West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital/West China Medical School, Sichuan University, Chengdu, China.
Proteomics-Metabolomics Platform of Core Facilities, West China-Washington Mitochondria and Metabolism Centre, Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu, China.
Transl Res. 2024 Jan;263:28-44. doi: 10.1016/j.trsl.2023.08.003. Epub 2023 Aug 22.
To reveal dysregulated metabolism hallmark that was associated with a severe acute pancreatitis (SAP) phenotype. In this study, LC-MS/MS-based targeted metabolomics was used to analyze plasma samples from 106 acute pancreatitis (AP) patients (34 mild, 38 moderate, and 34 severe) admitted within 48 hours from abdominal pain onset and 41 healthy controls. Temporal metabolic profiling was performed on days 1, 3, and 7 after admission. A random forest (RF) was performed to significantly determine metabolite differences between SAP and non-SAP (NSAP) groups. Mass spectrometry imaging (MSI) and immunohistochemistry were conducted for the examination of pancreatic metabolite and metabolic enzyme alterations, respectively, on necrosis and paracancerous tissues. Simultaneously determination of serum and pancreatic tissue metabolic alterations using an L-ornithine-induced AP model to discover metabolic commonalities. Twenty-two significant differential metabolites screened by RF were selected to build an accurate model for the prediction of SAP from NSAP (AUC = 0.955). Six of 22 markers were found by MSI with significant alterations in pancreatic lesions, reduced ornithine-related metabolites were also identified. The abnormally expressed arginase2 and ornithine transcarboxylase were further discovered in combination with time-course metabolic profiling in the SAP animal models, the decreased ornithine catabolites were found at a late stage of inflammation, but ornithine-associated metabolic enzymes were activated during the inflammatory process. The plasma metabolome of AP patients is distinctive, which shows promise for early SAP diagnosis. AP aggravation is linked to the activated ornithine metabolic pathway and its inadequate levels of catabolites in in-situ lesion.
揭示与严重急性胰腺炎（SAP）表型相关的失调代谢特征。在这项研究中，使用基于 LC-MS/MS 的靶向代谢组学分析了 106 名急性胰腺炎（AP）患者（34 名轻度、38 名中度和 34 名重度）入院 48 小时内的血浆样本和 41 名健康对照者。在入院后第 1、3 和 7 天进行了时间代谢谱分析。随机森林（RF）用于显著确定 SAP 和非 SAP（NSAP）组之间代谢物的差异。质谱成像（MSI）和免疫组织化学分别用于检查坏死和癌旁组织中胰腺代谢物和代谢酶的改变。同时使用 L-鸟氨酸诱导的 AP 模型测定血清和胰腺组织代谢变化，以发现代谢共性。通过 RF 筛选出 22 个有显著差异的代谢物，建立了一个从 NSAP 预测 SAP 的准确模型（AUC=0.955）。MSI 发现 22 个标志物中有 6 个在胰腺病变中有明显改变，还鉴定出鸟氨酸相关代谢物减少。在 SAP 动物模型中，结合时间过程代谢谱进一步发现异常表达的精氨酸酶 2 和鸟氨酸转羧酶，在炎症的晚期发现鸟氨酸代谢物减少，但在炎症过程中，鸟氨酸相关代谢酶被激活。AP 患者的血浆代谢组是独特的，这为早期 SAP 诊断提供了希望。AP 加重与激活的鸟氨酸代谢途径及其在原位病变中的代谢物水平不足有关。
