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

基本信息

批准号：
9883036
负责人：
LEE ARMISTEAD DENSON
金额：
$ 66.7万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-12 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883036
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&apos s disease Data Diagnosis Dietary Carbohydrates Disease Disease remission Dose Enzymes Epithelial Epithelial Cells Epithelium 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 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 microbiota improved outcome indexing inflammatory disease of the intestine infliximab innovation intestinal epithelium metatranscriptomics microbial microbiota mouse model novel prebiotics prevent response young adult

项目摘要

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) 是慢性疾病，衰弱性疾病在生命的第二个和第三个十年中发病率达到高峰，同时取得了相当大的进展。尽管已经在优化药物治疗以实现缓解方面取得了进展，但复发是常见且不可预测的。微生物群可能会导致肠道炎症和临床复发。具有有益健康作用的“益生元”有望恢复 IBD 患者健康的肠道微生物群在这里，我们提出了益生元母乳寡糖的首次研究， 2’-岩藻糖基乳糖 (2’-FL)，用于维持 IBD 缓解我们的首要假设是 2’-FL。 IBD 补充剂是安全且耐受性良好的，同时可增加粪便双歧杆菌丰度和我们将通过进行随机安慰剂试验来检验这一假设。受控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和 2'-FL 作为 IBD 膳食补充剂的耐受性我们将测试 1、5 或 10 克 2'-FL 与 2 克的比较。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昔单抗或阿达木单抗抗 TNF 治疗的安全性和耐受性将使用经过验证的方法进行评估。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。 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已确定的粪便。宏基因组、宏转录组和代谢物测定，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，重点是丁酸的产生。将通过确定 2’-FL 对粪便双歧杆菌增加的剂量依赖性效应进行评估我们将在分析中考虑 FUT2 分泌状态。通过提供关键的 I/IIa 期安全性和有效性数据来支持 III 期 RCT，从而在该领域产生影响我们的 NIH 支持的 IBD 临床研究网络测试 2'-FL 在直接调节有益的方面的功效微生物群，从而增强持续的临床缓解，最终，拟议的研究将促进治疗。临床实践向个性化微生物治疗干预的根本转变。