Table_1_Longitudinal Metabolomics Reveals Ornithine Cycle Dysregulation Correlates With Inflammation and Coagulation in COVID-19 Severe Patients.docx

COVID-19 is a severe disease in humans, as highlighted by the current global pandemic. Several studies about the metabolome of COVID-19 patients have revealed metabolic disorders and some potential diagnostic markers during disease progression. However, the longitudinal changes of metabolomics in COVID-19 patients, especially their association with disease progression, are still unclear. Here, we systematically analyzed the dynamic changes of the serum metabolome of COVID-19 patients, demonstrating that most of the metabolites did not recover by 1–3 days before discharge. A prominent signature in COVID-19 patients comprised metabolites of amino acids, peptides, and analogs, involving nine essential amino acids, 10 dipeptides, and four N-acetylated amino acids. The levels of 12 metabolites in amino acid metabolism, especially three metabolites of the ornithine cycle, were significantly higher in severe patients than in mild ones, mainly on days 1–3 or 4–6 since onset. Integrating blood metabolomic, biochemical, and cytokine data, we uncovered a highly correlated network, including 6 cytokines, 13 biochemical parameters, and 49 metabolites. Significantly, five ornithine cycle-related metabolites (ornithine, N-acetylornithine, 3-amino-2-piperidone, aspartic acid, and asparagine) highly correlated with “cytokine storms” and coagulation index. We discovered that the ornithine cycle dysregulation significantly correlated with inflammation and coagulation in severe patients, which may be a potential mechanism of COVID-19 pathogenicity. Our study provided a valuable resource for detailed exploration of metabolic factors in COVID-19 patients, guiding metabolic recovery, understanding the pathogenic mechanisms, and creating drugs against SARS-CoV-2 infection.

COVID-19是一种严重的人类疾病，正如当前全球大流行所凸显的那样。已有多项针对COVID-19患者代谢组（metabolome）的研究，揭示了疾病进展过程中的代谢紊乱与若干潜在诊断标志物。然而，COVID-19患者代谢组的纵向变化，尤其是其与疾病进展的关联，目前仍不明确。本研究系统分析了COVID-19患者血清代谢组的动态变化，结果显示多数代谢物在患者出院前1~3天仍未恢复正常。COVID-19患者的一项显著代谢特征涵盖氨基酸、肽及其类似物类代谢物，包括9种必需氨基酸、10种二肽以及4种N-乙酰化氨基酸。在发病后第1~3天或第4~6天，重症患者体内12种氨基酸代谢相关代谢物的水平显著高于轻症患者，其中尤以3种鸟氨酸循环（ornithine cycle）相关代谢物为甚。通过整合血液代谢组学、生化指标与细胞因子数据，本研究揭示了一个高度关联的网络，涵盖6种细胞因子、13项生化参数以及49种代谢物。值得注意的是，5种与鸟氨酸循环相关的代谢物（鸟氨酸、N-乙酰鸟氨酸、3-氨基-2-哌啶酮、天冬氨酸与天冬酰胺）与"细胞因子风暴"及凝血指标显著相关。本研究发现，重症患者体内的鸟氨酸循环失调与炎症反应及凝血功能异常显著相关，这或为COVID-19致病机制的潜在一环。本研究为深入探究COVID-19患者的代谢相关因素提供了宝贵的研究资源，可为代谢康复、阐明致病机制以及研发抗SARS-CoV-2感染的药物提供重要指导。