Fecal Microbiota Transplant in Veterans with Cirrhosis

肝硬化是退伍军人发病率和死亡率的主要原因，主要是由于并发症， 腹水和肝性脑病（HE）。HE与全身性促炎环境有关， 肠道屏障受损和肠道生态失调尽管最大限度的治疗（乳果糖/利福昔明）， 一部分退伍军人的HE持续复发，这是其护理人员和VHA的主要负担 系统我们最近发表了一项关于粪便微生物移植（FMT）的小型随机试验， 这是安全的，并防止总和HE相关的住院治疗。这是与 良好的胆汁酸（BA）和微生物变化，使用一种FMT持续>1年。类似的小口腔 胶囊FMT试验正在我们中心进行，安全性信号良好。也有证据表明，在非 FMT研究表明，无微生物部分可以与全FMT一样有效。然而， FMT在肝硬化中的应用有待进一步研究。 我们假设“通过口腔和直肠联合途径进行粪便微生物移植是安全的， 耐受性和相关的住院率较低，改善肠道微生物组成的调节， 与接受FMT治疗的患者相比，肝性脑病患者的功能和脑功能 从单独的途径或与安慰剂一起;这种改善是由微生物产品介导的”。我们将测试这个 双翻译目标假设 目的1：确定来自合理供体的FMT双重口服和直肠给药对 临床结局（住院、脑功能、生活质量）和宿主-微生物群相互作用 （具有全身性和肠道炎症的微生物组成和胆汁酸组成）， 与单种给药途径和安慰剂相比，在使用 随机II期临床试验。复发性HE门诊患者（n=100）将随机分为4组 （第1组：双重口服和直肠FMT，第2组：口服FMT和直肠安慰剂，第3组：口服安慰剂和直肠FMT，第4组：口服安慰剂和直肠安慰剂，第5组：口服安慰剂和直肠安慰剂，第6组：口服安慰剂和直肠安慰剂，第7组：口服安慰剂和直肠安慰剂，第8组：口服安慰剂和直肠安慰剂，第9组：口服安慰剂和直肠安慰剂，第10组：口服安慰剂和直肠安慰剂 FMT和第4组：口服和直肠安慰剂），并在FDA IND双盲临床试验中随访6个月。 审判FMT捐赠者将根据OpenBiome的有益分类群使用机器学习进行选择 供体（合作者），将用于所有FMT分配的受试者。主要结局为全因 住院治疗患者将接受肝硬化严重程度、脑功能、肠功能和肝功能的基线评估。 沿着收集血清和粪便，并进行粪便胆汁酸谱分析。患者将 随访至6个月的结果。我们将确定FMT对全身炎症、肠道炎症和炎症反应的影响。 渗透性、胆汁酸谱及其与组间微生物组成和临床结果的关系。 目的2：使用免疫组织化学方法测定人FMT对神经炎症和肠道微生物功能的影响。 无菌小鼠和常规无菌小鼠（无菌） 来自FMT供体的上清液。目前尚不清楚FMT材料的哪些成分，微生物或 它们的产物如胆汁酸介导其作用。由以下物质生成的完整和无微生物上清液 合并的FMT供体样品、受体的基线样品和FMT后样品将用于人源化GF 小鼠此外，传统的阿尔茨海默病小鼠将使用相同的方案接受健康的供体材料。 将研究定植后常规的血小板减少性紫癜小鼠和GF小鼠之间神经炎症的差异 以及在用整个样品和仅用微生物产物定殖的那些之间。的特定变化 将研究肠胆汁酸谱作为这些变化的介质。 该团队一直致力于临床和转化肝硬化研究的专业知识， 老兵这些结果将为未来确定FMT在肝脏疾病中的作用的试验奠定基础， 从微生物的角度帮助在这一服务不足的人群中确定更好的供体-患者匹配。

Liver cirrhosis is a major cause of morbidity and mortality in Veterans, primarily due to complications such as ascites and hepatic encephalopathy (HE). HE is linked with a systemic pro-inflammatory milieu propagated by an impaired intestinal barrier and gut dysbiosis. Despite maximal therapy (lactulose/rifaximin), a significant proportion of Veterans have HE that continues to recur, which is a major burden on their caregivers and VHA system. We have recently published a small randomized trial of fecal microbial transplantation (FMT), in this population, which was safe and prevented total and HE-related hospitalizations. This was associated with favorable bile acid (BA) and microbial changes which lasted for >1 year with one FMT. A similar small oral capsule FMT trial is underway at our center with good safety signals. There is also evidence in non-cirrhotic FMT studies that microbe-free portions can be as effective as full FMT. However, the mechanism of action of FMT in cirrhosis is needs further investigation. We hypothesize that “Fecal microbial transplant delivered from the combined oral and rectal route is safe, well- tolerated and associated with lower hospitalizations, improved modulation of gut microbial composition and functionality and brain function in patients with hepatic encephalopathy compared to those treated with FMT from either routes alone or with placebo; this improvement is mediated by microbial products”. We will test this hypothesis using two translational aims Aim 1: To determine the effect of dual oral and rectal administration of FMT from a rational donor on clinical outcomes (hospitalizations, brain function, quality of life) and host-microbiota interactions (microbial composition and bile acid composition with systemic and intestinal inflammation), compared to single route of administration and placebo, in cirrhotic patients with HE using a randomized, phase II clinical trial. Outpatients with recurrent HE (n=100) will be randomized into four groups (Group 1: Dual oral and rectal FMT, Group 2: Oral FMT and rectal placebo, Group 3: Oral placebo and Rectal FMT and Group 4: Oral and rectal placebo) and followed for 6 months under an FDA IND double-blind clinical trial. FMT donors will be selected using machine learning on the basis of beneficial taxa from OpenBiome donors (collaborator), which will be used for all FMT-assigned subjects. The primary outcome is all-cause hospitalizations. Patients will undergo baseline evaluation for cirrhosis severity, brain function, intestinal permeability along with collection of serum and stool and fecal bile acid profile analysis. Patients will be followed till 6 months for outcomes. We will define the effect of FMT on systemic inflammation, intestinal permeability, bile acid profile, and its linkage with microbial composition and clinical outcomes between groups. Aim 2: To determine the effect of human FMT on neuro-inflammation and gut microbial function using germ-free mice and conventional cirrhotic mice with microbe-rich and microbe-free (sterile) supernatants from the FMT donors. It is not clear which components of the FMT material, the microbes or their products such as bile acids, mediate its effects. Entire and microbe-free supernatants generated from pooled FMT donor samples, recipients’ baseline samples and post-FMT samples, will be used to humanize GF mice. In addition, conventional cirrhotic mice will receive healthy donor material using the same protocol. Differences in neuro-inflammation will be studied between conventional cirrhotic and GF mice after colonization and between those colonized with entire samples and with only microbial products. A specific change in intestinal bile acid profile as a mediator of these changes will be investigated. The team has been working cohesively with expertise in clinical and translational cirrhosis research in Veterans. These results will set the foundation for future trials determining the role of FMT in liver disease and help define better donor-patient matches from a microbial perspective in this underserved population.