Skip to main content

Hepatocellular Cancer and Gut Microbiome: Time to Untie Gordian’s Knot

Journal of Gastrointestinal Cancer volume 52, pages 1309–1313 (2021)Cite this article

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide and the incidence is growing on a global scale. About 90% of cases develop on the cirrhotic liver and the etiology is multifactorial. Increasing number of studies suggest that gut microbiota influences the development and progression of liver diseases, including chronic hepatic inflammation, fibrosis, cirrhosis, and HCC. The key role of gut microbiota in carcinogenesis seems to be associated with genomic instability of host cells and immune dysregulation. Recent clinical studies showed that a stable and healthy microbiota initially could have the ability to resist the emergence of chronic inflammation and, therefore, prevent the induction of carcinogenic cells in various organs such as the esophagus, stomach, colon, and liver. The progression from inflammation to cancer is a stepwise process occurring by the concerted action of several factors such as dysbiosis, increased gut permeability, diet, metabolomic, genetic, and epigenetic changes. In this article, we aimed to review the possible role of gut microbiota in the development, progression, and treatment of HCC.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Zhang C, Yang M, Ericsson AC. The potential gut microbiota-mediated treatment options for liver cancer. Front Oncol. 2020;10:1–8. https://doi.org/10.3389/fonc.2020.524205.

    Article  Google Scholar 

  2. Meng C, Bai C, Brown TD, Hood LE, Tian Q. Human gut microbiota and gastrointestinal cancer. Genomics Proteomics Bioinformatics. 2018;16:33–49. https://doi.org/10.1016/j.gpb.2017.06.002.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma Nat Rev Dis Primers. 2016;2:1–23. https://doi.org/10.1038/nrdp.2016.18.

    Article  Google Scholar 

  4. Ponziani FR, Bhoori S, Castelli C, Putignani L, Rivoltini L, Del Chierico F, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in non-alcoholic fatty liver disease. Hepatology. 2019;69:107–20. https://doi.org/10.1002/hep.30036.

    Article  CAS  PubMed  Google Scholar 

  5. Monte MJ, Marin JJG, Antelo A, Vazquez-Tato J. Bile acids: Chemistry, physiology, and pathophysiology. World J Gastroenterol. 2009;15:804–16. https://doi.org/10.3748/wjg.15.804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A. 2011;108:4523–30. https://doi.org/10.1073/pnas.1006734107.

    Article  PubMed  Google Scholar 

  7. Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A. 2006;103:12511–6. https://doi.org/10.1073/pnas.0601056103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Holmes E, Kinross J, Gibson GR, Burcelin R, Jia W, Pettersson S, et al. Therapeutic modulation of microbiota-host metabolic interactions. Sci Transl Med. 2012;4 137rv136.  https://doi.org/10.1126/scitranslmed.3004244

  9. Musso G, Gambino R, Cassader M. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med. 2011;62:361–80. https://doi.org/10.1146/annurev-med-012510-175505.

    Article  CAS  PubMed  Google Scholar 

  10. Jia W, Xie G, Jia W. Bile acid–microbiota cross-talk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol. 2018;15:111–28. https://doi.org/10.1038/nrgastro.2017.119.

    Article  CAS  PubMed  Google Scholar 

  11. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA. 2009;106:3698–703. https://doi.org/10.1073/pnas.0812874106.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dilek N, Papapetropoulos A, Toliver-Kinsky T, Szabo C. Hydrogen sulfide: an endogenous regulator of the immune system. Pharmacol Res. 2020;161: 105119. https://doi.org/10.1016/j.phrs.2020.105119.

    Article  CAS  PubMed  Google Scholar 

  13. Macfarlane GT, Steed H, Macfarlane S. Bacterial metabolism and health-related effects of galacto-oligosaccharides and other prebiotics. J Appl Microbiol. 2008;104:305–44. https://doi.org/10.1111/j.1365-2672.2007.03520.x.

    Article  CAS  PubMed  Google Scholar 

  14. Yang H, Duan Z. The local defender and functional mediator: gut microbiome. Digestion. 2018;97:137–45. https://doi.org/10.1159/000484687.

    Article  CAS  PubMed  Google Scholar 

  15. Albhaisi SAM, Bajaj JS, Sanyal AJ. Role of gut microbiota in liver disease. Am J Physiol Gastrointest Liver Physiol. 2020;318:G84-98. https://doi.org/10.1152/ajpgi.00118.2019.

    Article  CAS  PubMed  Google Scholar 

  16. Hattori N, Ushijima T. Epigenetic impact of infection on carcinogenesis: mechanisms and applications. Genome Med. 2016;8(1):10. https://doi.org/10.1186/s13073-016-0267-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Putoczki TL, Thiem S, Loving A, Busuttil RA, Wilson NJ, Ziegler PK, et al. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell. 2013;24:257–71. https://doi.org/10.1016/j.ccr.2013.06.017.

    Article  CAS  PubMed  Google Scholar 

  18. Garrett WS. Cancer and the microbiota. Science. 2015;348(6230):80–6. https://doi.org/10.1126/science.aaa4972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017;14(9):527–39. https://doi.org/10.1038/nrgastro.2017.72.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;2012(21):504–16. https://doi.org/10.1016/j.ccr.2012.02.007.

    Article  CAS  Google Scholar 

  21. Yu LX, Yan HX, Liu Q, Yang W, Wu HP, Dong W, et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology. 2010;52(4):1322–33. https://doi.org/10.1002/hep.23845.

    Article  CAS  PubMed  Google Scholar 

  22. Loo TM, Kamachi F, Watanabe Y, Yoshimoto S, Kanda H, Arai Y, et al. Gut microbiota promotes obesity-associated liver cancer through PGE(2)-mediated suppression of antitumor immunity. Cancer Discov. 2017;7:522–38. https://doi.org/10.1158/2159-8290.CD-16-0932.

    Article  CAS  PubMed  Google Scholar 

  23. Payne CM, Weber C, Crowley-Skillicorn C, Dvorak K, Bernstein H, Bernstein C, et al. Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis. 2007;28:215–22. https://doi.org/10.1093/carcin/bgl139.

    Article  CAS  PubMed  Google Scholar 

  24. Qiu M, Huang K, Liu Y, Yang Y, Tang H, Liu X, et al. Modulation of intestinal microbiota by glycyrrhizic acid prevents high-fat diet-enhanced pre-metastatic niche formation and metastasis. Mucosal Immunol. 2019;12(4):945–57. https://doi.org/10.1038/s41385-019-0144-6.

    Article  CAS  PubMed  Google Scholar 

  25. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504:451–5. https://doi.org/10.1038/nature12726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–73. https://doi.org/10.1126/science.1241165.

    Article  CAS  PubMed  Google Scholar 

  27. Palm NW, de Zoete MR, Flavell RA. Immune-microbiota interactions in health and disease. Clin Immunol. 2015;159:122–7. https://doi.org/10.1016/j.clim.2015.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vijay-Kumar M, Gewirtz AT. Flagellin: key target of mucosal innate immunity. Mucosal Immunol. 2009;2:197–205. https://doi.org/10.1038/mi.2009.9.

    Article  CAS  PubMed  Google Scholar 

  29. Yuan J, Chen C, Cui J, Lu J, Yan C, Wei X, et al. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metab. 2019;30:1172. https://doi.org/10.1016/j.cmet.2019.11.006.

    Article  CAS  PubMed  Google Scholar 

  30. Wang X, Fu X, Van Ness C, Meng Z, Ma X, Huang W. Bile acid receptors and liver cancer. Curr Pathobiol Rep. 2013;1:29–35. https://doi.org/10.1007/s40139-012-0003-6.

    Article  PubMed  Google Scholar 

  31. Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, et al. Gut microbiomemediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360:eaan5931.  https://doi.org/10.1126/science.aan5931

  32. Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia. 2017;19:848–55. https://doi.org/10.1016/j.neo.2017.08.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7. https://doi.org/10.1126/science.aan3706.

    Article  CAS  Google Scholar 

  34. Sepehri Z, Kiani Z, Kohan F, Alavian SM, Ghavami S. Toll like receptor 4 and hepatocellular carcinoma; a systematic review. Life Sci. 2017;179:80–7. https://doi.org/10.1016/j.lfs.2017.04.025.

    Article  CAS  PubMed  Google Scholar 

  35. Gao C, Qiao T, Zhang B, Yuan S, Zhuang X, Luo Y. TLR9 signaling activation at different stages in colorectal cancer and NF-kappaB expression. OncoTargets Ther. 2018;11:5963–71. https://doi.org/10.2147/OTT.S174274.

    Article  CAS  Google Scholar 

  36. Sun L-Y, Yang Y-S, Qu W, Zhu Z-J, Wei L, Ye Z-S, et al. Gut microbiota of liver transplantation recipients. Sci Rep. 2017;7:3762. https://doi.org/10.1038/s41598-017-03476-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schwabe RF, Greten TF. Gut microbiome in HCC- Mechanisms, diagnosis and therapy. J Hepatol. 2020;72:230–8. https://doi.org/10.1016/j.jhep.2019.08.016.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Acibadem Altunizade Hospital, Yurtcan Sok: No:1 34662, Üsküdar, Istanbul, Turkey

    Cem Aygün

  2. Department of Gastroenterology, Acibadem University School of Medicine, Istanbul, Turkey

    Nurdan Tözün

Authors
  1. Cem Aygün
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nurdan Tözün
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cem Aygün.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Aygün, C., Tözün, N. Hepatocellular Cancer and Gut Microbiome: Time to Untie Gordian’s Knot. J Gastrointest Canc 52, 1309–1313 (2021). https://doi.org/10.1007/s12029-021-00736-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-021-00736-5

Keywords

  • Hepatocellular carcinoma
  • Carcinogenesis
  • Microbiota
  • Dysbiosis