The vision of GALAXY is to optimize personalized healthcare, by stratifying individuals who would benefit from targeted healthcare efforts versus those who would not, and thus to reduce the economic burden for health care systems and to improve health outcome for the patients.
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.
GALAXY is unique in this perspective that we will achieve a better understanding, deliver novel biomarkers and simultaneously test the clinical impact of altering the microbiome in order to prevent disease progression.
New avenues for understanding the complex clinical phenotypes in alcoholic liver disease
Alcoholic liver disease is a complex, multifactorial disease. There is increasing evidence that gut microbial dysbiosis, where the microbiome becomes unbalanced and the symbiotic relationship between the host and microbiome is lost, plays a role in liver diseases. GALAXY studies the gut–liver axis of patients at risk to develop cirrhosis through a large clinical study. GALAXY goes beyond the state-of-the-art by studying the host and gut microbiome in patients with alcoholic liver fibrosis, thereby providing a new avenue of understanding of how alcoholic liver fibrosis develops in people with alcohol overuse.
Development and application of systems medicine approaches
For complex and multifactorial diseases, individual factors involved in the etiology of the disease often do not explain the disease. In the case of alcoholic liver fibrosis, even alcohol use is not a good predictor of the disease, highlighting the importance of an integrative approach that takes multiple factors into account. Given the role of gut-liver axis in alcoholic liver fibrosis, it is imperative to characterize this axis. However, simple and isolated readouts are not sufficient to characterize this axis, as this axis equally affects liver, gut, gut microbiome and host metabolism, among others. Thus GALAXY will develop and apply a systems medicine approach to model the gut-liver axis in the pathophysiology of alcoholic liver fibrosis. GALAXY will perform metatranscriptomics, metagenomics, genomics and metabolomics of liver, blood, faeces and urine. Novel systems medicine tools will be developed to combine and integrate the different datasets.
Integration of biomedical and clinical data to produce or refine disease models using advanced statistical, computational and mathematical approaches
GALAXY integrates metatranscriptomics, metagenomics, genomics and metabolomics of liver, blood, faeces and urine in combination with clinical data of healthy controls and alcohol over-consuming patients.
Validation of the predictive value of such models in well-phenotyped patient cohorts, taking due account of gender
GALAXY builds upon multi–omics analyses and data from extensive clinical investigations and clinical data to establish biomarkers that are able to identify alcohol over-using persons at risk to develop alcoholic liver disease. We will validate our model and associated biomarkers through a novel clinical study where. Extra attention will be given to gender analysis since females are more susceptible to alcoholic liver disease than men from an unknown mechanism, whereas alcohol overuse is more commonly seen in men.