Portal blood flow in humans is approximately 1000–1200 mL/min. Thus, the liver constantly confronts food-derived

antigens and bacterial components such as lipopolysaccharide (LPS) translocated from the gut into the portal vein; however, the liver has the unique capacity to induce immune tolerance. Previously, regulatory T cells (Treg), Kupffer cells, natural killer T (NKT) cells and hepatic stellate cells (HSC) were reported to contribute to immune tolerance in the liver. Interaction between Treg and Kupffer cells promotes the secretion of interleukin (IL)-10 from Treg, and the depletion of Treg breaks antigen-specific immune tolerance.[2] The depletion of liver NKT cells also exacerbates hepatic inflammation in carbon tetrachloride-induced liver injury.[3] HSC induce the apoptosis STAT inhibitor of conventional CD4+ T cells in a Fas/Fas ligand-dependent manner and increase Treg proliferation via cell–cell contact; moreover, HSC-expanded Treg express high levels of programmed cell death 1 and cytotoxic T-lymphocyte antigen 4, show enhanced production of IL-10, and cause the suppression of alloreactive CD4+ T-cell proliferation.[4] Toll-like receptors (TLR), which comprise a highly conserved

family of receptors that recognizes specific pathogen-associated molecular patterns (PAMP), play a key role in innate immunity by triggering inflammatory responses 上海皓元 to the main ligands of TLR. Various TLR are expressed on liver cells (Table 1). The liver constantly encounters various antigens, and in order to prevent organ failure due to hyperactivation of JAK activation the immune system, TLR tolerance to repeated stimuli is induced.[11] On the other hand, a breakdown in TLR tolerance

results in persistent inflammation and contributes to the development of chronic liver diseases. Singh et al.[12] reported that bacterial translocation comparably occurs in both normal and diseased livers such as primary biliary cirrhosis (PBC) and non-alcoholic steatohepatitis (NASH) although the expression of TLR2 and TLR4 is enhanced in the diseased livers than normal. In normal biliary epithelial cells (BEC), repeated LPS-stimuli induced hyporeactivity to LPS.[13] However, BEC from PBC patients show hyperreactivity to LPS.[14] Herein, we review the association of gut microbiota with the pathogenesis of chronic liver diseases such as NASH, primary sclerosing cholangitis (PSC) and PBC. NON-ALCOHOLIC FATTY LIVER disease (NAFLD) is recognized as a common liver disorder that represents the hepatic manifestation of metabolic syndrome, and encompasses a spectrum of hepatology, ranging from simple steatosis to cirrhosis.[15, 16] NASH is the progressive form of liver injury and characterized by steatosis, lobular inflammation, hepatocyte ballooning, Mallory’s hyaline and fibrosis.