双峰血浆代谢组学策略鉴定炎症性肠病中的新型炎症代谢物。

Bimodal plasma metabolomics strategy identifies novel inflammatory metabolites in inflammatory bowel diseases.

作者信息

Yau Yunki Y, Leong Rupert W L, Shin Sean, Bustamante Sonia, Pickford Russell, Hejazi Leila, Campbell Beth, Wasinger Valerie C

机构信息

Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales, Kensington, NSW 2000, Australia and Department of Gastroenterology, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.

Department of Gastroenterology, Concord Repatriation General Hospital, Concord, NSW 2139, Australia and the Department of Gastroenterology, Bankstown-Lidcombe Hospital, Bankstown, NSW 2200, Australia.

出版信息

Discov Med. 2014 Sep;18(98):113-24.

PMID:25227752

Abstract

INTRODUCTION

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by variable phenotypes. Metabolites are signatures of biochemical activity that can reveal unknown pathogenic pathways. We employed untargeted mass spectrometry (MS) based metabolomics to identify novel inflammatory mechanisms in IBD and a targeted assay to quantify metabolites of the auto-immunomodulating kynurenine pathway (KP) in IBDs and health.

MATERIALS AND METHODS

Metabolome analysis of CD, UC, and control plasmas was performed on a Liquid Chromatography (LC)-MS/MS system. KP metabolites quinolinic acid (QA) and picolinic acid (PA) were quantified by gas chromatography/MS.

RESULTS

Nineteen UC, 25 CD, and 9 control plasmas were analyzed: 34 metabolites exhibited abundance profiles associated with CD by global metabolome analysis (P≤0.05, false discovery rate q≤0.01). Notably, inflammatory-implicated metabolites angiotensin IV (P=0.049, q<0.001), diphthamide (P=0.018, q<0.001), and GM3 gangliosides (P<0.001, q<0.001) were increased in CD. By targeted kynurenine metabolites assay, QA (73.53 ng/mL ± 23.40 SD) and combined kynurenine metabolites (CKM) were increased in CD (120.19 ± 39.71) compared to controls (QA 50.14 ± 15.04; P<0.01; CKM 92.73 ± 26.30; P<0.01). CD QA positively correlated with CDAI (r=0.85; P<0.01), CRP (r=0.46; P=0.01), and ESR (r=0.42; P=0.03), while CKMs correlated with CDAI (r=0.615; P<0.01) and CRP (r=0.615; P=0.02).

CONCLUSIONS

Associations of angiotensin IV, diphthamide, and GM3 gangliosides with CD implicate novel pathways in activating a Th1/Th17 inflammatory profile. Increased QA concentrations in CD may indicate a defective auto-immunomodulation mechanism.

摘要

引言

克罗恩病（CD）和溃疡性结肠炎（UC）是具有多种表型特征的炎症性肠病（IBD）。代谢物是生化活性的标志，可揭示未知的致病途径。我们采用基于非靶向质谱（MS）的代谢组学来识别IBD中的新型炎症机制，并采用靶向分析法定量IBD患者和健康人群中自身免疫调节犬尿氨酸途径（KP）的代谢物。

材料与方法

在液相色谱（LC）-MS/MS系统上对CD、UC和对照血浆进行代谢组分析。通过气相色谱/MS对KP代谢物喹啉酸（QA）和吡啶甲酸（PA）进行定量。

结果

分析了19份UC、25份CD和9份对照血浆：通过整体代谢组分析，34种代谢物呈现出与CD相关的丰度谱（P≤0.05，错误发现率q≤0.01）。值得注意的是，与炎症相关的代谢物血管紧张素IV（P = 0.049，q < 0.001）、白喉酰胺（P = 0.018，q < 0.001）和GM3神经节苷脂（P < 0.001，q < 0.001）在CD中增加。通过靶向犬尿氨酸代谢物分析，与对照组相比，CD中的QA（73.53 ng/mL ± 23.40标准差）和总犬尿氨酸代谢物（CKM）增加（CD中QA为120.19 ± 39.71，对照组为50.14 ± 15.04；P < 0.01；CD中CKM为92.73 ± 26.30，对照组为92.73 ± 26.30；P < 0.01）。CD中的QA与CDAI呈正相关（r = 0.85；P < 0.01）、与CRP呈正相关（r = 0.46；P = 0.01）、与ESR呈正相关（r = 0.42；P = 0.03），而CKM与CDAI呈正相关（r = 0.615；P < 0.01）、与CRP呈正相关（r = 0.615；P = 0.02）。