Restoring innate immunity in cirrhosis with faecal microbial transplantation

Chronic liver disease (CLD) is becoming more common in the UK, where repeated liver damage causes the liver to become shrunken and scarred. This is known as cirrhosis of the liver which is now the fifth commonest cause of death in the UK killing 15,200 people each year. The average age of its victims is 19 years younger than those with cancer or heart disease. Liver disease in the UK stands out as the one glaring exception to the vast improvements made during the past 30 years in health and life expectancy for chronic disorders such as stroke, heart disease, and many cancers. It is estimated that 10-20% of the UK population are at risk of developing some degree of liver disease within their lifetime. Patients with cirrhosis have an increased risk of developing infections resulting in hospital admission. Developing infection can lead to fatal liver failure. Reducing this unacceptable high level of premature mortality in the UK has become a research priority.

Our body contains trillions of microscopic organisms called bacteria which play an important role in keeping us healthy. These bacteria live mainly in our bowel and help our immune system fight infection. There are increased numbers of bowel bacteria in patients with cirrhosis with more 'unfriendly' bacteria which emit substances which disrupt the immune system. These patients often develop severe infections which result in them being hospitalised and often dying.
We do not have a good understanding of how bowel bacteria (called the gut microbiome) contribute to the development of CLD and progression to fatal liver failure. However, it has been shown that replacing the unhealthy bowel bacteria in patients with cirrhosis with bacteria donated from a healthy person by performing a type of bowel bacteria transplant, often nicknamed a 'poo transplant' and formally known as a 'faecal microbiota transplant' or 'FMT' is safe and well tolerated by patients. FMT can reduce the numbers of 'unfriendly' bacteria in the bowel which has positive health benefits.

There is a growing understanding of the role that gut bacteria play in maintaining our health and immune system. The liver is closely linked to the gut and is the first organ to challenge bacteria and their by-products escaping from the gut. This causes activation of the immune system which becomes exhausted and is then unable to fight infection predisposing patients to developing life-threatening infections.

I hypothesise that recently described mucosa-associated invariant T (MAIT) cells which are key regulators of abnormal interactions between the gut bacteria and the immune system in patients with cirrhosis could be modified by FMT to restore a healthy gut microbiome and strengthen the immune system. It is the aim of this research programme to define the mechanisms by which intestinal bacteria regulate the function of MAIT cell populations implicated in driving the progression of cirrhosis and to assess the role of FMT as a treatment to restore MAIT cell function.

I will be isolating MAIT cells from stored samples taken from patients with cirrhosis before and after FMT and examining their response to bacterial challenge. I will evaluate the immune cells that are present in patients with cirrhosis and the mechanisms by which these cells become exhausted.

These innovative experiments will identify the mechanisms by which gut bacteria control the immune system and how this process is dysregulated in cirrhosis. It will provide a mechanistic rationale for the use of FMT in cirrhosis and generate a deeper understanding of the interplay between the gut and the immune system allowing for the development of novel treatments in this area of increasing clinical need.

Background: Chronic liver disease (CLD) is characterised by perturbations in the healthy gut microbiome with reduced microbial diversity and relative over-expression of pathogenic species termed 'cirrhotic dysbiosis'. This correlates with the severity of underlying liver disease and predicts survival. Cirrhotic dysbiosis is associated with gut barrier dysfunction and bacterial translocation, culminating in systemic inflammation and driving profound innate immune dysfunction. Faecal microbial transplantation (FMT) is a novel therapeutic strategy undergoing randomised controlled trial (RCT) evaluation in patients with advanced cirrhosis however the cellular and molecular mechanisms underlying its beneficial impact are poorly understood.

Hypothesis: We have developed a research tissue biobank of cirrhotic patients at baseline and on days 7, 30 and 90 following FMT (n=24) or placebo (n=8). Our preliminary work demonstrates stark contrasts in the diversity and type of bacterial species in patients with CLD that is sustainably impacted upon by FMT. I hypothesize that FMT will ameliorate MAIT cell dysfunction and restore systemic innate immunity in patients with CLD and cirrhosis-associated immune dysfunction (CAID).

Key Goals:
- To explore whether FMT restores peripheral MAIT cell frequency and function in cirrhotic patients.
- To investigate the oligoclonal MAIT cell repertoire in cirrhotic dysbiosis and the impact of FMT.

This project proposal will be the first demonstration of links between chronic perturbations of the gut microbiome in cirrhosis and the reshaping of innate immunity in a human model of dysbiosis. These experiments will advance our understanding of microbiota-host interactions and will offer mechanistic rationale for the use of FMT to manipulate immune cell function, not only in cirrhotic patients but also in other diseases with underlying dysbiosis.