。其他数据在手稿或补充信息文件中提供。。

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Download referencesAcknowledgementsWe thank all participants and investigator involved in the UK Biobank, the FinnGen study, Yiheng Chen et al. and Jinghua Zhao et al. for providing GWAS summary statistics.FundingThis work is supported by National Natural Science Foundation of China (82374321).Author informationAuthor notesThese authors contributed equally: Yaqi Zhang and Heng Xu.Authors and AffiliationsSchool of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, ChinaYaqi Zhang, Yang Tang, Yuhang Li & Fengjie ZhengSchool of Life Sciences, Beijing University of Chinese Medicine, Beijing, ChinaHeng XuAuthorsYaqi ZhangView author publicationsYou can also search for this author in.

下载参考文献致谢我们感谢英国生物库，芬根研究，陈一恒等人和赵京华等人提供GWAS汇总统计数据的所有参与者和研究者。资助这项工作得到了国家自然科学基金（82374321）的支持。作者信息作者注意到这些作者做出了同样的贡献：张亚奇和徐恒。作者和附属机构北京中医药大学中医学院，北京中医药大学生命科学学院，北京中医药大学，北京中医药大学，北京中医药大学，北京中医药大学，北京中医药大学，北京中医药大学。

PubMed Google ScholarHeng XuView author publicationsYou can also search for this author in

PubMed Google ScholarHeng XuView作者出版物您也可以在

PubMed Google ScholarYang TangView author publicationsYou can also search for this author in

PubMed Google ScholarYang TangView作者出版物您也可以在

PubMed Google ScholarYuhang LiView author publicationsYou can also search for this author in

PubMed Google ScholarYuhang LiView作者出版物您也可以在

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PubMed Google ScholarContributionsAll authors contributed to the study conception and design. Y.Z. and H.X. were responsible for data collection. Y.Z., H.X. and Y.T. were responsible for data analysis. Y.Z., H.X. and Y.T. were responsible for data visualization communications.

PubMed谷歌学术贡献所有作者都为研究概念和设计做出了贡献。Y、 Z.和H.X.负责数据收集。Y、 Z.，H.X.和Y.T.负责数据分析。Y、 Z.，H.X.和Y.T.负责数据可视化通信。

Y.L. and F.Z. were responsible for the control of the subject matter. Y.L. and F.Z. were responsible for writing. All authors have read and approved the final version of the manuscript and consent to its publication.Corresponding authorsCorrespondence to.

Y、 L.和F.Z.负责控制主题。Y、 L.和F.Z.负责写作。所有作者均已阅读并批准稿件的最终版本，并同意其出版。通讯作者通讯。

Yuhang Li or Fengjie Zheng.Ethics declarations

余杭李或郑凤杰。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

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这项研究不需要机构审查委员会的批准，因为它仅基于已发布或公开可用的数据。

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Reprints and permissionsAbout this articleCite this articleZhang, Y., Xu, H., Tang, Y. et al. The levels of amino acid metabolites in serum induce the pathogenesis of atopic dermatitis by mediating the inflammatory protein S100A12.

转载和许可本文引用本文Zhang，Y.，Xu，H.，Tang，Y。等人。血清中氨基酸代谢物的水平通过介导炎症蛋白S100A12诱导特应性皮炎的发病机制。

Sci Rep 14, 23435 (2024). https://doi.org/10.1038/s41598-024-74522-1Download citationReceived: 16 March 2024Accepted: 26 September 2024Published: 08 October 2024DOI: https://doi.org/10.1038/s41598-024-74522-1Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

科学报告1423435（2024）。https://doi.org/10.1038/s41598-024-74522-1Download引文收到日期：2024年3月16日接受日期：2024年9月26日发布日期：2024年10月8日OI：https://doi.org/10.1038/s41598-024-74522-1Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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KeywordsMendelian randomizationMediation analysisAtopic dermatitisMetabolitesInflammatory proteins

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