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

炎症性肠病(IBD)、克罗恩病(CD)和溃疡性结肠炎(UC)是一种慢性和 衰弱性疾病在人生的第二个和第三个十年发病率最高。虽然取得了长足的进步 在优化药物治疗以实现缓解方面取得了进展，复发是常见的和不可预测的。更改后的 微生物区系可能会导致肠道炎症和临床复发。微生物区系可获得的膳食碳水化合物 具有有益健康作用的“益生素”有望恢复IBD患者健康的肠道微生物区系 并防止临床复发。在这里，我们提出了对益生菌人乳低聚糖的首次研究， 2‘-岩藻糖基乳糖(2’-FL)，用于维持IBD的缓解。我们的首要假设是2‘-FL 补充IBD将是安全和耐受性良好的，同时增加粪便双歧杆菌丰度和 丁酸盐的作用呈剂量依赖性。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，并完成以下目标：目标1.定义剂量依赖安全性和 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，而不是2克 葡萄糖安慰剂作为儿童和青壮年IBD稳定缓解期患者的日常饮食补充 接受英夫利昔单抗或阿达利单抗抗肿瘤坏死因子治疗。安全性和耐受性将使用验证的 临床疾病活动指数，一种新型的电子症状跟踪器，以及粪便钙质保护蛋白。目标2.定义 2‘-FL作为IBD膳食补充剂的剂量依赖效应。我们将利用我们已建立的粪便 后基因组、后转录和代谢物分析，以测试2‘FL剂量范围对 肠道微生物群落和相关的代谢功能，重点是丁酸盐的生产。功效 将通过测定2‘-FL对增加的粪便双歧杆菌和 丁酸盐的丰度。我们将在分析中说明FUT2分泌子状态。这些研究将会有很高的 通过提供关键的I/IIa阶段安全和效力数据，支持第三阶段随机对照试验，从而在实地产生影响 我们由美国国立卫生研究院支持的IBD临床研究网络，以测试2‘-FL直接调节有益的效果 微生物区系，从而加强持续的临床缓解。最终，拟议的研究将促进 临床实践的根本性转变，转向个性化的微生物治疗干预。

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.