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

基本信息

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
项目类别：
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

项目摘要

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.

肝硬化及其并发症肝性脑病（HE）是发病率和死亡率的主要原因之一在美国，HE 的死亡率与肠道菌群失调有关，通常用抗生素、益生元或抗生素来治疗。然而，尽管有这样的标准，HE 仍经常复发并导致再入院。 HE 的多次发作可导致累积性不可逆转的脑损伤。复发性 HE 是一个重要的未满足需求，需要转化干预。（FMT）是治疗复发性艰难梭菌的有效转化方法。我们的初步数据表明：通过 Openbiome 合理选择的捐赠者进行一次性 FMT 灌肠是安全的然而，上消化道途径更适合患者，并且可能产生有利影响。 Openbiome 的 G3 FMT 胶囊作用于小肠。和大肠，可用于艰难梭菌。我们将使用从其中专门挑选的一名供体。开放生物组库，其微生物特征最能满足 HE 中与有益细菌相关的微生物群缺陷最终目标是将口服 FMT 定义为可行的方法。我们的假设是，粪便移植可以合理地治疗复发性 HE 患者。通过胶囊输送的衍生供体对于肝硬化和 HE 患者来说是安全且耐受性良好的与肠道微生物群组成和粘膜防御的显着改善有关。主要目的是：评估通过口服胶囊进行粪便移植的安全性和耐受性从肝脏疾病和症状的角度来看，肝硬化和 HE 的合理来源捐献者是次要目标。 (1) 定义粪便、十二指肠和乙状结肠粘膜微生物群组成的变化口服 FMT 后与 FMT 前基线相比 (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、炎症细胞因子表达和屏障蛋白表达的比较 (3) 评估口服 FMT 后全身炎症细胞因子和内毒素的变化。与 FMT 前基线相比，这将是一项针对肝硬化 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合作 CTSA Openbiome。两位 CTSA 分别在肠肝轴和粘膜防御研究方面拥有专业知识。这项研究将构成大型、安慰剂对照、随机试验的平台，以验证该研究的有效性。服务不足的人群在科学和临床上对肠脑轴的理解有所改善。该提案由两个独立的 CTSA 中心响应 PA-16-343，并执行涉及“翻译人类微生物组的研究”和“精准医学”作为推进知识的方法 CTSA 联盟。