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）是一种慢性炎症性肠道疾病，影响超过100万美国人。 尽管医学治疗取得了进展，但仍有近一半需要生物药物治疗的患者会发展为 难治性疾病因此，迫切需要新的UC治疗方法。 几项随机对照试验（RCT）的新数据表明，粪便微生物群移植 (FMT)治疗UC安全有效。尽管广泛的临床前研究显示， 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治疗UC疗效的变异性限制了其临床影响。我们自己团队的研究， 其他研究表明，供体微生物组的组成与临床反应有关。我们 初步数据扩展了这些发现与应变水平表征表明，核心可转移 微生物群与UC中对FMT的临床反应相关。详细了解 促进这些有益菌的转移和植入，以提高临床疗效 UC的FMT。饮食是肠道微生物组的关键调节剂， 炎症，但饮食和/或益生元补充对微生物植入和临床 FMT的结果从未得到检验。因此，迫切需要评估膳食营养素的作用， 在塑造微生物群和FMT治疗UC的临床结局方面的干预措施。该提案将评估 一个基本假设，即膳食纤维补充剂可以通过塑造FMT的临床疗效， 微生物植入和特定可转移微生物的功能。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临床结局的潜在影响， 一项随机、双盲、安慰剂对照的FMT（含或不含开放标签膳食纤维）试验 补充用于治疗轻度至中度UC;（ii）定义纤维补充对 UC患者FMT后的微生物植入和免疫细胞功能。如果成功，我们的研究将提供 关键支持的作用，膳食纤维在塑造FMT的结果。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，以支持设计 更大的后续临床研究。鉴于这种干预的可行性和实用性，这项工作的结果 有可能将FMT转化为UC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.