Crosstalk between intestine-microbiota-liver in steatohepatitis and progression to cellular hepatocarcinome in mice

• Grant number: 24/16241-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2025
• End date: June 30, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Mariana Mesquita Fonseca
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 20/04159-8 - mTORC2 and mTORC1 biology and involvement in steatosis development and progression to steatohepatitis and hepatocellular carcinoma, AP.TEM

Abstract

The high prevalence of Metabolic Associated Fatty Liver Disease (MAFLD) and the incomplete understanding of the molecular mechanisms underlying its development and progression, particularly in advanced stages such as cirrhosis and hepatocellular carcinoma (HCC), pose significant challenges to public health. Preliminary studies suggest that the intestinal microbiota plays a crucial role in the progression of these diseases, both in humans and animal models. This project aims to investigate the interactions between the intestine, the intestinal microbiota, and the liver in the progression of non-alcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) in male mice using two experimental models: one genetically induced by the deletion of Pten and Raptor in hepatocytes, and the other through a choline-deficient and low-methionine diet (CDA). The project will analyze the bacterial composition of the microbiota, the hepatic and serum metabolome, and alterations in intestinal permeability and inflammation. Additionally, the impact of microbiota depletion through antibiotics and microbiota transfer via fecal microbiota transplantation (FMT) on disease progression will be evaluated. The objective is to characterize the molecular mechanisms involved, enabling the identification of new therapeutic targets and providing a solid scientific foundation for the development of novel strategies aimed at treating MAFLD and its more severe complications. (AU)