Gut microbiome–mediated bile acid metabolism regulates liver cancer via NKT cells
Open accessAbstract
Bile acids and liver cancer: Liver cancer is a leading cause of cancer-related deaths in the United States. The composition of the gut microbiome influences many human diseases, including liver inflammatory disorders. Ma et al. found that commensal gut bacteria can recruit the immune system to control the growth of liver tumors in mice (see the Perspective by Hartmann and Kronenberg). Clostridium species modified bile acids to signal liver sinusoidal endothelial cells to produce the chemokine CXCL16. This recruited natural killer T (NKT) immune cells to perform antitumor surveillance of the liver. Growth of both primary and metastatic cancer was reduced by NKT cell–driven killing. Science , this issue p. eaan5931 ; see also p. 858
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Microbial-derived bile acids regulate natural killer T cell responses to liver cancer.
“Although influences of microbial-derived BAs in regulating natural killer T cell responses to liver cancer have been described (12), it remains unclear whether or how hepatic BA synthesis contributes to immune suppression, particularly its regulation of tumor-specific CD8+ T cell responses and its role in immune tolerance within the liver.”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [12]
Feeding secondary bile acids or bile acid-metabolizing bacteria Clostridium scindens attenuated NKT cell-mediated liver-selective tumor inhibition.
“Feeding secondary bile acids or bile acid-metabolizing bacteria Clostridium scindens attenuated NKT cell-mediated liver-selective tumor inhibition [47].”
From Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies (2022) · cites this paper as [47]
In mouse models, liver cancer immunosurveillance depends on NKT cell activation.
“In mouse models, liver cancer immunosurveillance depends on natural killer T (NKT) cell activation19.”
From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [19]
Feeding secondary bile acids or colonization with bile acid-metabolizing bacteria abrogated both NKT cell accumulation and tumor inhibition in mice.
“Feeding secondary bile acids or colonization with bile acid-metabolizing bacteria abrogated both NKT cell accumulation and tumor inhibition in mice [81].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [81]
Antibiotics treatment caused depletion of gram-positive bacteria involved in primary-to-secondary bile acid conversion, therefore increasing the expression of CXCL16.
“Antibiotics treatment caused depletion of gram-positive bacteria involved in primary-to-secondary bile acid conversion, therefore increasing the expression of CXCL16 [81] (Fig. 2).”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [81]
Primary bile acids increased CXCL16 expression, whereas secondary bile acids showed the opposite effect.
“Ma et al. found that primary bile acids increased CXCL16 expression, whereas secondary bile acids showed the opposite effect [81].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [81]
Similar findings were confirmed in patients with primary liver cancer.
“Similar findings were confirmed in patients with primary liver cancer [81].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [81]
Upregulation of CXCL16 induced accumulation and activation of CXCR6+NKT cells, which produced more IFN-γ and suppressed liver tumor growth.
“As the only ligand for CXCR6, upregulation of CXCL16 induced accumulation and activation of CXCR6+NKT cells, which produced more IFN-γ and suppressed liver tumor growth [81] (Fig. 2).”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [81]
Blocking bile acid biotransformation suppressed liver cancer through chemoattracting natural killer T cells (NKT).
“Another recent study showed blocking bile acid biotransformation suppressed liver cancer through chemoattracting natural killer T cells (NKT), which are innate-like T lymphocytes expressing both TCR and innate-immune-like receptors.”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [81]
Increasing evidence supports an additional category of complicit microbes and microbial functions that promote carcinogenesis but are not sufficient to cause cancer.
“Increasing evidence suggests an important additional category of “complicit” microbes and microbial functions that promote carcinogenesis but are insufficient to cause cancer (18, 20, 25, 38, 44–47).”
From The microbiome and human cancer (2021) · cites this paper as [45]
Microbially produced secondary bile acids lower hepatic sinusoidal CXCL16 expression, preventing CXCR6+ natural killer T cell aggregation and liver cancer immunosurveillance; vancomycin treatment eliminates this carcinogenic effect.
“A second is microbially-produced secondary bile acids, which reduce hepatic sinusoidal CXCL16 expression (the sole ligand for CXCR6) and prevent CXCR6+ natural killer T (NKT) cell aggregation and liver cancer immunosurveillance — this carcinogenic effect is eliminated by vancomycin treatment (45).”
From The microbiome and human cancer (2021) · cites this paper as [45]
Gut microbial metabolites, including polyamines, short-chain fatty acids, indoles, vitamins, and bile acids, mediate gut microbiota effects on extraintestinal tumors by influencing the cancer-immunity dialog.
“the production of gut microbial metabolites (polyamines 58,65-67 , short-chain fatty acids [68][69][70][71] , indoles [72][73][74][75] , vitamins [76][77][78][79] , bile acids 80,81 ) that impact the cancer-immunity dialog.”
From Impact of the ONCOBIOME network in cancer microbiome research (2025) · cites this paper as [80]
Intestinal commensal Clostridium species utilize bile acids as messengers to enhance the antitumoral effect of hepatic CXCR6+ NKT cells, affecting primary and metastatic liver tumors.
“the intestinal commensal Clostridium species utilize bile acids as messengers to enhance the antitumoral effect of hepatic CXCR6+ NKT cells, affecting both primary and metastatic liver tumors.189”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [189]
Microbiome-derived small molecules have carcinogenic effects via regulation of immune responses in liver malignancy.
“Recent studies also demonstrated carcinogenic effects of microbiome-derived small molecules via regulation of immune responses in liver malignancy”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [189]
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- Authors
- Ma, C., Han, M., Heinrich, B., Fu, Q., Zhang, Q., Sandhu, M., Agdashian, D., Terabe, M., Berzofsky, J. A., Fako, V., Ritz, T., Longerich, T., Theriot, C. M., McCulloch, J. A., Roy, S., Yuan, W., Thovarai, V., Sen, S. K., Ruchirawat, M., Korangy, F., Wang, X. W., Trinchieri, G., & Greten, T. F.
- Affiliations
- National Institutes of Health (US)
- Universitätsklinikum Aachen (DE)
- University Hospital Heidelberg (DE)
- North Carolina State University (US)
- Chulabhorn Research Institute (TH)
- Corresponding author
- Greten, Tim F.
- ORCID
- Venue
- Science
- Published
- 2018-05-25
- Volume
- 360
- Issue
- 6391
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6407885
- OpenAlex
- W2804448077
- Cited by
- 1,508
- References
- 39
- Citations by year
- 2026: 152 · 2025: 221 · 2024: 186 · 2023: 227 · 2022: 237 · 2021: 212 · 2020: 142 · 2019: 95 · 2018: 35
- FWCI
- 43.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- National Institutes of Health (R35GM119438)
- National Cancer Institute (ZIA BC 011345, ZO1 SC 004020, Z01 BC 010876)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- gut microbiota, bile acid metabolism, liver cancer, NKT cells, Clostridium, liver sinusoidal endothelial cells, CXCL16, antitumor immunity, commensal bacteria, liver metastasis
- MeSH terms
- Gastrointestinal Microbiome, Chemokine CXCL16, Receptors, CXCR6, Animals, Bile Acids and Salts, Clostridium, Humans, Immunologic Surveillance, Liver, Liver Neoplasms, Lymphocyte Depletion, Mice, Inbred C57BL, Neoplasm Metastasis, Mice, Natural Killer T-Cells
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