Dosing and Pilot Efficacy of 2'-Fucosyllactose in Inflammatory Bowel Disease

2-岩藻糖基乳糖治疗炎症性肠病的剂量和试验效果

• 批准号: 10394798
• 负责人: LEE ARMISTEAD DENSON
• 金额: $ 46.73万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-12 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394798
• 关键词: Adult; Anti-Tumor Necrosis Factor Therapy; Antibodies; Bifidobacterium; Biogenesis; Biological Assay; Butyrates; Carbohydrates; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Crohn' s disease; Data; Diagnosis; Dietary Carbohydrates; Disease; Disease remission; Dose; Enzymes; Epithelial; Epithelial Cells; Excision; Fucose; Future; Genes; Genetic Polymorphism; Glucose; Growth; Health; Homeostasis; Human Milk; Incidence; Individual; Infant; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Leukocyte L1 Antigen Complex; Life; Link; Lymphocyte Function; Metabolic; Metagenomics; Mitochondria; Mucositis; Mucous Membrane; Oligosaccharides; Outcome; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Predisposition; Production; Proteobacteria; Randomized; Randomized Controlled Trials; Regulatory T-Lymphocyte; Relapse; Risk; Safety; Specialist; Supplementation; Symptoms; TNF gene; Testing; Therapeutic Intervention; Ulcerative Colitis; United States National Institutes of Health; Volatile Fatty Acids; Withdrawal; adalimumab; beneficial microorganism; clinical practice; clinical remission; cytokine; dietary supplements; disorder risk; dysbiosis; efficacy testing; feeding; genetic signature; gut inflammation; gut microbiota; improved outcome; indexing; infliximab; innovation; intestinal epithelium; metatranscriptomics; microbial; microbiota; mouse model; novel; prebiotics; prevent; response; young adult

The Inflammatory Bowel Diseases (IBD), Crohn Disease (CD) and Ulcerative Colitis (UC), are chronic and debilitating disorders with peak incidence in the second and third decades of life. While considerable progress has been made in optimizing medications to achieve remission, relapse is common and unpredictable. Altered microbiota likely drive gut inflammation and clinical relapses. Microbiota-accessible dietary carbohydrates with beneficial health effects, known as “prebiotics,” hold promise for restoring healthy gut microbiota in IBD and preventing clinical relapse. Here, we propose the first studies of the prebiotic human milk oligosaccharide, 2’-fucosyllactose (2’-FL), for maintaining remission in IBD. Our overarching hypothesis is that 2’-FL supplementation in IBD will be safe and well tolerated, while increasing fecal Bifidobacterium abundance and butyrate in a dose dependent manner. We will test this hypothesis by conducting a randomized, placebo- controlled dose-ranging study and completing the following Aims: Aim 1. Define dose dependent safety and tolerability of 2’-FL as a dietary supplement in IBD. We will test 1, 5, or 10 gm 2’-FL compared to 2 gm glucose placebo as a daily dietary supplement in pediatric and young adult IBD patients in stable remission receiving infliximab or adalimumab anti-TNF therapy. Safety and tolerability will be assessed using validated clinical disease activity indices, a novel electronic symptom tracker, and fecal calprotectin. Aim 2. Define dose dependent efficacy of 2’-FL as a dietary supplement in IBD. We will utilize our established fecal metagenomic, metatranscriptomic, and metabolite assays to test the effect of a range of 2’FL doses upon the gut microbial community and associated metabolic functions with a focus upon butyrate production. Efficacy will be assessed by determining the dose dependent effect of 2’-FL upon increased fecal Bifidobacterium and butyrate abundance. We will account for FUT2 secretor status in the analysis. These studies will have a high impact in the field by providing critical phase I/IIa safety and efficacy data in support of a phase III RCT using our NIH-supported IBD clinical research network to test the efficacy of 2’-FL in directly modulating beneficial microbiota and thereby enhancing sustained clinical remission. Ultimately the proposed studies will promote a fundamental shift in clinical practice towards personalized microbial therapeutic interventions.

炎症性肠病（IBD），克罗恩病（CD）和溃疡性结肠炎（UC）是慢性的， 在生命的第二十年和第三十年中，与最高事件的疾病使人衰弱。虽然进步很大 为了优化药物以实现缓解，继电器是常见且无法预测的。改变 微生物群可能会驱动肠道注射和临床接力。微生物群可访问的饮食碳氢化物 具有有益的健康影响，称为“益生元”，有望恢复IBD中健康的肠道菌群 并防止临床缓解。在这里，我们提出了益生元人乳寡糖的首次研究， 2'-羟基肌动蛋白（2'-FL），用于在IBD中保持缓解。我们的总体假设是2'-fl IBD中的补充将是安全且耐受性的，同时增加了粪便双歧杆菌抽象和 以剂量依赖的方式键酸。我们将通过进行随机的安慰剂来检验这一假设 受控剂量范围研究并完成以下目的：目标1。定义依赖剂量的安全性和 IBD中2'-FL作为饮食补充剂的耐受性。我们将测试1、5或10克2'-FL，而2 gm 葡萄糖安慰剂作为小儿和年轻成人IBD患者的每日饮食补充剂 接受英夫利昔单抗或阿达木单抗抗TNF疗法。安全性和耐受性将使用经过验证的 临床疾病活动指数，一种新型的电子症状跟踪器和粪便钙染色素。目标2。定义 2'-FL剂量依赖性效率作为IBD的饮食补充剂。我们将利用我们已建立的粪便 元基因组，元文字和代谢物阿萨斯，以测试2'Fl剂量的范围对 肠道微生物群落和相关的代谢功能，重点是丁酸酯。功效 将通过确定2'-FL对增加粪便双歧杆菌和 丁酸酯抽象。我们将在分析中考虑FUT2分泌的状态。这些研究将有很高的 通过提供关键阶段I/IIA的安全性和效率数据来支持该领域的影响，以支持使用III期RCT 我们的NIH支持的IBD临床研究网络，以测试2'-FL直接调节有益的效率 微生物群，从而增强持续的临床缓解。最终，拟议的研究将促进 临床实践向个性化微生物治疗干预措施的基本转变。