A randomized, placebo-controlled clinical trial examining the efficacy of Fecal Microbiota Transplantation (FMT) and subsequent dietary fiber in patients with moderate ulcerative colitis (MINDFUL)

一项随机、安慰剂对照临床试验，检验粪便微生物群移植 (FMT) 和随后的膳食纤维对中度溃疡性结肠炎 (MINDFUL) 患者的疗效

• 批准号: 10631895
• 负责人: randy s longman
• 金额: $ 33.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631895
• 关键词: Affect; American; Animal Model; Bacteria; Biological; Cell physiology; Cells; Clinical; Clinical Research; Colitis; Complex; Computer software; Data; Diet; Dietary Fiber; Dietary Intervention; Dietary Supplementation; Engraftment; Enzymes; Fiber; Immune; Immunity; Immunologics; Inflammatory Bowel Diseases; Intervention; Intestines; Medical; Metagenomics; Microbe; Mucositis; Nutrient; Outcome; Participant; Patients; Pharmaceutical Preparations; Placebos; Polysaccharides; Psyllium; Randomized; Randomized, Controlled Trials; Refractory Disease; Research; Research Infrastructure; Resources; Role; Shapes; Source; Supplementation; Testing; Ulcerative Colitis; Volatile Fatty Acids; Work; bioinformatics pipeline; chronic inflammatory disease; clinical efficacy; clinical infrastructure; clinical remission; design; double-blind placebo controlled trial; effective therapy; efficacy evaluation; fecal transplantation; follow-up; gut inflammation; gut microbiome; healing; improved; inclusion criteria; meetings; metabolomics; microbial; microbiome; microbiome analysis; microbiota; novel; novel strategies; novel therapeutic intervention; open label; pre-clinical research; prebiotics; primary endpoint; randomized placebo-controlled clinical trial; response; secondary endpoint

Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine affecting over 1 million Americans. Despite advances in medical therapies, nearly half of the patients requiring biologic medications will develop medically refractory disease. As such, there is an urgent need for new treatment approaches for UC. Emerging data from several randomized controlled trials (RCTs) suggest that fecal microbiota transplantation (FMT) is safe and effective for the treatment of UC. Although extensive pre-clinical research showing a central role for the gut microbiome in regulating animal models of colitis support these encouraging clinical findings, variability in the efficacy of FMT for UC has limited the clinical impact. Research from our own group and others has shown that the composition of the donor microbiome is associated with clinical response. Our preliminary data extend these findings with strain level characterization showing that a core transferable microbiota correlates with clinical response to FMT in UC. A detailed understanding of the mechanisms that promote the transfer and engraftment of these beneficial bacteria is needed to enhance the clinical efficacy of FMT for UC. Diet is a critical regulator of the intestinal microbiome and its subsequent impact on intestinal inflammation, but the effect of diet and/or prebiotic supplementation on microbial engraftment and clinical outcome following FMT has never been tested. It is, therefore, a critical need to assess the role for dietary interventions in shaping the microbiome and clinical outcomes of FMT for UC. This proposal will evaluate the fundamental hypothesis that dietary fiber supplementation can improve the clinical efficacy of FMT by shaping microbial engraftment and function of specific transferable microbes. We propose the following aims to evaluate this hypothesis: (i) to test the potential impact of fiber to improve clinical outcomes of FMT for UC with a randomized, double-blind, placebo-controlled trial of FMT with or without open-label dietary fiber supplementation for the treatment of mild to moderate UC; (ii) to define the impact of fiber supplementation on microbial engraftment and immune cell function after FMT in patients with UC. If successful, our study will offer critical support for the role of dietary fiber in shaping the outcome of FMT. Furthermore, our microbiome, metabolomic, and immunologic characterization will provide key mechanistic analysis to support the design of larger follow-up clinical studies. Given the feasibility and practicality of this intervention, results from this work have the potential to transform FMT for UC as well as other indications.

溃疡性结肠炎 (UC) 是一种慢性肠道炎症性疾病，影响超过 100 万美国人。 尽管医学疗法取得了进步，但近一半需要生物药物的患者会出现 医学上难治性疾病。因此，迫切需要新的 UC 治疗方法。 多项随机对照试验 (RCT) 的新数据表明，粪便微生物群移植 （FMT）对于治疗 UC 是安全有效的。尽管广泛的临床前研究表明， 肠道微生物组在调节结肠炎动物模型中的作用支持了这些令人鼓舞的临床发现， FMT 对 UC 疗效的可变性限制了其临床影响。我们自己的团队的研究和 其他人表明，供体微生物组的组成与临床反应相关。我们的 初步数据通过应变水平表征扩展了这些发现，表明核心可转移 微生物群与 UC 中 FMT 的临床反应相关。详细了解其机制 需要促进这些有益细菌的转移和定植，以提高临床疗效 UC 的 FMT。饮食是肠道微生物群及其对肠道的后续影响的关键调节剂 炎症，但饮食和/或益生元补充对微生物植入和临床的影响 FMT 后的结果从未经过测试。因此，迫切需要评估饮食的作用 塑造微生物组和 FMT 治疗 UC 临床结果的干预措施。该提案将评估 基本假设是补充膳食纤维可以通过塑造肠道菌群来提高 FMT 的临床疗效。 特定可转移微生物的微生物植入和功能。我们提出以下目标 评估这一假设：(i) 测试纤维对改善 FMT 治疗 UC 临床结果的潜在影响 一项随机、双盲、安慰剂对照的 FMT 试验，含或不含开放标签膳食纤维 用于治疗轻度至中度 UC 的补充剂； (ii) 定义补充纤维对身体的影响 UC 患者 FMT 后的微生物植入和免疫细胞功能。如果成功的话，我们的研究将提供 膳食纤维在塑造 FMT 结果中的作用的关键支持。此外，我们的微生物组， 代谢组学和免疫学表征将提供关键的机制分析来支持设计 更大规模的后续临床研究。鉴于这种干预措施的可行性和实用性，本工作的结果 有潜力将 FMT 转化为 UC 以及其他适应症。