Strongly associated with the epidemics of obesity and type 2 diabetes mellitus (T2DM) that are testing healthcare systems worldwide, Non-Alcoholic Fatty Liver Disease (NAFLD) is an increasingly common cause of advanced liver disease in the aging population of Europe. NAFLD is a spectrum of hepatic fat accumulation (steatosis); steatosis plus inflammation (non-alcoholic steatohepatitis, NASH); fibrosis/cirrhosis; and hepatocellular carcinoma in the absence of high alcohol consumption. Up to 30% of the EU population have NAFLD, which will be the main aetiology underlying liver transplants by 2020. However, NAFLD is characterized by substantial inter-patient variability in severity and rate of progression. What determines this is unknown. A large population is at risk, but only some experience morbidity. NAFLD severity is currently best assessed by liver biopsy, an invasive, costly and risky procedure - factors that hinder treatment. There is a need to understand the biological and environmental factors that drive inter-patient variability and to develop robust and more acceptable methods for diagnosis, risk stratification and therapy so that effective medical care may be targeted to those that will benefit most. The overall EPoS concept is that improved understanding of pathogenic processes and drivers of disease progression will best be achieved when multiple ‘omics’ approaches are applied to a single cohort of patients to build a multi-dimensional record of how systems are perturbed across the entire spectrum of disease. NAFLD sits at the intersection of key biological processes: carbohydrate/lipid homeostasis, immune/inflammatory activation, wound healing/fibrosis and cancer biology. Once completed, EPoS promises to deliver a substantial and definitive atlas of pathophysiological variation across a spectrum of progressive liver disease. Translation of these findings will therefore impact on closely related pathologies including T2DM and cardiovascular disease.

Alcohol overuse is an important societal challenge with annual healthcare costs of over €22 billion in Europe. Alcohol is the main cause of liver cirrhosis, which is the 5th and 7th most common cause of life years lost in respectively Eastern and Western Europe. Cirrhosis is considered irreversible but its precursor, liver fibrosis, is reversible when detected before disease progression. GALAXY proposes that crosstalk between the gut microbiome and the liver influences the development and progression of alcoholic liver fibrosis. Here, a ‘dysbiotic’ microbiome in susceptible individuals leads to progressive liver fibrosis in combination with alcohol overuse. Therefore, interventions aiming to restore a healthy gut microbiome will reduce disease development. We will use state-of-the-art systems medicine tools to improve understanding of the complex interplay present during alcoholic liver fibrosis, to identify at-risk individuals in time and to develop personalised healthcare strategies for alcohol over-users (20% of the EU population >15 years old). GALAXY brings together partners with unique research competences in clinical hepatology, microbiome, multi-omics, biomarkers and bioinformatics. Our aim is to develop novel systems medicine tools which integrate clinical, multi-omics and lifestyle information from alcohol over-users at various stages of the disease and healthy individuals in order to: 1) identify signatures of host-microbial cross-talk during disease development and progression, 2) translate this into biomarkers for diagnosis, stratification and treatment monitoring in alcohol over users, and 3) evaluate new interventions to modulate gut microbiota towards prevention and mitigation of the disease in at-risk individuals. We will also study societal and economic impact of GALAXY biomarkers and treatments to accelerate future development. The GALAXY consortium includes strong SME partners who will enable the results to be exploited commercially.