Bax Bridget E, Uçar Sema Kalkan
School of Health and Medical Sciences, City St George's, University of London, London SW17 0RE, UK.
Division of Metabolism and Nutrition, Department of Pediatrics, Ege University Medical Faculty, Izmir 35100, Turkey.
Int J Mol Sci. 2025 Sep 18;26(18):9107. doi: 10.3390/ijms26189107.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by pathogenic mutations in the nuclear gene, which encodes the cytosolic enzyme thymidine phosphorylase. In addition to the systemic accumulation of thymidine and deoxyuridine, several case studies have reported abnormalities in a range of other metabolites in patients with MNGIE. Since metabolites are intermediates or end-products of numerous biochemical reactions, they serve as highly informative indicators of an organism's metabolic activity. This study aimed to perform an untargeted metabolomic profiling to determine whether individuals with MNGIE exhibit a distinct plasma metabolic signature compared to 15 age- and sex-matched healthy controls. Metabolites were profiled using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS). A total of 160 metabolites were found to be significantly upregulated and 260 downregulated in patients with MNGIE. KEGG pathway enrichment analysis revealed disruptions in 20 metabolic pathways, with arachidonic acid metabolism and bile acid biosynthesis being the most significantly upregulated. Univariate receiver operating characteristic (ROC) curve analyses identified 23 individual metabolites with diagnostic potential, each showing an area under the curve (AUC) ≥ 0.80. We propose that an impaired resolution of inflammation contributes to a chronic inflammatory state in MNGIE, potentially driving disease progression. Additionally, we suggest that the gut-liver axis plays a central role in MNGIE pathophysiology, with hepatic function being bidirectionally influenced by gut-derived factors.
线粒体神经胃肠性脑肌病（MNGIE）由核基因中的致病性突变引起，该基因编码胞质酶胸苷磷酸化酶。除了胸苷和脱氧尿苷在体内的系统性蓄积外，多项病例研究报告了MNGIE患者一系列其他代谢物存在异常。由于代谢物是众多生化反应的中间产物或终产物，它们是生物体代谢活性的高度信息性指标。本研究旨在进行非靶向代谢组学分析，以确定与15名年龄和性别匹配的健康对照相比，MNGIE患者是否表现出独特的血浆代谢特征。使用超高效液相色谱-质谱联用仪（UHPLC-MS）对代谢物进行分析。共发现160种代谢物在MNGIE患者中显著上调，260种代谢物下调。KEGG通路富集分析显示20条代谢通路受到干扰，其中花生四烯酸代谢和胆汁酸生物合成上调最为显著。单变量受试者工作特征（ROC）曲线分析确定了23种具有诊断潜力的个体代谢物，每种代谢物的曲线下面积（AUC）≥0.80。我们提出，炎症消退受损导致MNGIE患者出现慢性炎症状态，可能推动疾病进展。此外，我们认为肠-肝轴在MNGIE病理生理学中起核心作用，肝功能受到肠道来源因素的双向影响。
