Patients with rheumatoid arthritis (RA) commonly experience a high prevalence of multiple metabolic diseases (MD), leading to higher morbidity and premature mortality. Here, we aimed to investigate the pathogenesis of MD in RA patients (RA_MD) through an integrated multi-omics approach. Fecal and blood samples were collected from a total of 181 subjects in this study for multi-omics analyses, including 16S rRNA and internally transcribed spacer (ITS) gene sequencing, metabolomics, transcriptomics, proteomics and phosphoproteomics. Spearman’s correlation and protein-protein interaction networks were used to assess the multi-omics data correlations. The Least Absolute Shrinkage and Selection Operator (LASSO) machine learning algorithm were used to identify disease-specific biomarkers for RA_MD diagnosis. Our results found that RA_MD was associated with differential abundance of gut microbiota such as Turicibacter and Neocosmospora, metabolites including decreased unsaturated fatty acid, genes related to linoleic acid metabolism and arachidonic acid metabolism, as well as downregulation of proteins and phosphoproteins involved in cholesterol metabolism. Furthermore, a multi-omics classifier differentiated RA_MD from RA with high accuracy (AUC: 0.958). Compared to gouty arthritis and systemic lupus erythematosus, dysregulation of lipid metabolism showed disease-specificity in RA_MD. The integration of multi-omics data demonstrates that lipid metabolic pathways play a crucial role in RA_MD, providing the basis and direction for the prevention and early diagnosis of MD, as well as new insights to complement clinical treatment options.

中文翻译：

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整合多组学研究显示，脂质代谢失调在代谢性疾病的 RA 患者中起重要作用


类风湿性关节炎 （RA） 患者通常患有多种代谢疾病 （MD） 的高患病率，导致更高的发病率和过早死亡。在这里，我们旨在通过综合多组学方法研究 RA 患者 （RA_MD） MD 的发病机制。本研究共收集 181 名受试者的粪便和血液样本进行多组学分析，包括 16S rRNA 和内部转录间隔区 （ITS） 基因测序、代谢组学、转录组学、蛋白质组学和磷酸化蛋白质组学。使用 Spearman 相关性和蛋白质-蛋白质相互作用网络评估多组学数据相关性。使用最小绝对收缩和选择运算符 （LASSO） 机器学习算法来识别用于RA_MD诊断的疾病特异性生物标志物。我们的结果发现，RA_MD 与肠道微生物群（如 Turicibacter 和 Neocosmospora）、代谢物（包括减少的不饱和脂肪酸）、与亚油酸代谢和花生四烯酸代谢相关的基因，以及参与胆固醇代谢的蛋白质和磷蛋白的下调有关。此外，多组学分类器以高精度 （AUC： 0.958） RA_MD 与 RA 区分开来。与痛风性关节炎和系统性红斑狼疮相比，脂质代谢失调在 RA_MD 中表现出疾病特异性。多组学数据的整合表明，脂质代谢途径在 RA_MD 中起着至关重要的作用，为 MD 的预防和早期诊断提供了基础和方向，并为补充临床治疗方案提供了新的见解。