Liver (non-alcoholic fatty liver disease)
Dr Marc-Emmanuel Dumas

Institution: Imperial College London
Title: Precision medicine through integrative metagenomics and phenomics in a human NAFLD cohort
Project Start Date:  1 March 2019
Completion Date: 28 August 2021

Summary:

Non-alcoholic fatty liver disease (NAFLD) starts with the build-up of fat in the liver and can lead to scarring and cirrhosis, where the scarred liver eventually shrinks and the risks of organ failure and cancer increase. Fatty liver also increases the risk of developing diabetes and cardiovascular diseases. One in three adults may have the early stages of NAFLD and patients may show few or no symptoms until the disease is advanced. While NAFLD can be diagnosed through ultrasound scan, it may not be detected until there is significant, potentially irreversible, liver damage.

The microbiome – all the genetic material carried by our gut microbes – is made of more than 10 million genes. The microbiome helps us break down foods we could otherwise not digest (e.g. fibre) to produce chemicals that help keep us healthy. In obesity, gut microbes lose the ability to make beneficial chemicals and instead start producing ones setting us on a disease track. In our recent study of 56 obese women, we saw a reduction in microbiome gene diversity in women with early-stage NALFD and found one microbial chemical contributed directly to fat accumulation in the liver.

We will attempt to answer the following questions:

• Can we further characterise the collapse in microbiome gene diversity we spotted in fatty liver disease?
• Can we identify new risk factors beyond obesity driving this reduction in microbiome gene diversity/function?
• Can we identify new protective microbial markers (i.e. microbiome genes or chemicals) and, thereby, new interventions preventing fatty liver disease?

To answer these questions, we will sequence the faecal metagenomes of 300 obese patients with or without NAFLD including 71 subjects before and after bariatric surgery (5 years of follow-up). This will give us greater insight into the reduction in microbiome gene diversity in NAFLD and microbiome functions associated with NAFLD than our previous small-scale study.

We will characterise new risk factors influencing the microbiome in NAFLD, beyond age, sex or obesity, using an extensive database (over 100 clinical measures) that we have compiled over the course of previous studies.

To identify signatures made of microbial markers of fatty liver disease between obese patients with and without NAFLD, we will study microbiome make-up, diversity and function together with clinical and biological data already collected from these patients – including blood and urine chemicals and liver biopsies.