Project description
Exploring the role of gut microbiota in fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is a condition where fat accumulates in the liver without excessive alcohol consumption. NAFLD has been linked to obesity and can lead to non-alcoholic steatohepatitis (NASH), which involves liver inflammation and damage. The ERC-funded FATGAP project focuses on how NAFLD and NASH are linked to gut microbiota, known for their role in metabolism and digestion. Preliminary data show that obese individuals with NAFLD-NASH demonstrate higher production of ethanol from dietary sugars such as fructose. Researchers will investigate the impact of genetic factors and medication use on microbial ethanol production
Objective
Obesity and subsequent non-alcoholic hepatic steatosis (NAFLD-NASH) are important determinants of morbidity and mortality being imbalanced between ethnicities living in Europe. However, relatively little is known about the underlying aetiology that drives NAFLD-NASH and currently no treatment is available. We and others have mapped alterations in gut microbiota to metabolic disease, focusing on the bacterial functions. FATGAP builds on our work showing that 40% of obese humans with NAFLD-NASH are characterized by high production of the (endogenous) microbially produced metabolite ethanol derived from mixed acid fermentation of dietary sugars. Our pilot data show that catabolism of the dietary sugar fructose by (small) intestinal high ethanol producing bacterial strains relates to increased plasma levels of this metabolite. While acidic by-products of mixed acid fermentation lower intestinal pH thereby inhibiting the ethanol production, proton pump inhibitors (PPIs) increase pH. Indeed, epidemiological data have linked PPI use with NAFLD-NASH. I therefore hypothesize that gut microbial ethanol production from dietary sugar fructose is intestinal pH dependent and is driven by PPI use in humans. First, I will link gut microbial composition/function in relation to impact of endogenous (genetic) and exogenous (medication use) factors in microbial ethanol production with NAFLD-NASH in multiethnic prospective cohorts Second, we will explore how variations in intestinal pH affect kinetics by which (labelled) fructose is catabolized into ethanol and how this process is regulated by (inhibitory) strains and microbially produced metabolites. Third, we aim to culture (CRISPRcas modified) alcohol-degrading bacterial strains which can degrade intestinal ethanol at all pH levels. Finally, I will perform in vivo animal and human intervention trials with these identified (engineered) lead bacterial strains and study the effect in human NAFLD-NASH.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Keywords
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2023-ADG
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1081 HV Amsterdam
Netherlands
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