Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice

Qiang Zhu, Li Zou, Kumaravelu Jagavelu, Douglas Simonetto, Robert C Huebert, Zhi Dong Jiang, Herbert L. Dupont, Vijay Shah

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Background & Aims: 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.

Original languageEnglish (US)
Pages (from-to)893-899
Number of pages7
JournalJournal of Hepatology
Volume56
Issue number4
DOIs
StatePublished - Apr 2012

Fingerprint

rifaximin
Toll-Like Receptor 4
Decontamination
Fibronectins
Liver Cirrhosis
Hepatic Stellate Cells
Fibrosis
Endothelial Cells
Bile Ducts
Ligation
Portal Hypertension
Lipopolysaccharides
Portal Pressure
Liver
Anti-Bacterial Agents
Liver Failure
Cell Movement
Blood Vessels
In Vitro Techniques

Keywords

  • Fibronectin
  • fibrosis
  • Intestinal decontamination
  • Lipopolysaccharide
  • Liver, angiogenesis
  • Rifaximin
  • Toll-like receptor 4

ASJC Scopus subject areas

  • Hepatology

Cite this

Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. / Zhu, Qiang; Zou, Li; Jagavelu, Kumaravelu; Simonetto, Douglas; Huebert, Robert C; Jiang, Zhi Dong; Dupont, Herbert L.; Shah, Vijay.

In: Journal of Hepatology, Vol. 56, No. 4, 04.2012, p. 893-899.

Research output: Contribution to journalArticle

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abstract = "Background & Aims: 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.",
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AU - Jiang, Zhi Dong

AU - Dupont, Herbert L.

AU - Shah, Vijay

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