Aishwarya Buvanendiran

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 complications^1,3,4. 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 acids^6,7 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 therapeutics^1,6-10. 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 mice^7,8. 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 therapy^7-10. Studies further promote antibiotic therapy to restructure gut microbiomes by restricting Bacteroides and Clostridium populations in reducing risk of HCC⁷.

1. Yu, L. & Schwabe, R. F. (2017). The gut microbiome and liver cancer: Mechanisms and clinical translation. Nature Reviews Gastroenterology & Hepatology, 14: 527–539.
2. Said, A. & Ghufran, A. (2017). Epidemic of non-alcoholic fatty liver disease and hepatocellular carcinoma. World Journal of Clinical Oncology, 8(6): 419-436.
3. 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.
4. 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.
5. 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.
6. 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
7. 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.
8. 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.
9. 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.
10. 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.