Integrated Phenotyping of the Gut-plAtelet-Liver AXIS in the Progression of Chronic Liver Disease (iGAL-AXIS)

Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver diseases and is now considered a global health problem. NAFLD is a spectrum of diseases ranging from simple hepatic steatosis (NAFL) to non-alcoholic Steatohepatitis (NASH). Over time, NAFLD may progress to cirrhosis and ultimately to hepatocellular carcinoma (HCC). The gold-standard for diagnosis is liver biopsy that allows to discriminate different types of steatosis, characterized by the accumulation of lipid droplets of different sizes in hepatocytes, with the largest droplets associated with the development of fibrosis and the severity of the disease. Future studies are needed to identify non- invasive diagnostic approaches alternative to liver biopsy. NAFLD is not considered a "hepato-centric" condition anymore. Bi-directional metabolic and immune lanes of communication with other organs, such as the gut, have been decoded. Gut dysbiosis, increased gut permeability and bacterial translocation within portal circulation have been reported in NAFLD, suggesting that the gut-liver axis represents a source of systemic and hepatic inflammation. Many studies suggest that platelets may be the link between gut and liver dysfunction. Beyond their role in hemostasis platelets can sense PAMPs and DAMPs and actively participate in the inflammatory response and in tissue remodeling, by releasing bioactive molecules and by interacting with leukocytes. Gut-derived metabolites and bacterial endotoxins promote platelet hyper-reactivity and recent studies point to an important role of platelets in regulating chronic liver inflammation. Platelet-derived cytokines, such as TGF-β, PDGF-β and CXCL4 promote hepatic fibrosis, and platelet count has been used as a surrogate marker of liver fibrosis FIB-4 index). Platelet number and platelet aggregates are increased in liver sinusoids of NASH patients and colocalise with neutrophil extracellular traps (NETs). In mice it was shown that platelet colonization of the liver is a critical step for the recruitment of CD8+ T cells and NKT cells, which drive NASH progression through the release of cytokines and the metabolic reprogramming of hepatocytes. In humans, inhibition of platelets with a combination of aspirin and clopidogrel has been shown to reduce the development of NASH and subsequent progression to cirrhosis and HCC. Mechanistic insights suggest that the role of platelets in NAFLD progression is mediated through the interaction with immune cells.