Liver and gut widely communicate through the bile ducts, the portal vein and the systemic mediators: this relationship is called the gut-liver axis (GLA), in which bile acids (BA) and their receptors play a critical role. GLA strongly influences inflammatory processes and immune responses. GLA dysfunctions underlie several hepatic metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
NAFLD includes a wide spectrum of chronic liver disorders ranging from liver steatosis to NASH, the latter characterized by different degrees of inflammation, hepatocellular damage and fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but recent evidences a role of gut microbiota and GLA dysfunction.
The present project aims to assess the role of intestinal inflammation in contributing to NAFLD occurrence and its progression into NASH. Particular emphasis will be placed on the relationship between gut inflammation, the associated microbial dysbiosis, bile receptor expression and NASH severity.
For this purpose, two murine models of NASH (High fat diet (HFD) treatment) and NASH+gut inflammation (HFD+ dextran sodium sulfate (DSS) treatments) as well as liver specimens from children with NASH and co-cultures of intestinal (Cavco2) and liver (HepG2) cells will be used.
The expression of BA receptors (FXR, PXR, TGR) and inflammatory cytokines (IL-6, IL-1beta, TNFalpha) will be analyzed by RT-PCR and will be related to gut inflammation and liver disease severity. The composition of gut microbiota will be assessed in mice fecal specimens, through NGS metagenomics. The potential use of glycyrrethic acid (DPG) to improve liver damage by reducing gut inflammation will be also analyzed.
This study will improve the knowledge of NASH pathogenesis by focusing on the GLA role aiming at exploring how the occurrence of gut inflammation influences the severity and progression of the disease.
