急性间歇性卟啉症的非靶向尿液代谢组学分析揭示了胆汁酸与血红素代谢之间的新型相互作用:有望用于患者长期管理的新生物标记物

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Inherited Metabolic Disease Pub Date : 2024-10-25 DOI:10.1002/jimd.12809
Thibaud Lefebvre, Thibaut Eguether, Etienne Thévenot, Antoine Poli, Emeline Chu-Van, Pranvera Krasniqi, Caroline Schmitt, Neila Talbi, Gaël Nicolas, Hervé Puy, Christophe Junot, Antonin Lamazière, Florence Castelli, Laurent Gouya, François Fenaille
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引用次数: 0

摘要

急性间歇性卟啉症是一种遗传性血红素合成错误。急性间歇性卟啉症主要涉及肝脏血红素合成,尽管其发生的基本病理生理学尚不清楚,急性卟啉症发作的严重程度仍难以控制。如果能更好地了解血红素合成与整体代谢之间的相互作用,就能改善对 AIP 患者的治疗。我们采用液相色谱-高分辨质谱联用技术,对114名明显AIP患者和无症状携带者的尿液进行了非靶向代谢组学分析。收集到的数据通过单变量和多变量分析进行了综合分析。通过将尿液样本中的色谱和质谱特征与我们化学库中的特征进行比对,共标注了 239 种代谢物。26种代谢物,包括卟啉前体、色氨酸或甘氨酸代谢的中间产物,以及意想不到的胆汁酸,在表型组之间显示出显著的浓度差异。定向定量分析证实了胆汁酸代谢失调,发现疏水性胆汁酸的失衡与共轭作用的变化有关,这在严重表型中更为明显。利用随机森林模型,胆酸/辰去氧胆酸比值可对重症患者和其他患者进行鉴别分类,诊断准确率达 84%。尿液样本分析显示,AIP 患者的代谢组发生了显著变化。胆汁酸的变化为原发性肝癌等慢性并发症的病理生理学提供了新的见解,同时也为预测最严重的表型提供了新的候选生物标记物。
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Nontargeted urine metabolomic analysis of acute intermittent porphyria reveals novel interactions between bile acids and heme metabolism: New promising biomarkers for the long-term management of patients.

Acute intermittent porphyria is an inherited error of heme synthesis. The underlying pathophysiology, involving mainly hepatic heme synthesis, is poorly understood despite its occurrence, and the severity of acute porphyria attack is still difficult to control. A better understanding of the interactions between heme synthesis and global metabolism would improve the management of AIP patients. An untargeted metabolomic analysis was performed on the urine of 114 patients with overt AIP and asymptomatic carriers using liquid chromatography coupled to high-resolution mass spectrometry. The collected data were analyzed by combining univariate and multivariate analyses. A total of 239 metabolites were annotated in urine samples by matching chromatographic and mass spectral characteristics with those from our chemical library. Twenty-six metabolites, including porphyrin precursors, intermediates of tryptophan or glycine metabolism and, unexpectedly, bile acids, showed significant concentration differences between the phenotypic groups. Dysregulation of bile acid metabolism was confirmed by targeted quantitative analysis, which revealed an imbalance in favor of hydrophobic bile acids associated with changes in conjugation, which was more pronounced in the severe phenotype. Using a random forest model, the cholic acid/chenodeoxycholic acid ratio enables the differential classification of severe patients from other patients with a diagnostic accuracy of 84%. The analysis of urine samples revealed significant modifications in the metabolome of AIP patients. Alteration in bile acids provides new insights into the pathophysiology of chronic complications, such as primary liver cancer, while also providing new biomarker candidates for predicting the most severe phenotypes.

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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
期刊最新文献
News from Valencia: JIMD themed issue on ureagenesis defects and allied disorders. The relation between dietary polysaccharide intake and urinary excretion of tetraglucoside. Nontargeted urine metabolomic analysis of acute intermittent porphyria reveals novel interactions between bile acids and heme metabolism: New promising biomarkers for the long-term management of patients. Exploring RNA therapeutics for urea cycle disorders. Therapeutic liver cell transplantation to treat murine PKU.
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