Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice
Open accessAbstract
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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Targeting the gut-microbiota-liver axis reduces liver fibrosis and portal hypertension in rodents.
“targeting the gut-microbiota–liver axis has been shown to reduce liver fibrosis 73,96 and portal hypertension97 in rodents”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [96]
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- Authors
- Zhu, Q., Zou, L., Jagavelu, K., Simonetto, D. A., Huebert, R. C., Jiang, Z.-D., DuPont, H. L., & Shah, V. H.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Shah, Vijay H.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 56
- Issue
- 4
- Pages
- 893-899
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC3307873
- OpenAlex
- W1970951405
- Cited by
- 144
- References
- 42
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 8 · 2023: 4 · 2022: 15 · 2021: 6 · 2020: 16 · 2019: 7 · 2018: 13 · 2017: 8 · 2016: 12 · 2015: 16 · 2014: 11 · 2013: 4 · 2012: 5
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R37AA021171)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK059615, R01DK059615, P30DK084567)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- liver fibrosis, rifaximin, intestinal decontamination, TLR4, fibronectin, hepatic stellate cells, liver endothelial cells, paracrine signaling, angiogenesis, portal hypertension, bile duct ligation, lipopolysaccharide, gut microbiota, liver cirrhosis
- MeSH terms
- Rifaximin, Animals, Anti-Bacterial Agents, Cell Movement, Cells, Cultured, Disease Models, Animal, Fibronectins, Humans, Hypertension, Portal, Intestines, Lipopolysaccharides, Liver Cirrhosis, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Mutant Strains, Neovascularization, Pathologic, Rifamycins, Disease Progression, Receptor Cross-Talk, Endothelial Cells, Toll-Like Receptor 4, Mice, Hepatic Stellate Cells
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