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Impact of the gut-liver axis on de novo and recurrent hepatocellular carcinoma in the presence non-alcoholic fatty liver disease

English title Impact of the gut-liver axis on de novo and recurrent hepatocellular carcinoma in the presence non-alcoholic fatty liver disease
Applicant Toso Christian
Number 182471
Funding scheme Project funding (Div. I-III)
Research institution Service de Chirurgie Viscérale Département de Chirurgie Hôpitaux Universitaires de Genève
Institution of higher education University of Geneva - GE
Main discipline Surgery
Start/End 01.01.2019 - 31.12.2022
Approved amount 632'000.00
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All Disciplines (2)

Discipline
Surgery
Internal Medicine

Keywords (4)

liver; carcinoma; obesity; hepatocellular

Lay Summary (French)

Lead
Les patients obèses accumulent de la graisse dans le foie, ce qui caractérise le NAFLD (non-alcoholic fatty liver disease). Cette maladie du foie est la plus fréquente dans les pays occidentaux. Avec le temps, ces patients peuvent aussi développer une inflammation et une fibrose hépatique (NASH : non-alcoholic steato-hepatitis), puis un cancer du foie.Les bactéries intestinales semblent participer au développement de ces maladies, mais l’importance de cet effet, et son possible traitement doivent être mieux compris.
Lay summary
Notre projet repose sur des modèles animaux de NAFLD et a pour but de:
- Explorer la possibilité de prévenir de cancer du foie chez le sujet obèse en transplantant des bactéries de souris minces. Nous étudions aussi l’effet sur le système immunitaire.
- Définir si une diminution de la pression veineuse en amont du foie (via un shunt chirurgical) peut prévenir le passage de produits bactériens depuis l’intestin, et le développement de NASH et de cancer au niveau du foie.
- Identifier si la transmission de bactérie de la mère obèse à sa descendance augmente le risque de NAFLD et de cancer du foie. Nous explorons aussi des moyens de prévenir ces anomalies.
Globalement, notre projet sur le NAFLD/NASH et sur le cancer du foie induit par le NAFLD répond à un problème épidémiologique majeur. Nous explorons les mécanismes impliqués et des possibles interventions, ce qui permettra de mieux comprendre l’effet de l’intestin sur le foie. Les traitements étudiés pourront être facilement étudiés en clinique.
Direct link to Lay Summary Last update: 26.11.2018

Responsible applicant and co-applicants

Employees

Project partner

Associated projects

Number Title Start Funding scheme
165837 Surgical management of hepatocellular carcinoma 01.01.2017 SNSF Professorships

Abstract

Patients with obesity can accumulate fat in the liver (steatosis), which is known as non-alcoholic fatty liver disease (NAFLD), the most common liver disease in Western countries. With time, immune cell infiltrate and fibrosis can appear, leading to non-alcoholic steato-hepatitis (NASH), and subsequently to hepatocellular carcinoma (HCC). An unhealthy lifestyle appears to be the main promoter of NAFLD, together with a number of identified gene variants. More recent data also suggests an impact of the bowel, as NAFLD is associated with an altered gut microbiota, and can be prevented by prebiotics, probiotics or antibiotics. However, the magnitude of the effect of the gut-liver axis on NALFD/NASH and NAFLD-related HCC and its use as a potential therapeutic target need further exploration.The current project is based on a mouse model of NAFLD with high-fat diet, and aims to:-Explore fecal microbiota transplantation (FMT) for the treatment of de novo and recurrent HCC: We will assess the magnitude of the effect of FMT, its required frequency, and its timing (early versus late). We also aim to define the mechanistic immune impact of FMT, looking at how it can modulate the anti-HCC effect of immunotherapy.-Define the impact of portal hypertension on NAFLD, and on de novo and recurrent HCC: The presence of NAFLD is associated with an increased portal pressure, which alters the bowel, increases the translocation of bacterial products, and further promotes NAFLD, creating a vicious circle. This study dissects the specific impact of portal hypertension on the bowel and the liver in a mouse model of NAFLD, and explores whether a porto-systemic shunt can interrupt the vicious circle, and prevent NAFLD as well as de novo and recurrent HCC.-Define the impact of maternal NAFLD on gut microbiota, metabolism, and HCC in the offspring: We will study whether the transmission of an altered gut microbiota from a NAFLD mother can lead to an altered metabolism and to NAFLD-related HCC in the offspring. We will identify ways to modulate this effect by lifestyle intervention in the pregnant NAFLD mouse. Finally, we will explore the underlying mechanism. The present project on NAFLD/NASH and NAFLD-related HCC is responding to a major epidemiological issue in the Western world. We will explore mechanisms and interventions that will better define the impact of the gut-liver axis. The acquired data will pave the way for translational clinical explorations looking at interventions already available in clinical practice, such as FMT, modulation of the portal pressure, and lifestyle chances during pregnancy.
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