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.
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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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
Yang H, Duan Z. The local defender and functional mediator: gut microbiome. Digestion. 2018;97:137–45. https://doi.org/10.1159/000484687.
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.
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.
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.
Garrett WS. Cancer and the microbiota. Science. 2015;348(6230):80–6. https://doi.org/10.1126/science.aaa4972.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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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
- Hepatocellular carcinoma