SubsidieMeestersFATty liver disease and Gutmicrobial Alcohol Production (FATGAP)
FATGAP aims to investigate the link between gut microbiota, dietary fructose, and NAFLD-NASH, exploring pH effects and developing engineered bacteria for potential treatment.
Projectdetails
Introduction
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.
Background
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.
Pilot Data
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 ethanol production, proton pump inhibitors (PPIs) increase pH. Indeed, epidemiological data have linked PPI use with NAFLD-NASH.
Hypothesis
I therefore hypothesize that gut microbial ethanol production from dietary sugar fructose is intestinal pH dependent and is driven by PPI use in humans.
Objectives
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Link Gut Microbial Composition/Function
First, I will link gut microbial composition/function in relation to the impact of endogenous (genetic) and exogenous (medication use) factors in microbial ethanol production with NAFLD-NASH in multiethnic prospective cohorts. -
Explore Intestinal pH Variations
Second, we will explore how variations in intestinal pH affect the kinetics by which (labelled) fructose is catabolized into ethanol and how this process is regulated by (inhibitory) strains and microbially produced metabolites. -
Culture Alcohol-Degrading Bacterial Strains
Third, we aim to culture (CRISPRcas modified) alcohol-degrading bacterial strains which can degrade intestinal ethanol at all pH levels. -
Perform In Vivo Trials
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.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 2.875.663 |
| Totale projectbegroting | € 2.875.663 |
Tijdlijn
| Startdatum | 1-9-2024 |
| Einddatum | 31-8-2029 |
| Subsidiejaar | 2024 |
Partners & Locaties
Projectpartners
- STICHTING AMSTERDAM UMCpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
MANUNKIND: Determinants and Dynamics of Collaborative ExploitationThis project aims to develop a game theoretic framework to analyze the psychological and strategic dynamics of collaborative exploitation, informing policies to combat modern slavery. | ERC STG | € 1.497.749 | 2022 | Details |
Elucidating the phenotypic convergence of proliferation reduction under growth-induced pressureThe UnderPressure project aims to investigate how mechanical constraints from 3D crowding affect cell proliferation and signaling in various organisms, with potential applications in reducing cancer chemoresistance. | ERC STG | € 1.498.280 | 2022 | Details |
Uncovering the mechanisms of action of an antiviral bacteriumThis project aims to uncover the mechanisms behind Wolbachia's antiviral protection in insects and develop tools for studying symbiont gene function. | ERC STG | € 1.500.000 | 2023 | Details |
The Ethics of Loneliness and SociabilityThis project aims to develop a normative theory of loneliness by analyzing ethical responsibilities of individuals and societies to prevent and alleviate loneliness, establishing a new philosophical sub-field. | ERC STG | € 1.025.860 | 2023 | Details |
MANUNKIND: Determinants and Dynamics of Collaborative Exploitation
This project aims to develop a game theoretic framework to analyze the psychological and strategic dynamics of collaborative exploitation, informing policies to combat modern slavery.
Elucidating the phenotypic convergence of proliferation reduction under growth-induced pressure
The UnderPressure project aims to investigate how mechanical constraints from 3D crowding affect cell proliferation and signaling in various organisms, with potential applications in reducing cancer chemoresistance.
Uncovering the mechanisms of action of an antiviral bacterium
This project aims to uncover the mechanisms behind Wolbachia's antiviral protection in insects and develop tools for studying symbiont gene function.
The Ethics of Loneliness and Sociability
This project aims to develop a normative theory of loneliness by analyzing ethical responsibilities of individuals and societies to prevent and alleviate loneliness, establishing a new philosophical sub-field.
Vergelijkbare projecten uit andere regelingen
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
Metabolic Gut Inflammation in Crohn's diseaseThis project aims to investigate how dietary polyunsaturated fatty acids trigger gut inflammation in Crohn's disease, establishing a link between diet and disease progression for potential therapeutic strategies. | ERC STG | € 1.493.875 | 2022 | Details |
Understanding Metabolic Activation of Dendritic Cells in Non-Alcoholic Fatty Liver DiseaseThis project aims to investigate the role of conventional dendritic cells in non-alcoholic steatohepatitis by exploring their immuno-metabolic functions and interactions with liver metabolism. | ERC STG | € 2.406.250 | 2022 | Details |
Validation of a new drug target in non-alcoholic steatohepatitisThis project aims to explore oxidative stress's role in non-alcoholic steatohepatitis (NASH) and develop new treatments by targeting MAP kinases p38 and JNK. | ERC POC | € 150.000 | 2023 | Details |
Vascular Control of NASH ProgressionThis project aims to characterize the gut-liver vasculature in NASH progression using spatial sorting and imaging to identify therapeutic targets and prognostic markers for HCC. | ERC COG | € 1.741.250 | 2024 | Details |
Metabolic Gut Inflammation in Crohn's disease
This project aims to investigate how dietary polyunsaturated fatty acids trigger gut inflammation in Crohn's disease, establishing a link between diet and disease progression for potential therapeutic strategies.
Understanding Metabolic Activation of Dendritic Cells in Non-Alcoholic Fatty Liver Disease
This project aims to investigate the role of conventional dendritic cells in non-alcoholic steatohepatitis by exploring their immuno-metabolic functions and interactions with liver metabolism.
Validation of a new drug target in non-alcoholic steatohepatitis
This project aims to explore oxidative stress's role in non-alcoholic steatohepatitis (NASH) and develop new treatments by targeting MAP kinases p38 and JNK.
Vascular Control of NASH Progression
This project aims to characterize the gut-liver vasculature in NASH progression using spatial sorting and imaging to identify therapeutic targets and prognostic markers for HCC.