Modulation of Gut-Brain Axis Using Fecal Microbiome Transplant Capsules in Cirrhosis

使用粪便微生物移植胶囊调节肝硬化的肠脑轴

• 批准号: 9335590
• 负责人: Jasmohan S Bajaj
• 金额: $ 17.34万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335590
• 关键词: Adverse effects; Affect; Antibiotics; Bacteria; Bacterial Translocation; Brain; Brain Injuries; Cirrhosis; Clinical; Clostridium difficile; Collaborations; Complication; Data; Duodenum; Endotoxins; Enterobacteriaceae; Feces; Goals; Hepatic Encephalopathy; Human Microbiome; Hyperammonemia; Impairment; Inflammation; Inflammatory; Intervention; Intestines; Investigational Therapies; Knowledge; Lactulose; Large Intestine; Link; Liver; Liver Cirrhosis; Liver diseases; Location; Methods; Microbe; Morbidity - disease rate; Mucous Membrane; North America; Oral; Outcome; Pathogenicity; Patients; Persons; Placebo Control; Prevention; Probiotics; Recurrence; Research; Route; Safety; Sigmoid colon; Small Intestines; Symptoms; Therapeutic; Time; Transplantation; Underserved Population; Universities; Virginia; Wisconsin; antimicrobial peptide; base; capsule; chronic liver disease; cognitive performance; cytokine; efficacy trial; enema administration; fecal transplantation; gut microbiota; high risk; improved; liver transplantation; medical schools; microbial; microbiome; microbiota; microbiota transplantation; mortality; neuroinflammation; open label; pill; prebiotics; precision medicine; protein expression; randomized trial; rifaximin; standard of care; translational approach; translational study; upper GI series

Cirrhosis and its complication, hepatic encephalopathy (HE) are one of the leading causes of morbidity and mortality in the US. HE is associated with gut dysbiosis that is usually treated with antibiotics, prebiotics or probiotics. However, however HE often continues to recur and cause readmissions despite this standard of care. Multiple episodes of HE can result in cumulative irreversible brain injury. Therefore the prevention of recurrent HE is an important unmet need that requires translational intervention. Fecal microbiota transplant (FMT) is an effective translational approach for recurrent Clostridium difficile. Our preliminary data suggest that a one-time administration of an FMT-enema using a rationally-selected donor via Openbiome is safe in cirrhosis and recurrent HE. However, an upper GI route is preferable for patients and could favorably impact the small intestine, where translocation often occurs. The G3 FMT capsule by Openbiome acts on the small and large intestine and is available for C.difficile. We will use one donor specifically selected from the Openbiome pool whose microbial profile best fulfils the microbiota deficits related to beneficial bacteria in HE patients, utilizing a “Precision Microbiome” approach. Ultimately the goal is to define oral FMT as a viable treatment approach for recurrent HE patients. Our hypothesis is that fecal transplants from a rationally derived donor delivered via capsules are safe and well tolerated in patients with cirrhosis and HE and are associated with significant improvement in gut microbiota composition, and mucosal defenses. The primary aim is: To evaluate the safety and tolerability of fecal transplant through oral capsules from a rationally derived donor in cirrhosis and HE from a liver disease and symptom standpoint. Secondary aims are (1) To define the changes in microbiota composition of the stool, duodenal and sigmoid colonic mucosa after oral FMT compared to pre-FMT baseline (2) To determine the effect of oral FMT on mucosal defenses by studying antimicrobial peptides, inflammatory cytokine expression and barrier protein expression compared to pre-FMT baseline. (3) To evaluate changes in systemic inflammatory cytokines and endotoxin after oral FMT compared to pre-FMT baseline. This will be an open-label trial of cirrhotic patients with HE carried out in collaboration CTSAs at Virginia Commonwealth University and the Medical College of Wisconsin along with Openbiome. Both CTSAs have expertise in the study of the gut-liver axis and mucosal defenses respectively. This research will form the platform for large, placebo-controlled, randomized trials for efficacy in this underserved population with scientific and clinical improvements in understanding of the gut-brain axis. This proposal is responsive to PA-16-343 by involving two separate CTSA hubs and performing “Translational studies of the human microbiome” and “Precision Medicine” as a method to advance knowledge within the CTSA consortium.

肝性脑病(HE)是肝硬变及其并发症的主要病因之一。 美国的死亡率。他与肠道菌群失调有关，这种病通常用抗生素、益生元或 益生菌。然而，尽管有这样的标准，他经常继续复发并导致重新入院 关心。多发HE可导致累积性不可逆脑损伤。因此，预防 复发的HE是一种重要的未得到满足的需求，需要转化性干预。粪便微生物区系移植 (FMT)是治疗复发性难辨梭菌的有效翻译方法。我们的初步数据表明 通过OpenBiome使用合理选择的供体一次性给予FMT灌肠是安全的 肝硬变和复发的HE。然而，上消化道途径对患者更可取，并可能有利地影响 小肠，经常发生移位的地方。OpenBiome的G3 FMT胶囊作用于小 和大肠，对艰难梭菌可用。我们将使用一名捐赠者，从 其微生物特征最好地满足了与HE中有益细菌相关的微生物区系缺陷的OpenBiome池 患者，利用“精密微生物组”方法。最终的目标是将口头FMT定义为可行的 复发性肝病患者的治疗方法。我们的假设是，从理性的角度来说，粪便移植 经胶囊给药的供者在肝硬变和肝硬变患者中是安全和耐受性良好的 与肠道微生物区系组成和粘膜防御能力的显著改善有关。 主要目的是：评估口服胶囊进行粪便移植的安全性和耐受性。 从肝病和症状的角度合理选择供体用于肝硬变和肝性脑病。次要目标 是(1)确定粪便、十二指肠和乙状结肠粘膜的微生物区系组成的变化 口服FMT后与FMT前的比较(2)通过以下方法确定口服FMT对粘膜防御的影响 研究抗菌肽、炎性细胞因子表达和屏障蛋白表达的比较 FMT前基线。(3)评价口服FMT后全身炎性细胞因子和内毒素的变化。 与FMT前的基线相比。这将是一项针对肝硬变合并HE患者的开放标签试验 弗吉尼亚联邦大学和威斯康星医学院的协作CTSA以及 OpenBiome。这两个CTSA分别在肠道-肝轴和粘膜防御方面具有专业知识。 这项研究将为大型、安慰剂对照、随机试验的疗效提供平台。 服务不足的人群在科学和临床上对肠道-脑轴的了解有所改善。这 提案响应PA-16-343，涉及两个独立的CTSA集线器并执行 《人类微生物组研究》和《精确医学》作为一种促进知识发展的方法 CTSA财团。