Promotion of Hepatocellular Carcinoma by the Intestinal Microbiota and TLR4
Open accessAbstract
Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma (HCC), a long-term consequence of chronic liver injury, inflammation, and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in non-bone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.
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HSC mediators besides RSPO3, such as HGF, and possibly neurotrophin-3 or epiregulin, may be involved in additional aspects of HSC-hepatocyte cross-talk and together with ECs collaboratively control hepatocyte health and functions.
“Moreover, HSC mediators besides RSPO3, such as HGF, but possibly also neurotrophin-319 or epiregulin60 may be involved in additional aspects of HSC–hepatocyte cross-talk and—together with ECs29,59—collaboratively control hepatocyte health and functions.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [60]
These pro-inflammatory mediators promote chronic liver disease and create conditions for hepatocellular carcinoma development.
“These pro-inflammatory mediators not only promote the development of CLD but also set the stage for the development of HCC13–15.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
In chronic liver disease, a failing gut barrier and altered gut microbiota drive chronic inflammation and liver disease progression, which raises the risk of hepatocellular carcinoma.
“However, a failing gut barrier and alterations of the gut microbiota in chronic liver disease (CLD) contribute to chronic inflammation and the progression of liver diseases12, and thereby increase risk for the development of hepatocellular carcinoma (HCC) as the final stage of the disease process 13–15.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
The bacterial microbiota promotes hepatocellular carcinoma in the setting of liver fibrosis, as shown by reduced hepatocellular carcinoma formation in TLR4-deficient, germ-free and antibiotic-treated mice in a DEN plus CCl4 model.
“Nonetheless, the bacterial microbiota has an important role in promoting HCC in the setting of liver fibrosis, as demonstrated by reduced HCC formation in TLR4-deficient, germ-free and antibiotic-treated mice in a diethylnitrosamine (DEN) plus CCl4 model of HCC13.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
The endogenous commensal microbiota provides hepatoprotective signals; complete absence of the gut microbiota increases liver injury, probably through lack of TLR4-mediated anti-apoptotic NF-κB signalling, and increases liver fibrosis.
“It has become apparent that the endogenous commensal microbiota provides hepatoprotective signals and that complete absence of the gut microbiota results in increased liver injury — probably owing to an absence of TLR4-mediated activation of anti-apoptotic NF-κB signalling — and a subsequent increase in liver fibrosis, as demonstrated in several models13,75,76.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Treatment with nonabsorbable antibiotics strongly reduces fibrosis despite increased liver injury.
“Consistent with previous studies71–73, treatment with nonabsorbable antibiotics resulted in a strong reduction of fibrosis despite increased liver injury13.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Experiments in bone-marrow-chimeric mice demonstrated that TLR4 on liver-resident cells is responsible for promoting fibrogenesis and hepatocarcinogenesis.
“Experiments in bone-marrow-chimeric mice demonstrated that TLR4 expressed on liver-resident cells (which include hepatocytes, HSCs and Kupffer cells) is responsible for promotion of fibrogenesis and hepatocarcinogenesis13.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Epiregulin-deficient mice display reduced hepatocarcinogenesis when treated with DEN plus CCl4.
“Accordingly, epiregulin-deficient mice displayed reduced hepatocarcinogenesis when treated with DEN+CCl413.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Inhibition of TLR4 signalling suppresses liver inflammation, fibrosis and hepatocellular carcinoma formation in mice and rats.
“Conversely, inhibition of TLR4 signalling suppresses liver inflammation, fibrosis and HCC formation in mice and rats13,14,73.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Chronic infusion of low-dose lipopolysaccharide via osmotic pumps promotes hepatocellular carcinoma development in mice.
“Accordingly, chronic infusion of low-dose LPS via osmotic pumps promotes HCC development in mice13.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Hepatocellular carcinoma development induced by DEN plus CCl4 is attenuated in gut-sterilized and germ-free mice compared with specific pathogen-free counterparts.
“As such, HCC development induced by the combination of DEN and CCl4 was attenuated in gut-sterilized and germ-free mice compared with their specific pathogen-free counterparts13.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Expression of the apoptosis marker cleaved caspase 3 in TLR4-deficient and gut-sterilized mice is inversely correlated with tumour formation.
“Accordingly, expression of the apoptosis marker cleaved caspase 3 in TLR4-deficient and gut-sterilized mice is inversely correlated with the formation of tumours13.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
In hepatic stellate cells, TLR4 activation leads to NF-κB-mediated upregulation of the hepatomitogen epiregulin.
“In HSCs, TLR4 activation leads to an NF-κB-mediated upregulation of the hepatomitogen epiregulin13.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Continuous gut sterilization with an oral cocktail of ampicillin, neomycin, metronidazole and vancomycin reduced the number and size of HCC induced by DEN+CCl4 or DMBA+HFD in mice.
“Continuous gut sterilization by a cocktail of oral antibiotics, consisting of ampicillin, neomycin, metronidazole and vancomycin, effectively reduced the number and size of HCC induced by DEN+CCl4 or DMBA+HFD in mice13,15.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Rifaximin reduces HCC development in the DEN-CCl4 model, though less efficiently than the quadruple antibiotic cocktail.
“Of note, rifaximin reduces HCC development in the DEN–CCl4 model of HCC, albeit less efficiently than the quadruple antibiotics cocktail described above13.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
In mice, giving antibiotics at late stages of carcinogenesis, when microscopic tumours already existed, reduced HCC more efficiently than giving them earlier.
“Of note, administration of antibiotics at late stages of carcinogenesis, when microscopic tumours already existed, was more efficient at reducing HCC in mice than administration at earlier stages13.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Preclinical studies show an approximately 80% reduction in HCC development in murine models.
“supported by a large number of studies preclinical studies showing a drastic (≈80%) reduction of HCC development in murine models13–15.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
Several studies have shown a key role for the TLR4 pathway as a mediator of the disease-promoting effects of the gut-liver axis in chronic liver disease and hepatocarcinogenesis.
“Several studies have shown a key role for the TLR4 pathway as a mediator of the disease-promoting effects of the gut–liver axis in CLD and hepatocarcinogenesis13,14,73.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [13]
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- Authors
- Dapito, D. H., Mencin, A., Gwak, G.-Y., Pradere, J.-P., Jang, M.-K., Mederacke, I., Caviglia, J. M., Khiabanian, H., Adeyemi, A., Bataller, R., Lefkowitch, J. H., Bower, M., Friedman, R., Sartor, R. B., Rabadan, R., & Schwabe, R. F.
- Affiliations
- Columbia University (US)
- Samsung Medical Center (KR)
- Hospital Clínic de Barcelona (ES)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Schwabe, Robert F.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 21
- Issue
- 4
- Pages
- 504-516
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3332000
- OpenAlex
- W2085153086
- Cited by
- 1,346
- References
- 50
- Citations by year
- 2026: 63 · 2025: 103 · 2024: 106 · 2023: 111 · 2022: 149 · 2021: 133 · 2020: 129 · 2019: 104 · 2018: 93 · 2017: 94 · 2016: 79 · 2015: 64 · 2014: 48 · 2013: 51 · 2012: 16
- FWCI
- 36.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 472 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by)
- UNC Libraries
- Funders
- National Institutes of Health (1F31 DK091980-01, P40RR018603, R01AA020211, R01DK076920, U54CA163111)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- hepatocellular carcinoma, gut microbiota, TLR4, gut-liver axis, chronic liver injury, hepatocarcinogenesis, bacterial translocation, epiregulin, apoptosis, HCC prevention, liver fibrosis, liver inflammation
- MeSH terms
- Animals, Epidermal Growth Factor, Humans, Intestines, Liver Diseases, Liver Neoplasms, Experimental, Mice, Inbred C57BL, Tumor Cells, Cultured, Apoptosis, Bacterial Translocation, Cell Proliferation, Toll-Like Receptor 4, Mice, Epiregulin
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