The Role of Obesity-Induced Lipoteichoic Acid, Lipopolysaccharide, and Deoxycholic Acid Microbiota Components in Hepatocellular Carcinoma Development
Introduction. Hepatocellular Carcinoma (HCC), a form of liver cancer where chronic liver disease leads to uncontrolled proliferation of adult hepatocytes1, mostly occurs in males over the age of 502 and develops poor prognosis characterized by portal hypertension, hepatic encephalopathy, and fatal cardiovascular complications1,3,4. Relative risks for developing liver cancer are 117% for overweight and 189% for obese subjects5. Studies show that high fat diets associated with obesity appear to alter gut microbiota known to convert primary bile acids into secondary bile acids6,7 and increase levels of bacterial metabolites such as secondary bile acid deoxycholic acid (DCA), lipopolysaccharide (LPS), and lipoteichoic acid (LTA) entering the bloodstream1. Although the presence of these metabolites in the liver is correlated with increased HCC growth, the exact mechanisms of how these metabolites promote tumorigenesis is unclear1. Emerging research, however, supports a suppressive role of microbial metabolites on hepatic antitumoral immunity, highlighting antibiotics and inflammation inhibitors as potential therapeutics1,6-10. Methods. HCC was induced in High Fat Diet mice models mice via steatohepatitis inducing high fat diet (STHD-01)7 or DMBA8. Gut microbiota was analyzed in vancomycin treated mice fecal samples via ABI Prism 3130xl DNA Sequencer and Gene Mapper7. Liver samples were harvested from euthanized mice7,8. Inflammatory COX2 and PGE2 expression were analyzed via mediator lipidomics in mice treated with DCA or LTA8. Western blots were performed on Human HepG2 cell lines treated in vitro with LPS to measure TLR4 protein levels9 or with different bile acids in high glucose-high fat conditions to assess tumor suppressor CEBPa levels in the cells10. Results. Antibiotics administration in STHD-01 mice resulted in reduced size and number of liver tumors7. Gut microbiome analyses of STHD-01 mice showed decreased populations of Bacteroides and Clostridium bacterial genera known to metabolize and convert primary bile acids into secondary bile acids in vancomycin treated STHD-01 mice7. DCA and LTA induced TLR2-mediated expression of inflammatory COX2 and PGE2, which are known to establish tumorigenic microenvironments8. Human hepatocyte lines in vitro showed down-regulation of tumor suppressor gene CEBPa in elevated bile acid 8 and elevated TLR4 signaling in LPS treatment. Conclusions. The gut-liver axis was observed to promote obesity-associated HCC through LTA or DCA-TLR2-mediated or LPS-TLR4-mediated activation of pro-inflammatory cytokines, chemokines, and proteases, providing PGE2, PTGER, and TLR4 as potential targets for HCC therapy7-10. Studies further promote antibiotic therapy to restructure gut microbiomes by restricting Bacteroides and Clostridium populations in reducing risk of HCC7.
- Yu, L. & Schwabe, R. F. (2017). The gut microbiome and liver cancer: Mechanisms and clinical translation. Nature Reviews Gastroenterology & Hepatology, 14: 527–539.
- Said, A. & Ghufran, A. (2017). Epidemic of non-alcoholic fatty liver disease and hepatocellular carcinoma. World Journal of Clinical Oncology, 8(6): 419-436.
- Dimitroulis D, Damaskos C, Valsami S, Davakis S, Garmpis N, Spartalis E, … Kouraklis G. (2017). From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world. World J Gastroenterol, 23(29): 5282-5294.
- Cholankeril, G., Patel, R., Khurana, S., & Satapathy, S.K. (2017). Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management. World J Hepatol, 9(11): 533-543.
- Balogh, J., Victor, D., Asham, E. H., Burroughs, S. G., Boktour, M., Saharia, A., … Monsour, H. P. (2016). Hepatocellular carcinoma: a review. Journal of Hepatocellular Carcinoma, 3, 41–53.
- Yoshimoto, S., Loo, T.M., Atarashi, K., et al. (2013). Obesity-induced gut microbial metabolite promotes liver cancer through senescense secretome. Nature, 499(7456): 97-101
- Yamada, S., Takashina, Y., Watanabe, M., et al. (2018). Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma mice. Oncotarget, 9(11): 9925-9939.
- Xie, G., Wang, X., Huang, F., Zhao, A., Chen, W., Yan, J., Zhang, Y., Lei, S., Ge, K., Zheng, X., Liu, J., Su, M., Liu, P., & Jia, W. (2016). Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. J. Cancer 139: 1764-1775.
- Loo, T.M., Kamachi, F., Watanabe, Y., et al. (2017). Gut microbiota promotes obesity-associated liver-cancer through PGE-mediated suppression of antitumor immunity. Cancer Discovery, 7(5): 522-538.
- Lin, A., Wang, G., Zhao, H., Zhang, Y., Han, Q., Zhang, C., Tian, Z., & Zhang, J. (2016). TLR signaling promotes a COX-2/PGE2/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells. Oncoimmunology 5(2): e1074376 1–11.