Endotoxin Accumulation Prevents Carcinogen-Induced Apoptosis and Promotes Liver Tumorigenesis in Rodents
Open accessAbstract
Increasing evidence suggests that the presence of endotoxemia is of substantial clinical relevance to patients with cirrhosis, but it is unclear whether and how gut-derived LPS amplifies the tumorigenic response of the liver. We found that the circulating levels of LPS were elevated in animal models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor Toll-like receptor 4 (TLR4) in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-κB activation and sensitizing the liver to reactive oxygen species (ROS)-induced toxicity, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4 -expressing myeloid cells in TLR4 -deficient mice restored diethylnitrosamine (DEN)-induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. Meanwhile, deletion of gut-derived endotoxin suppressed DEN-induced cytokine production and compensatory proliferation, whereas in vivo LPS pre-challenge promotes hepatocyte proliferation. Conclusion: Our data indicate that sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in patients with cirrhosis who are at risk of developing HCC. (Hepatology 2010.)
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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 [14]
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 [14]
High circulating lipopolysaccharide levels in mice and patients with chronic liver disease and hepatocellular carcinoma demonstrate a leaky gut during multiple stages of chronic liver disease and hepatocarcinogenesis.
“High circulating LPS levels in mice and patients with CLD as well as in HCC14,24,77,78 demonstrate the presence of a leaky gut during multiple stages of CLD and hepatocarcinogenesis (FIG. 1).”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [14]
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 [14]
Activation of the LPS-TLR4 signalling pathway in Kupffer cells leads to TNF- and IL6-dependent compensatory hepatocyte proliferation and reduced oxidative stress and apoptosis.
“Moreover, it has been demonstrated that activation of the LPS–TLR4 signalling pathway in Kupffer cells leads to TNF- and IL6-dependent compensatory hepatocyte proliferation as well as reduced oxidative stress and apoptosis14.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [14]
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 [14]
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 [14]
Gut ecology is associated with cancer, cardiovascular disease, obesity, diabetes, and muscle wasting.
“associations between gut ecology and cancer [16], cardiovascular disease [17], obesity [6], diabetes [18], and muscle wasting [19]”
From Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis (2018) · cites this paper as [16]
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References 39 · Cited by 349
- Authors
- Yu, L.-X., Yan, H.-X., Liu, Q., Yang, W., Wu, H.-P., Dong, W., Tang, L., Lin, Y., He, Y.-Q., Zou, S.-S., Wang, C., Zhang, H.-L., Cao, G.-W., Wu, M.-C., & Wang, H.-Y.
- Affiliations
- Second Military Medical University (CN)
- Venue
- Hepatology
- Published
- 2010-10
- Volume
- 52
- Issue
- 4
- Pages
- 1322-1333
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2094514571
- Cited by
- 349
- References
- 39
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 25 · 2023: 27 · 2022: 41 · 2021: 39 · 2020: 25 · 2019: 28 · 2018: 23 · 2017: 19 · 2016: 16 · 2015: 16 · 2014: 13 · 2013: 18 · 2012: 14
- FWCI
- 8.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (30921006, 30871293)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- endotoxin, lipopolysaccharide, hepatocellular carcinoma, hepatocarcinogenesis, TLR4, NF-κB activation, reactive oxygen species, diethylnitrosamine, hepatocyte apoptosis, compensatory proliferation, liver inflammation, gut microbiota, bacterial translocation, liver cirrhosis, myeloid cells, cytokine production
- MeSH terms
- Animals, Carcinogens, Diethylnitrosamine, Carcinoma, Hepatocellular, Intestines, Lipopolysaccharides, Liver Cirrhosis, Liver Neoplasms, Male, Neomycin, Polymyxin B, NF-kappa B, Apoptosis, Reactive Oxygen Species, Cell Proliferation, Toll-Like Receptor 4, Mice, Rats
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