Peripheral Blood Exosome Lipids as Biomarkers of Disease Activity in Crohn’s Disease

外周血外泌体脂质作为克罗恩病疾病活动的生物标志物

• 批准号: 9767782
• 负责人: Terrence A. Barrett
• 金额: $ 19.27万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767782
• 关键词: Address; Biological Markers; C-reactive protein; Cells; Charge; Clinical; Clinical assessments; Clostridium difficile; Consensus; Control Groups; Crohn' s disease; Data; Data Set; Dendritic Cells; Development; Diagnostic; Disease; Disease remission; Endoscopy; Epithelial Cells; Goals; Image; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Kentucky; Knowledge; Leukocyte L1 Antigen Complex; Leukocytes; Link; Lipids; Longitudinal Studies; Mass Spectrum Analysis; Medical; Mesenchymal; Newly Diagnosed; Pathology; Patient Monitoring; Patients; Pattern; Plasma; Principal Component Analysis; Process; Public Health; Refractory; Research; Resolution; Sampling; Sensitivity and Specificity; Speed; Structure; Testing; Tissues; Universities; Work; base; clinical research site; design; disorder control; exosome; follow-up; improved; indexing; individual patient; macrophage; mass spectrometer; neutrophil; novel; novel therapeutics; peripheral blood; response; sample collection; specific biomarkers; tool

Abstract Management of inflammatory bowel disease (IBD) patients requires knowledge of disease status to inform treatment decisions. Commonly used biomarkers such as clinical disease activity indices, C reactive protein (CRP) and fecal calprotectin achieve suboptimal sensitivity and specificity for intestinal inflammation1. Data provided indicate that peripheral blood exosome (PBE) lipid composition distinguishes active IBD from normal patients (Fig. 1). We contend that PBE lipid compositions will provide clinicians with a highly sensitive and specific biomarker to assess disease activity without invasive testing. The need to identify subtle disease derives from the consensus conclusion that “deep remission” should be the endpoint of therapy. Thus, monitoring of patients with intent to suppress subclinical inflammation has emerged as a treatment goal3. Exosomes are lipid-encased, subcellular (60-80 nm) structures released into the peripheral blood at from intestinal epithelial cells (IEC), activated leukocytes (e.g. neutrophils, macrophages, dendritic cells, etc.) and mesenchymal cells during inflammation3. We used an ultrahigh resolution Orbitrap mass spectrometer to analyze lipid compositions of PBEs from patients (>25/group). Principal component analysis (PCA) of PBE lipid intensities showed a wide separation of datapoints between active IBD and normal controls and a heatmap analysis of differential abundance revealed high within-group correlations and low between-group correlations suggesting that distinct lipids can be resolved that correlate with disease activity. In this two year project, we propose to collect plasma from 1) moderate-severe, 2) mildly-active and 3) quiescent Crohn’s disease (CD) patients as well as inflammatory (C. difficile-infected) and 4) normal controls. Using CD allows us to test whether PBE composition detects levels of mild (in many cases, subclinical) disease activity as this identifies patients not in deep remission, a goal of medical therapy. In Aim 1, PBE lipid-based classifiers will be developed to discriminate mildly-active from severely-active CD and controls. In Aim 2, PBE lipids will be examined longitudinally within individual patients before and after therapy to identify lipids correlate with clinical response. Such information will also be passed to Aim 1 to develop more robust classifiers. Testing patterns of PBE lipids in responsive and refractory patients is intended to improve the robustness of the classifiers. Studies in Aim 1 and 2 are greatly enhanced by the inclusion of a second clinical site (Baylor University) to provide samples to validate (or not) data from University of Kentucky. The long-term goal will be to justify studies to identify a “exosomal lipid signature” panel that provide a novel set of biomarkers for discriminating levels of CD disease activity and informing treatment decisions. We post that the creation of a CD exosome lipid biomarker test will obviate the need for follow-up endoscopy in the majority of patients.

抽象的 炎症性肠病 (IBD) 患者的管理需要了解疾病状况以提供信息 治疗决定。临床疾病活动指数、C反应蛋白等常用生物标志物 (CRP) 和粪便钙卫蛋白对肠道炎症的敏感性和特异性不理想1。数据 所提供的数据表明外周血外泌体 (PBE) 脂质成分可将活动性 IBD 与 正常患者（图1）。我们认为 PBE 脂质组合物将为临床医生提供高度敏感的 以及无需侵入性测试即可评估疾病活动的特定生物标志物。识别细微疾病的必要性 源自“深度缓解”应该是治疗终点的共识结论。因此， 旨在抑制亚临床炎症的患者监测已成为一种治疗方法 目标3。外泌体是脂质包裹的亚细胞（60-80 nm）结构，在 来自肠上皮细胞 (IEC)、活化的白细胞（例如中性粒细胞、巨噬细胞、树突状细胞等） 和炎症期间的间充质细胞3。我们使用超高分辨率 Orbitrap 质谱仪 分析患者（>25/组）PBE 的脂质成分。 PBE 脂质的主成分分析 (PCA) 强度显示活动性 IBD 和正常对照之间的数据点有很大的分离以及热图 差异丰度分析显示组内相关性高，组间相关性低 这表明可以解析与疾病活动相关的不同脂质。在这个为期两年的项目中，我们 建议从 1) 中重度、2) 轻度活跃和 3) 静止期克罗恩病 (CD) 收集血浆 患者以及炎症（艰难梭菌感染）和4）正常对照。使用 CD 可以让我们测试 PBE 组合物是否检测到轻度（在许多情况下，亚临床）疾病活动水平，如这所确定 未达到深度缓解的患者，这是药物治疗的目标。在目标 1 中，基于 PBE 脂质的分类器将是 开发用于区分轻度活动性和重度活动性 CD 和对照。在目标 2 中，PBE 脂质将是 在治疗前后对个体患者进行纵向检查，以确定与临床相关的血脂 回复。此类信息还将传递给目标 1，以开发更强大的分类器。测试模式 有反应和难治性患者的 PBE 脂质旨在提高分类器的稳健性。 通过纳入第二个临床中心（贝勒大学），大大加强了目标 1 和 2 的研究 提供样本来验证（或不验证）肯塔基大学的数据。长期目标是证明合理性 研究确定了“外泌体脂质特征”组，该组提供了一组用于区分的新型生物标志物 CD 疾病活动水平并为治疗决策提供信息。我们发布 CD 外泌体的创建 脂质生物标志物测试将消除大多数患者进行后续内窥镜检查的需要。

项目成果

Editorial: opioids in inflammatory bowel disease-primum non nocere. Authors' reply.

社论：阿片类药物在炎症性肠病中的应用-primum non nocere。

• DOI: 10.1111/apt.16292
• 发表时间: 2021
• 期刊: Alimentary pharmacology & therapeutics
• 影响因子: 7.6
• 作者: Rhudy,Christian;Perry,CourtneyL;Barrett,TerrenceA
• 通讯作者: Barrett,TerrenceA