Restoring innate immunity in cirrhosis with faecal microbial transplantation

慢性肝病（CLD）在英国越来越常见，反复的肝损伤导致肝脏萎缩和疤痕。这被称为肝硬化，现在是英国第五大常见的死亡原因，每年造成15，200人死亡。其受害者的平均年龄比癌症或心脏病患者年轻19岁。英国的肝脏疾病是过去30年来在中风，心脏病和许多癌症等慢性疾病的健康和预期寿命方面取得巨大进步的一个明显例外。据估计，10-20%的英国人口在其一生中有发生某种程度肝病的风险。肝硬化患者发生感染的风险增加，导致住院。发展中的感染可导致致命的肝功能衰竭。在英国，降低这种不可接受的高水平过早死亡率已成为研究的优先事项。我们的身体含有数万亿种称为细菌的微生物，它们在保持我们的健康方面发挥着重要作用。这些细菌主要生活在我们的肠道中，帮助我们的免疫系统对抗感染。肝硬化患者的肠道细菌数量增加，更多的“不友好”细菌会释放破坏免疫系统的物质。这些患者通常会发生严重的感染，导致他们住院治疗，并经常死亡。我们对肠道细菌（称为肠道微生物组）如何促进CLD的发展和致命性肝衰竭的进展没有很好的了解。然而，已经证明，通过进行一种肠道细菌移植，用健康人捐赠的细菌替换肝硬化患者中不健康的肠道细菌，通常被称为“粪便移植”，正式称为“粪便微生物群移植”或“FMT”，是安全的，患者耐受性良好。FMT可以减少肠道中“不友好”细菌的数量，这对健康有益。人们越来越了解肠道细菌在维持我们的健康和免疫系统中所起的作用。肝脏与肠道密切相关，是第一个挑战细菌及其副产物从肠道逃逸的器官。这会导致免疫系统的激活，使其变得疲惫不堪，然后无法对抗感染，从而使患者易患危及生命的感染。细胞是肝硬化患者肠道细菌和免疫系统之间异常相互作用的关键调节因子，可以通过FMT进行修饰，以恢复健康的肠道微生物组并增强免疫功能。系统本研究计划的目的是确定肠道细菌调节MAIT细胞群功能的机制，这些细胞群参与驱动肝硬化的进展，并评估FMT作为恢复MAIT细胞功能的治疗方法的作用。我将从肝硬化患者FMT前后的储存样本中分离MAIT细胞，并检查它们对细菌挑战的反应。我将评估肝硬化患者体内存在的免疫细胞以及这些细胞耗尽的机制。这些创新的实验将确定肠道细菌控制免疫系统的机制，以及这一过程在肝硬化中是如何失调的。它将为FMT在肝硬化中的应用提供一个机制理论基础，并对肠道和免疫系统之间的相互作用产生更深入的理解，从而在这一日益增加的临床需求领域开发新的治疗方法。

Chronic liver disease (CLD) is becoming more common in the UK, where repeated liver damage causes the liver to become shrunken and scarred. This is known as cirrhosis of the liver which is now the fifth commonest cause of death in the UK killing 15,200 people each year. The average age of its victims is 19 years younger than those with cancer or heart disease. Liver disease in the UK stands out as the one glaring exception to the vast improvements made during the past 30 years in health and life expectancy for chronic disorders such as stroke, heart disease, and many cancers. It is estimated that 10-20% of the UK population are at risk of developing some degree of liver disease within their lifetime. Patients with cirrhosis have an increased risk of developing infections resulting in hospital admission. Developing infection can lead to fatal liver failure. Reducing this unacceptable high level of premature mortality in the UK has become a research priority.Our body contains trillions of microscopic organisms called bacteria which play an important role in keeping us healthy. These bacteria live mainly in our bowel and help our immune system fight infection. There are increased numbers of bowel bacteria in patients with cirrhosis with more 'unfriendly' bacteria which emit substances which disrupt the immune system. These patients often develop severe infections which result in them being hospitalised and often dying. We do not have a good understanding of how bowel bacteria (called the gut microbiome) contribute to the development of CLD and progression to fatal liver failure. However, it has been shown that replacing the unhealthy bowel bacteria in patients with cirrhosis with bacteria donated from a healthy person by performing a type of bowel bacteria transplant, often nicknamed a 'poo transplant' and formally known as a 'faecal microbiota transplant' or 'FMT' is safe and well tolerated by patients. FMT can reduce the numbers of 'unfriendly' bacteria in the bowel which has positive health benefits. There is a growing understanding of the role that gut bacteria play in maintaining our health and immune system. The liver is closely linked to the gut and is the first organ to challenge bacteria and their by-products escaping from the gut. This causes activation of the immune system which becomes exhausted and is then unable to fight infection predisposing patients to developing life-threatening infections.I hypothesise that recently described mucosa-associated invariant T (MAIT) cells which are key regulators of abnormal interactions between the gut bacteria and the immune system in patients with cirrhosis could be modified by FMT to restore a healthy gut microbiome and strengthen the immune system. It is the aim of this research programme to define the mechanisms by which intestinal bacteria regulate the function of MAIT cell populations implicated in driving the progression of cirrhosis and to assess the role of FMT as a treatment to restore MAIT cell function. I will be isolating MAIT cells from stored samples taken from patients with cirrhosis before and after FMT and examining their response to bacterial challenge. I will evaluate the immune cells that are present in patients with cirrhosis and the mechanisms by which these cells become exhausted. These innovative experiments will identify the mechanisms by which gut bacteria control the immune system and how this process is dysregulated in cirrhosis. It will provide a mechanistic rationale for the use of FMT in cirrhosis and generate a deeper understanding of the interplay between the gut and the immune system allowing for the development of novel treatments in this area of increasing clinical need.