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)

溃疡性结肠炎(UC)是一种慢性肠道炎症性疾病，影响着100多万美国人。 尽管医学治疗取得了进步，但近一半需要生物药物治疗的患者将会出现 医学上难治的疾病。因此，迫切需要新的UC治疗方法。 来自几个随机对照试验(RCT)的新数据表明，粪便微生物区系移植 (FMT)治疗UC安全有效。尽管广泛的临床前研究表明 肠道微生物群在调节结肠炎动物模型中的作用支持这些令人鼓舞的临床发现， FMT治疗UC疗效的变异性限制了其临床影响。来自我们自己团队的研究和 其他研究表明，供体微生物组的组成与临床反应有关。我们的 初步数据扩展了这些发现，应变水平表征表明，核心是可转移的 微生物区系与UC患者对FMT的临床反应相关。详细了解以下机制： 促进这些有益细菌的转移和植入是提高临床疗效所必需的 UC的FMT。饮食是肠道微生物群及其对肠道的影响的关键调节因素 炎症，但饮食和/或补充益生菌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 塑造微生物群和FMT治疗UC临床结局的干预措施。这项提案将评估 补充膳食纤维可通过塑造改善FMT临床疗效的基本假设 特定可转移微生物的微生物嫁接和功能。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 一项使用或不使用开放标签膳食纤维的FMT随机、双盲、安慰剂对照试验 补充治疗轻中度UC；(Ii)确定补充纤维对 UC患者FMT后微生物植入和免疫细胞功能的变化如果成功，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，我们的微生物群， 代谢学和免疫学特征将提供关键的机制分析，以支持设计 更大规模的后续临床研究。鉴于这种干预的可行性和实用性，这项工作的结果 有可能改变UC的FMT以及其他适应症。

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.