Fecal microbiota transplant for Alcohol-Associated Cirrhosis

目前治疗AUD的药物选择只有部分成功，而且在肝硬变方面的证据基础很低。肠 可能由酒精引起的生物失调导致了肝硬变的发展。我们的首要目标是 开发一种针对肠道微生物区系的有效治疗方法，以减轻AUD和AROD的影响 穿过肠道-肝脏-脑轴。我们的方法基于粪便微生物区系移植(FMT)，最初 为难辨梭状芽胞杆菌反复感染(RCDI)而开发。我们还展示了随机、安慰剂-- 不同FMT制剂对肝硬变的益处和安全性的对照临床试验。此外，在一个 最近对积极饮酒的肝硬变患者进行的随机试验表明，FMT减少了酒精含量 消费和渴望，改善认知和心理社会健康相关的生活质量(HRQOL) 与安慰剂的对比。我们还发现胶囊植入和灌肠FMT植入相似。FDA监管FMT 作为一种药物和生物。我们的团队使用良好的制造实践来制造FMT产品 液体和冷冻干燥的胶囊制剂。 我们的假设是，使用FMT重组肠道微生物区系将减少酒精摄入量 与AUD和肝硬变患者的安慰剂进行比较。为了测试这一点，我们将进行阶段1b/2a 使用标准化口服的双盲、安慰剂对照、随机临床试验 AUD和肝硬变患者基线和第30天的微囊化FMT制剂(FMT)。 目的1：测量FMT对饮酒的影响。主要结果是禁欲天数 与安慰剂相比，FMT治疗3个月。我们将使用以下工具评估日常饮酒量和饮酒量 患者报告的措施和客观的尿液和血浆标志物。 目的2：确定FMT对安全性和肝功能的影响。我们将监测安全结果和肝脏 在整个试验过程中发挥作用。 目的3：确定FMT对微生物组成和功能的影响。大便的对比分析 微生物组成和血清代谢组学将在组内和组内进行。目标明确 代谢组学将专注于由微生物区系产生或调节的神经活性代谢物，例如， γ-氨基丁酸、谷氨酸、吲哚类化合物和胆汁酸。 目的4：利用认知功能确定FMT对脑功能障碍和患者报告的结果的影响 测试和HRQOL测试。我们将使用经过验证的工具(疾病)评估HRQOL和认知 影响概况，脑部应用程序Stroop，心理测量学肝性脑病评分)。 我们将招募80名AUD肝硬变患者(随机1：1服用FMT和安慰剂)，接受FDA Ind。这个 团队拥有获得患者、微生物专业知识、基础设施和AUD试验经验来开展试验。

Current medication options for AUD have only partial success and have a low evidence base in cirrhosis. Gut dysbiosis, which may be initiated by alcohol, contributes to cirrhosis development. Our overarching goal is to develop a potent therapeutic targeting the intestinal microbiota to alleviate the impact of AUD and AROD through the gut-liver-brain axis. We base our approach on fecal microbiota transplant (FMT), originally developed for recurrent Clostridioides difficile infection (rCDI). We have also shown in randomized, placebo- controlled clinical trials the benefit and safety of different FMT formulations in cirrhosis. Furthermore, in a recent randomized trial of actively drinking AUD cirrhotic patients, we demonstrated that FMT reduced alcohol consumption and craving, and improved cognition and psychosocial health-related quality of life (HRQOL) versus placebo. We also found similar engraftment with capsule versus enema FMT. The FDA regulates FMT as a drug and a biologic. Our group uses Good Manufacturing Practices to manufacture FMT products in both liquid and freeze-dried, encapsulated formulations. Our hypothesis is that restructuring the gut microbiota using FMT will reduce alcohol consumption compared to placebo in patients with AUD and cirrhosis. To test this, we will conduct a Phase 1b/2a double-blind, placebo-controlled, randomized clinical trial using administration of a standardized oral encapsulated FMT preparation (FMT) at baseline and day 30 in patients with AUD and cirrhosis. Aim 1: Measure the effect of FMT on alcohol consumption. The primary outcome is number of abstinent days at three months in FMT compared to placebo. We will assess daily alcohol consumption and cravings using patient-reported measures and objective urinary and plasma markers. Aim 2: Determine the impact of FMT on safety and liver dysfunction. We will monitor safety outcomes and liver function throughout the trial. Aim 3: Determine the impact of FMT on microbial compositional and function. Comparative analyses of stool microbial composition, and serum metabolomics will be performed between and within groups. Targeted metabolomics will be focused on neuroactive metabolites that are produced or modulated by microbiota, e.g., SCFA, γ-aminobutyric acid (GABA), glutamate, indolic compounds, and bile acids. Aim 4: Determine the impact of FMT on brain dysfunction and patient-reported outcomes using cognitive testing and HRQOL testing. We will evaluate HRQOL and cognition using validated instruments (Sickness Impact Profile, EncephalApp Stroop, Psychometric Hepatic Encephalopathy Score). We will enroll 80 participants with AUD cirrhosis (randomized 1:1 to FMT versus placebo) under FDA IND. The team has access to patients, microbial expertise, infrastructure and AUD trial experience to carry out the trial.