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

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.