Gao Jianping, Zhang Jian, Tang Lei
Department of Ophthalmology, The First People's Hospital of Changde City (Changde Hospital, Xiangya School of Medicine, Central South University), Changde, 415000, Hunan, China.
Department of Ophthalmology, The First People's Hospital of Changde City (Changde Hospital, Xiangya School of Medicine, Central South University), Changde, 415000, Hunan, China.
Exp Eye Res. 2025 Jul;256:110399. doi: 10.1016/j.exer.2025.110399. Epub 2025 Apr 22.
Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has emerged as a potential contributor to diabetic retinopathy (DR) progression. However, its molecular mechanisms in DR remain unclear. This study integrates network toxicology and multi-omics analyses to elucidate TMAO's role in DR pathogenesis. We identified TMAO-related targets through integration of CTD, SuperPred, and GeneCards databases. Differential expression analysis of DR-related genes was performed using GSE60436 and GSE102485 datasets. We intersected these with TMAO targets to identify key genes. Functional enrichment and pathway analyses were conducted, followed by immune cell infiltration assessment using ssGSEA. Machine learning algorithms (LASSO and RF) identified key marker genes, validated through GSE94019 dataset and in vitro experiments. Molecular docking explored interactions between TMAO and key proteins. We identified 45 TMAO-related targets implicated in DR. Functional analysis revealed enrichment in stress response and inflammatory pathways. Differential pathway analysis indicated significant upregulation of immune and apoptotic pathways in DR. Immune cell infiltration analysis showed increased levels of cytotoxic and inflammatory cells in DR. CASP3, CXCR4, and MAPK1 emerged as key marker genes, their expression significantly upregulated in PDR patients. Molecular docking highlighted stable interactions between TMAO and these proteins, suggesting potential modulation of their activity. TMAO-associated targets are enriched in inflammatory, oxidative, and apoptotic pathways in PDR tissues, suggesting a potential (but not causal) link to DR pathology. Our findings highlight the gut-retina axis in DR and provide a framework for targeting TMAO-mediated mechanisms in diabetic complications.
氧化三甲胺（TMAO）是一种由肠道微生物群产生的代谢产物，已成为糖尿病视网膜病变（DR）进展的潜在促成因素。然而，其在DR中的分子机制仍不清楚。本研究整合网络毒理学和多组学分析，以阐明TMAO在DR发病机制中的作用。我们通过整合CTD、SuperPred和GeneCards数据库确定了TMAO相关靶点。使用GSE60436和GSE102485数据集对DR相关基因进行差异表达分析。我们将这些与TMAO靶点进行交叉分析，以确定关键基因。进行功能富集和通路分析，随后使用单样本基因集富集分析（ssGSEA）评估免疫细胞浸润。机器学习算法（套索回归和随机森林）确定了关键标记基因，并通过GSE94019数据集和体外实验进行了验证。分子对接探索了TMAO与关键蛋白之间的相互作用。我们确定了45个与DR相关的TMAO靶点。功能分析显示在应激反应和炎症通路中富集。差异通路分析表明DR中免疫和凋亡通路显著上调。免疫细胞浸润分析显示DR中细胞毒性和炎症细胞水平增加。半胱天冬酶3（CASP3）、趋化因子受体4（CXCR4）和丝裂原活化蛋白激酶1（MAPK1）成为关键标记基因，它们在增殖性糖尿病视网膜病变（PDR）患者中的表达显著上调。分子对接突出了TMAO与这些蛋白之间的稳定相互作用，表明其活性可能受到调节。PDR组织中与TMAO相关的靶点在炎症、氧化和凋亡通路中富集，提示与DR病理存在潜在（但非因果）联系。我们的研究结果突出了DR中的肠-视网膜轴，并为针对糖尿病并发症中TMAO介导的机制提供了一个框架。
