Apoliprotein E is a ligand found in remnant lipoproteins that is recognized by various receptors in the liver. In humans, ApoE deficiency, or the presence of mutant forms of ApoE, results in type III hyperlipidemia characterized by the presence of elevated VLDL lipoproteins and early age onset of atherosclerosis. ApoE deficient mice are a widely used model of atherosclerosis, hyperlipidemia and steatosis. Thus, while ApoE2/2 mice develop a severe hyperlipidemia and atherosclerosis on a standard diet, they fail to develop liver inflammation, unless exposed to an additional hitting agent, making this setting a suitable model for testing the effects of therapeutic intervention on progression of lipid-related disorders in the liver and cardiovascular system. In the present study we have investigated the effects of VSL#3, a mixture of eight probiotic strains, in the progression of liver and vascular damage caused by challenging ApoE�C/�C with a low concentration of dextrane sulphate sodium, a well characterized intestinal barrier braking agent. The results of these studies demonstrate that a low grade inflammation increases intestinal permeability and leads to insulin resistance, transition from steatosis to NASH and exacerbated atherosclerosis and that all these disorders are efficiently prevented by a therapeutic intervention with a probiotic preparation. The study establishes that intervention on the intestinal microbiota is an effective therapeutic option in the treatment of systemic disorders. Because probiotic intervention resets immunoactivation and metabolism in multiple organs, we have then investigated whether it modulate the expression of nuclear receptors involved in reciprocal regulation of immune system and metabolism. Previous studies have established a role for nuclear receptors in mediating the effects of probiotics in rodent models of inflammation. Because an inverse regulation exists between several members of nuclear receptor superfamily and inflammation, we have assessed whether Lomitapide Mesylate products of probiotic metabolism might directly regulate the activity of these regulatory factors. The growing understanding of the functional role of human gut microbiota is showing that this enormous microbial population is instrumental in the control of host energy and lipid metabolism. Thus, while metagenomic studies are progressively deciphering the role of Tulathromycin B bacterial genes and proteins in the regulation of host’s metabolism, specific bacterial enterotypes have been associated to the development of human diseases such as diabetes and obesity. Despite the relation of the intestinal microbiota with the host is mutual, the mechanisms by which the intestinal immune system copes with the gut microbiota to contain local inflammation and prevent systemic dysregulation of immunity and metabolism are still poorly defined. In this report we have shown that low grade intestinal inflammation induced by administering ApoE2/2 mice with DSS results in a widespread inflammation whose signature markers were a systemic shift toward a Th1 phenotype along with a severe deterioration of the insulin signalling in the liver and adipose tissue. Because these changes were prevented by a probiotic intervention, these results highlight the central role of the intestinal microbiota in the pathogenesis of heretofore seemingly unrelated systemic inflammatory and metabolic disorders. Oxygen is essential for the survival of all eukaryotic cells, and metazoans are heavily dependent on this element to meet their large metabolic demands. At the cellular level, 90% of oxygen is consumed in oxidative phosphorylation. Consistent with a central role of oxygen in aerobic metabolism, all metazoan cells respond to an imbalance between demand and supply of oxygen by activating a gene expression program aimed at restoring oxygen supply and reducing its consumption.