Dietary Interactions and Risk of Non-Alcoholic Fatty Liver Disease: Epigenetics, Immune Factors and Gut Microbiome from Cohort Studies Across India 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. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.