Author: Chung, Po Sin
Title: Identification, functional characterization and therapeutic implication of Akkermansia muciniphila in non-alcoholic fatty liver disease-induced hepatocellular carcinoma
Advisors: Lee, Terence (ABCT)
Degree: M.Phil.
Year: 2021
Subject: Fatty liver
Liver -- Diseases
Hong Kong Polytechnic University -- Dissertations
Department: Department of Applied Biology and Chemical Technology
Pages: xiv, 135 pages : color illustrations
Language: English
Abstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world mainly due to the high prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Non-alcoholic fatty liver disease (NAFLD)-induced HCC is an emerging malignancy in the developed world and its targeted therapy is currently not available. NAFLD is the most common liver disease, affecting 20-40% of adults worldwide. The spectrum of liver pathology extends from simple steatosis, in which the only feature is excessive fat deposition within hepatocytes, to NASH, in which additional features include hepatocyte injury, liver inflammation and pericellular fibrosis, which will progress to cirrhosis and HCC. Therefore, understanding how NAFLD progresses to HCC will benefit on the identification of novel strategies against this deadly disease. Recently, several studies have reported that the intestinal microbiota plays an important role in the pathogenesis of NAFLD. However, how the gut microbiota altered in the process of NAFLD-induced HCC remains unknown. With our established NAFLD-induced HCC mouse model, coupled with 16S rDNA sequencing analysis, we identified that Akkermansia muciniphila was decreased by 40-fold from healthy to HCC tissues in a stepwise manner for the first time. Given the physiological function of A. muciniphila in the maintenance of intestinal integrity, we hypothesize that a decrease in A. muciniphila may lead to impairment of the intestinal lining, which subsequently increases the flux of LPS and peptidoglycan via the portal vein, resulting in inflammatory responses and alteration in related metabolic pathways. Using an orthotopic HCC mouse model treated with the methionine and choline deficient (MCD) diet, we showed that daily administration of A. muciniphila could effectively attenuate the development of NAFLD-induced HCC, as evidenced by significant decreases in the tumour size and luciferase signal. With this interesting finding, we further elucidated the molecular mechanism of the tumour suppressive role of A. muciniphila in NAFLD-induced HCC mouse model. Firstly, we found that A. muciniphila may possibly strengthen the gut integrity, as evidenced by the increase in E-cadherin expression in the intestinal lining. Secondly, A. muciniphila potentially alleviates severity of steatosis, as shown by decreases in fat deposition and expression of genes related to fatty acid metabolism. By bulk RNA sequencing analysis coupled with Gene Set Enrichment Analysis (GSEA), we showed that several signaling pathways including PI3K/AKT, mTOR, Kras, Wnt/β-catenin, hedgehog, and cholesterol metabolism were downregulated upon treatment with A. muciniphila. Strikingly, A. muciniphila potentially reverses the immunosuppressive environment in NAFLD-induced HCC, as evidenced by the decrease in populations of monocytic myeloid derived suppressor cells (m-MDSCs), regulatory B (Breg) cells, and M2-like macrophages. This result reveals that supplementation of A. muciniphila may augment the efficacy of immune checkpoint therapy for NAFLD-induced HCC patients. In conclusion, this study may lead to the development of the first gut microbiota-targeted strategy to prevent or treat NAFLD-induced HCC. Our study will shed light on novel therapeutic targeted therapies against NAFLD-induced HCC. Further in-depth mechanistic investigation is needed prior to therapeutic application.
Rights: All rights reserved
Access: open access

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