title: Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice.
abstract: OBJECTIVE
  Liver fibrosis is associated with angiogenesis and leads to portal hypertension. Certain antibiotics reduce complications of liver failure in humans, however, the effects of antibiotics on the pathologic alterations of the disease are not fully understood. The aim of this study was to test whether the non-absorbable antibiotic rifaximin could attenuate fibrosis progression and portal hypertension in vivo, and explore potential mechanisms in vitro.
  
  
  METHODS
  The effect of rifaximin on portal pressure, fibrosis, and angiogenesis was examined in wild type and Toll-like receptor 4 (TLR4) mutant mice after bile duct ligation (BDL). In vitro studies were carried out to evaluate the effect of the bacterial product and TLR agonist lipopolysaccharide (LPS) on paracrine interactions between hepatic stellate cells (HSC) and liver endothelial cells (LEC) that lead to fibrosis and portal hypertension.
  
  
  RESULTS
  Portal pressure, fibrosis, and angiogenesis were significantly lower in BDL mice receiving rifaximin compared to BDL mice receiving vehicle. Studies in TLR4 mutant mice confirmed that the effect of rifaximin was dependent on LPS/TLR4 pathway. Fibronectin (FN) was increased in the BDL liver and was reduced by rifaximin administration and thus, was explored further in vitro as a potential mediator of paracrine interactions of HSC and LEC. In vitro, LPS promoted FN production from HSC. Furthermore, HSC-derived FN promoted LEC migration and angiogenesis.
  
  
  CONCLUSIONS
  These studies expand our understanding of the relationship of intestinal microbiota with fibrosis development by identifying FN as a TLR4 dependent mediator of the matrix and vascular changes that characterize cirrhosis.
authors.affiliation: Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhu
authors.forename: Li
authors.initials: L
authors.lastname: Zou
authors.forename: Kumaravelu
authors.initials: K
authors.lastname: Jagavelu
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Simonetto
authors.forename: Robert C
authors.initials: RC
authors.lastname: Huebert
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Jiang
authors.forename: Herbert L
authors.initials: HL
authors.lastname: DuPont
authors.forename: Vijay H
authors.initials: VH
authors.lastname: Shah
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D005353:Fibronectins / Q000187:drug effects* / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D006975:Hypertension, Portal / Q000517:prevention & control; D007422:Intestines / Q000187:drug effects / Q000382:microbiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D020239:Receptor Cross-Talk / Q000187:drug effects* / Q000502:physiology; D012294:Rifamycins / Q000494:pharmacology* / Q000627:therapeutic use; D000078262:Rifaximin; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D005353:Fibronectins; D008070:Lipopolysaccharides; D012294:Rifamycins; D051197:Toll-Like Receptor 4; D000078262:Rifaximin