Obesity promotes Non Alcoholic Fatty Liver Diseases (NAFLD) through mechanisms involving the gut microbiota. From 2 cohorts of obese women (FLORINASH FP7), in which a multilevel omics approach was used, we identified a microbiome architecture indicating increased dietary lipids processing. This was associated with hepatic insulin signaling perturbations, a transcriptomic profile indicative of NAFLD and triglyceride accumulation. From two other cohorts (MICIMAB & ROLIVER), transcriptomic analyses from intestinal biopsies and 16S sequencing of liver samples suggested: 1. impaired intestinal defense favoring translocation of bacteria towards the liver, inflammation and lipid deposition and 2. impaired intestinal and liver lipid metabolism. The interaction between dietary lipids and the gut microbiota in the etiology of NAFLD is unknown and could impair intestinal defense and lipid handling. Using original and complementary models of genetically modified mice and germ-free mice colonized with human microbiota, we will study the impact of different lipid-enriched diets on: 1. gut microbiota and its causal role in liver disease; 2. intestinal immune- and non-immune defense systems; 3. translocation of bacteria towards the liver responsible for inflammation; 4. lipid handling processes in the liver and the intestine (bile acids/FXR and fatty acids/PPAR); 5. gender by studying the role of the estrogen receptor (ER) in the gut microbiota/dietary lipids interplay.