Fecal Microbiota Transplant in Veterans with Cirrhosis

肝硬变是退伍军人发病率和死亡率的主要原因，主要原因是并发症，如 腹水和肝性脑病(HE)。他与一种全身性促炎环境有关， 肠道屏障受损和肠道生物失调。尽管进行了最大限度的治疗(乳果糖/利福昔明)，但显著 退伍军人中有一部分HE持续复发，这对他们的照顾者和VHA来说是一个主要负担 系统。我们最近发表了一项粪便微生物移植(FMT)的小型随机试验。 这是安全的，并防止了总住院和与HE相关的住院。这与 良好的胆汁酸(BA)和微生物变化，持续一年的FMT。一种类似的小口 胶囊FMT试验正在我们的中心进行，安全信号良好。在非肝硬变患者中也有证据表明 FMT研究表明，不含微生物的部分可以与完全FMT一样有效。然而，它的作用机制 FMT在肝硬变中的作用有待进一步研究。 我们假设“从口腔和直肠联合途径进行的粪便微生物移植是安全的，嗯- 耐受并与较低的住院率相关，改善肠道微生物组成的调节，以及 肝性脑病患者与FMT治疗患者的功能和脑功能比较 无论是单独使用还是使用安慰剂；这种改善都是由微生物产品介导的。我们将对此进行测试 使用两个翻译目的的假设 目的1：确定合理供者的FMT口服和直肠双重给药的效果。 临床结果(住院、脑功能、生活质量)和宿主-微生物区系的相互作用 (微生物组成和胆汁酸组成与全身和肠道炎症)， 与单一给药途径和安慰剂相比，在肝硬变患者中使用 随机、II期临床试验。门诊复发肝性脑病患者(n=100)随机分为四组 (第1组：口服直肠FMT，第2组：口服FMT+直肠安慰剂，第3组：口服安慰剂+直肠 FMT和第4组：口服和直肠安慰剂)，在FDA IND双盲临床试验下随访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 捐赠者(合作者)，将用于所有FMT分配的受试者。主要结果是一切原因。 住院治疗。患者将接受肝硬变严重程度、脑功能、肠道的基线评估 通透性与采集的血清和大便及粪便胆汁酸谱分析。病人将会是 术后随访至6个月。我们将确定FMT对全身炎症、肠道 渗透性、胆汁酸分布及其与微生物组成和临床结果之间的联系。 目的：研究人FMT对神经炎症和肠道微生物功能的影响。 无菌小鼠和常规肝硬变小鼠富含微生物和无微生物(无菌) 来自FMT捐赠者的上清液。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，是其影响的中介。产生的完整和无微生物的上清液 混合的FMT供体样本、受者的基线样本和FMT后样本将用于使GF人性化 老鼠。此外，传统的肝硬变小鼠将使用相同的方案接受健康的供体材料。 定植后，将研究传统肝硬变小鼠和正常小鼠神经炎症的差异。 以及那些用整个样本定居的和只用微生物产品定居的。一项具体的变化 肠道胆汁酸谱作为这些变化的中介将被调查。 该团队一直与临床和转化性肝硬变研究方面的专业知识紧密合作 退伍军人。这些结果将为未来的试验确定FMT在肝脏疾病和 从微生物的角度帮助在这一服务不足的人群中定义更好的捐赠者与患者匹配。

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.