FATty 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.

Subsidie
€ 2.875.663
2024

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

  1. 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.

  2. 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.

  3. 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.

  4. Perform Intervention 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

Startdatum1-9-2024
Einddatum31-8-2029
Subsidiejaar2024

Partners & Locaties

Projectpartners

  • STICHTING AMSTERDAM UMCpenvoerder

Land(en)

Netherlands

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