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， 在生命的第二个和第三个十年中发病率最高的衰弱性疾病。虽然取得了相当大的进展， 虽然在优化药物以实现缓解方面取得了进展，但复发是常见的和不可预测的。改变 微生物群可能会导致肠道炎症和临床复发。微生物可利用的膳食碳水化合物 具有有益健康的作用，被称为“益生元”，有望恢复IBD患者健康的肠道微生物群。 并防止临床复发。在这里，我们提出了益生元人乳低聚糖的第一个研究， 2 '-岩藻糖基乳糖（2'-FL），用于维持IBD的缓解。我们的总体假设是，2 '-FL 补充IBD将是安全的和良好耐受的，同时增加粪便双歧杆菌丰度， 丁酸以剂量依赖性方式。我们将通过随机的安慰剂试验来检验这个假设- 对照剂量范围研究，并完成以下目标：目标1。定义剂量依赖性安全性， 2 '-FL作为IBD患者膳食补充剂的耐受性。我们将测试1、5或10 gm 2 '-FL与2 gm相比 葡萄糖安慰剂作为稳定缓解的儿童和年轻成人IBD患者的每日膳食补充剂 接受英夫利西单抗或阿达木单抗TNF治疗。安全性和耐受性将使用经验证的 临床疾病活动指数、新型电子症状追踪器和粪便钙卫蛋白。目标2.定义 2 '-FL作为IBD膳食补充剂的剂量依赖性功效。我们将利用我们建立的粪便 宏基因组学、元转录组学和代谢物测定，以测试一系列2 'FL剂量对 肠道微生物群落和相关的代谢功能，重点是丁酸盐的产生。疗效 将通过确定2 '-FL对粪便双歧杆菌增加的剂量依赖性影响来评估， 丁酸盐丰度我们将在分析中考虑FUT 2分泌状态。这些研究将有很高的 通过提供关键的I/IIa期安全性和疗效数据，支持III期RCT， 我们的NIH支持的IBD临床研究网络，以测试2 '-FL在直接调节有益的 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的根本转变。