Metabonomic Stratification of Fatty Liver Disease

Lead Research Organisation: Imperial College London
Department Name: Metabolism, Digestion and Reproduction


Non-alcoholic Fatty Liver Disease (NAFLD) refers to a spectrum of liver damage that progressively develops in four main stages and is characterized by the accumulation of excess fat in the liver. It is thought to affect 20 - 30% of western countries' population with an increasing worldwide prevalence. The exact pathogenesis of NAFLD remains incompletely understood.

In recent years the effect of the gut microbiome on liver function has been extensively studied and several gut-metabolic biomarkers have been correlated to the development of Non-alcoholic Steatohepatitis (NASH), the second stage of NAFLD. These metabolic signatures include imbalances in aromatic amino acids (AAA), branch-chain amino acids (BAA) and phenylacetic acid (PAA), which has been found to prompt the hepatic steatosis phenotype by a human-to-mouse Faecal Microbiota Transplantation (FMT).

Understanding the contribution of the metabolites produced by the gut microbiome to NASH could allow for the development of precision microbiome-targeted therapies. However, the exact molecular mechanistic links of the gut microbiome to disease progression and pathogenesis in NAFLD remain elusive. A novel approach to treat or prevent NASH may involve extensive molecular phenotyping of the microbiome for the prediction of susceptibility to NASH in patients followed by the manipulation of the gut microbiota.

There is increasing evidence that microbiome-related interventions in NAFLD such as FMT are promising however there is a lack of well-designed and standardized clinical studies. Nevertheless, until the pathways by which the gut microbiome provokes NASH are identified, the development of microbiome-targeted therapies will be restricted.

These experiments will demonstrate novel gut-microbiome metabolic signature differences between patients with NASH and healthy controls through untargeted metabolomics coupled with statistical analysis and will investigate the effectiveness of FMT as a method of gut-microbiome targeted therapy for NASH patients. This will be carried out by identifying gut-microbiota metabolic biomarkers in healthy individuals to determine the metabolic profile of the ideal donor for FMT and to establish a comprehensive control.

Desirable metabolic signatures of healthy individuals from the AIRWAVE study will be compared with metabolic profiles of NASH patients from the Biobank and the Liver Clinic at St Marys Hospital. Metabolic phenotyping is used for the detection of the most relevant gut-microbiota metabolic biomarkers associated with NASH. This will be facilitated through untargeted metabolic profiling by Nuclear Magnetic Resonance (NMR) spectroscopy and Mass Spectrometry (MS). Untargeted Metabolic Profiling allows for comprehensive analysis of the gut metabolome and the discovery of new associated metabolic biomarkers. Furthermore, the metabolic biomarkers and liver phenotypes of NASH patients post-FMT will be co-analysed and correlated to the FLORINASH dataset through untargeted metagenomics to identify the casual pathways by which the microbiome incites NASH.

In this experiment, it is hypothesised that the metabotype of patients with NASH will be reconditioned to mimic the metabolic phenotype of a healthy control post FMT and further confirmed by in-depth shotgun metagenomic analysis.


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