| Author |
Douhara, Akitoshi Kawaratani, Hideto Nishimura, Norihisa Namisaki, Tadashi Fukui, Hiroshi Moriya, Kei Noguchi, Ryuichi Takeda, Kosuke Yoshiji, Hitoshi Kitade, Mitsuteru Aihara, Yosuke Okura, Yasushi Kaji, Kosuke |
| Description |
Country affiliation: Japan Author Affiliation: Douhara A ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Moriya K ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Yoshiji H ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Noguchi R ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Namisaki T ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Kitade M ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Kaji K ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Aihara Y ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Nishimura N ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Takeda K ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Okura Y ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Kawaratani H ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.); Fukui H ( Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 6348521, Japan.) |
| Abstract |
Previous clinical studies have demonstrated that endotoxin/tolllike receptor 4 (TLR4) signaling is critical in the inflammatory pathways associated with nonalcoholic steatohepatitis (NASH). In human and animal studies, NASH was associated with portal lipopolysaccharide (LPS) and the plasma LPS level was hypothesized to be associated with small intestinal bacterial overgrowth, change in composition of the microbiota and increased intestinal permeability. The aim of the present study was to investigate the roles of endogenous endotoxin and TLR4 in the pathogenesis of NASH. The effects of antibiotics were assessed in vivo using a choline deficiency amino acid (CDAA)induced experimental liver fibrosis model. Antibiotics, including polymyxins and neomycins, were orally administered in drinking water. Antibiotics attenuated hepatic stellate cell (HSC) activation and liver fibrosis via TGFß and collagen in an experimental hepatic fibrosis model. The mechanism by which antibiotics attenuated LPSTLR4 signaling and liver fibrosis was assessed. Notably, TLR4 mRNA level in the liver was elevated in the CDAA group and the CDAAinduced increase was significantly reduced by antibiotics. However, no significant differences were observed in the intestine among all groups. Elevated mRNA levels of LPS binding protein, which was correlated with serum endotoxin levels, were recognized in the CDAA group and the CDAAinduced increase was significantly reduced by antibiotics. The intestinal permeability of the CDAA group was increased compared with the cholinesupplemented amino acid group. The tight junction protein (TJP) in the intestine, determined by immunohistochemical analysis was inversely associated with intestinal permeability. Antibiotics improved the intestinal permeability and enhanced TJP expression. Inhibition of LPSTLR4 signaling with antibiotics attenuated liver fibrosis development associated with NASH via the inhibition of HSC activation. These results indicated that reduction of LPS and restoration of intestinal TJP may be a novel therapeutic strategy for treatment of liver fibrosis development in NASH. |
