Multimodal profiling of inflammatory and immune cells to determine stage and treatment response in non-alcoholic steatohepatitis and type II diabetes

非酒精性脂肪肝，简称脂肪肝，是全球慢性肝病最常见的原因。它影响了欧洲三分之二的2型糖尿病患者和四分之三以上的肥胖患者。脂肪肝是由肝细胞中脂肪的积聚引起的。对于大多数人来说，脂肪肝是一种良性疾病，但六分之一的人会继续发展为侵袭性疾病，称为非酒精性脂肪性肝炎，简称NASH。NASH是肝脏中的一种炎症形式，可以损伤肝细胞。NASH可导致肝脏瘢痕形成，并最终在一些患者中导致肝硬化、肝衰竭甚至肝癌。照顾脂肪肝患者的医生和护士面临的挑战是确定哪些患者可能会发展成更具侵袭性的疾病，以便干预和治疗可以针对最需要的人。我们知道NASH患者，特别是那些肝脏有瘢痕或纤维化的患者，患晚期疾病的风险更大。然而，诊断NASH和纤维化的唯一方法是做肝活检。这是一种侵入性和昂贵的测试，涉及将针头穿过皮肤，并采取可以在显微镜下研究的肝脏小样本。虽然这是一个非常有用的测试，但不可能使用肝活检来找出数百万脂肪肝患者中哪些处于危险之中，以及谁具有不太可能进展的轻度形式。目前，一些非侵入性的血液检测或扫描是可行的，但它们本身不够准确，无法指导当今的患者护理或研究正在开发的许多新治疗方法。该项目的研究人员旨在通过了解更多关于NASH发展的方式来解决这个问题，特别关注炎症。炎症是我们身体对感染和损伤的反应。在炎症中，包括免疫细胞在内的专门细胞被打开以对抗感染和修复受损组织。肝脏炎症是NASH的主要特征，免疫细胞也可以在2型糖尿病和肥胖患者的脂肪组织和血液中找到。然而，尽管许多团队正在寻找NASH的新测试和治疗方法，但他们并没有研究免疫系统的细胞，尽管这些细胞是NASH的关键特征。这个项目将填补我们知识上的这一空白。该项目的研究人员已经发现，血液中某些免疫细胞（称为T细胞）的数量在良性脂肪肝和NASH之间存在差异，现在他们想更详细地研究这一点。他们将研究患有2型糖尿病、肥胖和脂肪肝的患者，这些患者即将接受减肥手术或减肥手术（这可以有效地治疗某些患者的脂肪肝）。研究人员将采集肝脏，脂肪组织和血液样本，并使用最先进的技术来寻找每个样本中2000多个免疫细胞中激活的所有基因。他们将比较不同阶段脂肪肝患者体内不同部位基因的开启或关闭模式。这将帮助他们了解免疫系统如何影响NASH。他们将研究他们在实验室中发现的免疫细胞，看看这些细胞是否会改变脂肪对肝细胞的毒性作用。然后，他们将在手术后一年要求接受手术的患者提供更多样本，以查看患者的免疫系统是否恢复正常，使用相同的尖端技术，这将表明他们在研究开始时发现的细胞确实是NASH问题的一部分。这项研究的结果将帮助研究人员更多地了解NASH，设计新的NASH测试，这意味着更少的人需要肝脏活检，甚至可能告诉我们未来治疗NASH的新方法。

Non-alcoholic fatty liver disease, or fatty liver for short, is the most common cause of chronic liver disease worldwide. It affects two thirds of people living with type 2 diabetes in Europe and over three quarters of people with obesity. Fatty liver is caused by a build-up of fat in liver cells. For most people, fatty liver is a benign condition, but one in six people will go on to develop the aggressive form of disease, called non-alcoholic steatohepatitis, called NASH for short. NASH is a form of inflammation in the liver and can damage the liver cells. NASH can lead to liver scarring and eventually, in some patients, to cirrhosis, liver failure and even liver cancer. The challenge to doctors and nurses looking after people with fatty liver is to identify which patients might go on to develop the more aggressive disease, so that interventions and treatments could be targeted to those at greatest need. We know that patients with NASH and particularly those with scarring or fibrosis in the liver are at greater risk of developing advanced disease. However, the only way to diagnose NASH and fibrosis is to do a liver biopsy. This is an invasive and costly test that involves passing a needle through the skin and taking a small sample of liver that can be studied under the microscope. Although it is a very useful test, it is not possible to use liver biopsy to find out which of the millions of patients with fatty liver are at risk, and who has the mild form that is unlikely to progress. Some non-invasive blood tests or scans are available, but they are not accurate enough, on their own, to guide patient care today or to study the many new treatments in development.The researchers in this project aim to address the problem by learning more about the way in which NASH develops, paying particular attention to inflammation. Inflammation is our body's response to infection and injury. In inflammation, specialised cells, including immune cells are switched on to fight infections and repair damaged tissues. Inflammation in the liver is the main feature of NASH, and immune cells can also be found in fat tissues and the blood of patients with type 2 diabetes and obesity. However, although lots of teams are looking for new tests and treatments for NASH, they are not studying cells of the immune system, despite the fact that these cells are a critical feature of NASH. This project will address this gap in our knowledge. The researchers in this project have already found that the numbers of certain immune cells, called T cells, in the blood differ between benign fatty liver and NASH and now they want to study this in more detail. They will study patients with type 2 diabetes, obesity and fatty liver who are about to have bariatric, or weight reduction surgery (which can effectively treat fatty liver in some patients). The researchers will take samples of liver, fat tissue and blood and use state-of-the-art technology to find all the genes that are activated in over 2000 individual immune cells from each specimen. They will compare the patterns of genes that are turned on or off in different parts of the body in patients with different stages of fatty liver. This will help them build a picture of how the immune system affects NASH. They will study the immune cells they discover in the laboratory and see whether these cells alter the toxic effects of fats on liver cells. They will then ask the patients who had surgery for further samples one year after the operation to see if the patients' immune systems have returned to normal, using the same cutting-edge techniques, which will indicate that the cells they discovered at the start of the study really are part of the problem in NASH. The results of this study will help the researchers understand more about NASH, design new tests for NASH that mean fewer people will need liver biopsy and may even tell us about new ways in which we can treat NASH in the future.