DataSheet_1_Metabolic Profiling at COVID-19 Onset Shows Disease Severity and Sex-Specific Dysregulation.docx

Backgroundmetabolic changes through SARS-CoV-2 infection has been reported but not fully comprehended. This metabolic dysregulation affects multiple organs during COVID-19 and its early detection can be used as a prognosis marker of severity. Therefore, we aimed to characterize metabolic and cytokine profile at COVID-19 onset and its relationship with disease severity to identify metabolic profiles predicting disease progression.Material and Methodswe performed a retrospective cross-sectional study in 123 COVID-19 patients which were stratified as asymptomatic/mild, moderate and severe according to the highest COVID-19 severity status, and a group of healthy controls. We performed an untargeted plasma metabolic profiling (gas chromatography and capillary electrophoresis-mass spectrometry (GC and CE-MS)) and cytokine evaluation.ResultsAfter data filtering and identification we observed 105 metabolites dysregulated (66 GC-MS and 40 CE-MS) which shown different expression patterns for each COVID-19 severity status. These metabolites belonged to different metabolic pathways including amino acid, energy, and nitrogen metabolism among others. Severity-specific metabolic dysregulation was observed, as an increased transformation of L-tryptophan into L-kynurenine. Thus, metabolic profiling at hospital admission differentiate between severe and moderate patients in the later phase of worse evolution. Several plasma pro-inflammatory biomarkers showed significant correlation with deregulated metabolites, specially with L-kynurenine and L-tryptophan. Finally, we describe a strong sex-related dysregulation of metabolites, cytokines and chemokines between severe and moderate patients. In conclusion, metabolic profiling of COVID-19 patients at disease onset is a powerful tool to unravel the SARS-CoV-2 molecular pathogenesis.ConclusionsThis technique makes it possible to identify metabolic phenoconversion that predicts disease progression and explains the pronounced pathogenesis differences between sexes.

背景：SARS-CoV-2感染导致的背景代谢变化已有报道，但尚未得到充分理解。这种代谢失调在COVID-19病程中影响多个器官，其早期检测可作为疾病严重程度的预后标志。因此，本研究旨在描述COVID-19发病初期的代谢和细胞因子特征，以及其与疾病严重程度之间的关系，以识别预测疾病进展的代谢谱。材料与方法：我们对123名COVID-19患者进行了回顾性横断面研究，根据最高COVID-19严重程度状态将其分为无症状/轻度、中度和重度组，并设立了一组健康对照者。我们进行了非靶向血浆代谢组学分析（气相色谱和毛细管电泳-质谱联用技术，GC和CE-MS）和细胞因子评估。结果：在数据过滤和鉴定后，我们观察到105种代谢物发生失调（66种GC-MS和40种CE-MS），且在不同COVID-19严重程度状态下表现出不同的表达模式。这些代谢物属于不同的代谢途径，包括氨基酸、能量和氮代谢等。观察到特定严重程度的代谢失调，例如L-色氨酸向L-犬尿氨酸的转化增加。因此，入院时的代谢组学分析能够区分后期病情恶化中的重症和轻症患者。几种血浆促炎生物标志物与失调代谢物显示出显著的关联性，尤其是与L-犬尿氨酸和L-色氨酸。最后，我们描述了重症和轻症患者之间代谢物、细胞因子和趋化因子之间强烈的性别相关性失调。结论：COVID-19患者在疾病初期的代谢组学分析是揭示SARS-CoV-2分子发病机制的有力工具。这种技术使得识别预测疾病进展的代谢表型转变成为可能，并解释了性别之间显著的发病机制差异。