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

非酒精性脂肪性肝病，简称脂肪肝，是世界范围内最常见的慢性肝病病因。它影响了欧洲三分之二的2型糖尿病患者和超过四分之三的肥胖者。脂肪肝是由肝细胞中的脂肪堆积引起的。对大多数人来说，脂肪肝是一种良性疾病，但六分之一的人会发展成一种侵袭性疾病，称为非酒精性脂肪性肝炎，简称NASH。NASH是一种肝脏炎症，会损害肝细胞。NASH可导致肝脏瘢痕形成，并最终在一些患者中导致肝硬化、肝功能衰竭甚至肝癌。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，以便针对那些最需要的患者进行干预和治疗。我们知道，NASH患者，特别是那些肝脏有瘢痕或纤维化的患者，发展为晚期疾病的风险更大。然而，诊断NASH和纤维化的唯一方法是肝活检。这是一种侵入性且昂贵的测试，需要将针头穿过皮肤，取一小块肝脏样本，然后在显微镜下进行研究。虽然这是一项非常有用的检查，但不可能通过肝活检来发现数百万脂肪肝患者中哪些有风险，哪些是不太可能进展的轻度脂肪肝。一些非侵入性血液检查或扫描是可用的，但它们本身不够准确，无法指导今天的患者护理或研究许多正在开发的新治疗方法。该项目的研究人员旨在通过更多地了解NASH的发展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特殊细胞被激活来对抗感染和修复受损组织。肝脏炎症是NASH的主要特征，在2型糖尿病和肥胖患者的脂肪组织和血液中也可以发现免疫细胞。然而，尽管许多团队正在寻找新的NASH测试和治疗方法，但他们并没有研究免疫系统细胞，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，良性脂肪肝和NASH患者血液中某种称为T细胞的免疫细胞的数量不同，现在他们希望对此进行更详细的研究。他们将研究即将进行减肥或减肥手术的2型糖尿病、肥胖和脂肪肝患者（这可以有效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，从每个样本中找到2000多个个体免疫细胞中被激活的所有基因。他们将比较不同阶段脂肪肝患者体内不同部位开启或关闭的基因模式。这将帮助他们建立免疫系统如何影响NASH的图像。他们将研究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，他们将在手术一年后要求接受手术的患者进一步取样，看看患者的免疫系统是否已经恢复正常，使用同样的尖端技术，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.