Dietary Interactions and Risk of Non-Alcoholic Fatty Liver Disease: Epigenetics, Immune Factors and Gut Microbiome from Cohort Studies Across India

肝病是当今世界最重要的非传染性疾病之一，每年造成200万人死亡。这种情况在低收入和中等收入国家尤其常见，在这些国家，它给卫生保健系统带来了相当大的负担。造成这种负担的部分原因是慢性乙肝和丙型肝炎，尽管我们现在有办法预防和有效治疗这些感染，许多发达国家已经为根除丙型肝炎和预防新的乙肝病例设定了现实的目标。因此，与肝炎相关的肝病的全球负担开始下降，但与此同时，与肥胖和过度饮酒有关的肝病显著增加。非酒精性脂肪性肝病(NAFLD)现在是世界上最常见的肝病，在印度也很常见，尽管在特定地区受影响的人数从10%到50%不等。非酒精性脂肪肝与肥胖有关，大多数非酒精性脂肪性肝病患者的肝脏中会有脂肪沉积。其中一小部分人的肝脏会继续发炎，这一阶段被称为非酒精性脂肪性肝炎(NASH)，并由此发展到肝硬变，这是最严重的肝脏损害形式。大多数NAFLD患者超重和/或患有包括糖尿病、血液胆固醇升高和高血压在内的代谢综合征。然而，NAFLD可以在没有这些特征的人身上发展。我们目前不明白为什么一些有风险因素的人会患上NAFLD，而另一些人则不会。此外，尤其是印度患者可能会患上“非酒精性脂肪肝”，这种病是在没有肥胖的情况下发生的。这表明肥胖和代谢综合征以外的因素可能对该人群中NAFLD和NASH的发展起重要作用。这些因素可能包括一个人的基因构成，或者他们的基因的工作方式--所谓的表观遗传因素。此外，众所周知，肠道中的细菌(微生物组)会影响人体免疫系统的工作方式，在患有肝病的患者中，肠道细菌经常发生变化。这些可能的机制因素在印度人群中都没有被研究过。我们可以从印度的三个地点接触到1000多名NAFLD患者和4000多名非NAFLD患者(作为对照)。关于他们的饮食、酒精摄入量、健康史和血液测试结果以及他们的DNA样本，已经有了广泛的信息。我们计划对招募的人进行纤维扫描--一种简单的非侵入性测试，以确定肝脏的疤痕有多严重，并观察他们的基因和表观遗传学变化。这些信息以及已有的信息将被用来确定该人群中NAFLD和NASH的风险因素。我们还将对一小部分人的尿液、血液和粪便进行实验室测试，以探索肠道细菌和身体免疫反应的变化。这些信息可能使我们能够为这种情况开发新的治疗方法。在这个项目期间收集的信息将使我们更好地了解在印度发展NAFLD和NASH的风险因素。它将允许在早期阶段识别风险人群，以便建议他们做出适当的生活方式改变，如减肥和改变饮食。它还将提供有关这种情况的实际原因的信息，这种情况可能会允许开发药物来治疗那些已经确定这种情况的人。

Liver disease is one of the most important non-infectious diseases in the world today, causing 2 million deaths each year. It is particularly common in low and middle-income countries where it imposes a considerable burden on health-care systems. Some of this burden is due to chronic hepatitis B and C infection, although we now have the means to prevent and effectively treat these infections and many developed countries have set realistic targets for eradicating hepatitis C and preventing new cases of hepatitis B. As a result, the global burden of hepatitis-related liver disease is beginning to fall, but at the same time there have been marked increases in liver disease associated with obesity and excess alcohol consumption. Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease worldwide, and is also common throughout India although the number of people affected in a given area can vary from< 10% to > 50%. NAFLD is associated with obesity, and the majority of people with NAFLD develop fatty deposits in their liver. A small number of these go on to develop inflammation in their liver and this stage is called non-alcoholic steatohepatitis (NASH) and from there to cirrhosis the most serious form of liver injury.The majority of people with NAFLD are overweight and/or have the 'metabolic syndrome' which includes diabetes, raised blood cholesterol and high blood pressure. However, NAFLD can develop in people who do not have these features. We don't currently understand why some people with risk factors develop NAFLD and others do not. Additionally, Indian patients in particular can develop 'lean NAFLD', which occurs in the absence of obesity. This suggests that factors other than obesity and the metabolic syndrome may be important for the development of NAFLD and NASH in this population. These factors could include a person's genetic makeup, or the way in which their genes work- so-called epigenetic factors. In addition, the bacteria in the gut (the microbiome) are known to affect the way in which the body's immune system works and gut bacteria are often altered in patents with liver disease. None of these possible mechanistic factors have been studied in Indian populations. We have access to over 1000 people with NAFLD, and over 4000 people without NAFLD (acting as controls) from three sites in India. Extensive information is already available on their diet, alcohol intake, health history and blood test results as well as samples of their DNA. We plan to undertake 'Fibroscans' on the people recruited-a simple non-invasive test to determine how scarred the liver is, and also to look at their genes and alterations in epigenetics. This information, together with the information already available will be used to identify risk factors for NAFLD and NASH in this population. We will also undertake laboratory tests on urine, blood and stools from a smaller subset of people to explore alteration in the bacteria in the gut and the body's immune responses. This information may allow us to develop new treatments for this condition The information gathered during this project will provide us with a better understanding of the risk factors for developing NAFLD and NASH in India. It will allow identification of people at risk at an early stage so they can be advised to make appropriate life-style changes such as weight loss and diet modification. It will also provide information on the actual 'cause' of the condition which might allow development of drugs to treat those people in whom the condition is already established.