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

肝硬化及其并发症肝性脑病（HE）是发病的主要原因之一， 死亡率在美国。HE与肠道生态失调有关，通常用抗生素、益生元或抗生素治疗。 益生菌然而，尽管有这种标准，但HE经常继续复发并导致再入院。 在乎多次HE发作可导致累积性不可逆脑损伤。因此，预防 复发性HE是一个重要的未满足的需求，需要翻译干预。粪便微生物群移植物 (FMT)是治疗复发性艰难梭菌的有效方法。我们的初步数据显示， 通过Openbiome使用合理选择的供体进行一次性FMT灌肠是安全的， 肝硬化和复发性HE。然而，上消化道途径对患者更可取， 小肠，在那里经常发生易位。Openbiome的G3 FMT胶囊作用于小 和大肠，并可用于艰难梭菌。我们将使用一个捐赠者， 开放生物群池，其微生物谱最能满足HE中与有益细菌相关的微生物群缺陷 患者，利用“精确微生物组”方法。最终的目标是将口服FMT定义为一种可行的 复发性HE患者的治疗方法。我们的假设是，粪便移植从一个合理的 通过胶囊输送的衍生供体在肝硬化和HE患者中安全且耐受良好， 与肠道微生物群组成和粘膜防御的显著改善有关。 主要目的是：评价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中合理来源的供体。次要目的 （1）确定粪便、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）为了确定口服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， 禁产条约前基线。(3)评价口服FMT后全身炎症细胞因子和内毒素的变化 与FMT前基线相比。这将是一项在患有HE的阿尔茨海默病患者中进行的开放标签试验， 弗吉尼亚联邦大学和威斯康星州医学院的合作CTSA沿着， 开放生物群两个CTSA分别在肠肝轴和粘膜防御研究方面具有专长。 这项研究将形成一个平台，为大型，安慰剂对照，随机试验的疗效，在这方面 在科学和临床上对肠-脑轴的理解有所改善。这 建议书是对PA-16-343的响应，涉及两个独立的CTSA中心，并执行“翻译 人类微生物组的研究”和“精准医学”作为一种方法，以推进知识在 CTSA财团。

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.