J Behary1,2,3, A E Raposo1,2, N M L Amorim1,2, H Zheng1,2, L Gong1,2, E McGovern1,2, J Chen4, K Liu4,5, J Beretov1,6, C Theocharous6, M T Jackson1,2, J Seet-Lee1,2, G W McCaughan4,5, E M El-Omar1,2,3, A Zekry7,8,9. 1. St George and Sutherland Clinical School, UNSW, Sydney, Australia. 2. Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia. 3. Department of Gastroenterology and Hepatology, St George Hospital, Sydney, Australia. 4. Liver Injury and Cancer, Centenary Institute, University of Sydney, Sydney, Australia. 5. AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia. 6. Department of Anatomical Pathology, St George Hospital, Sydney, Australia. 7. St George and Sutherland Clinical School, UNSW, Sydney, Australia. a.zekry@unsw.edu.au. 8. Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia. a.zekry@unsw.edu.au. 9. Department of Gastroenterology and Hepatology, St George Hospital, Sydney, Australia. a.zekry@unsw.edu.au.
Abstract
BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.
BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.
Authors: Naoki Ikenaga; Susan B Liu; Deanna Y Sverdlov; Shuhei Yoshida; Imad Nasser; Qingen Ke; Peter M Kang; Yury Popov Journal: Am J Pathol Date: 2014-12-02 Impact factor: 4.307
Authors: Vishal Singh; Beng San Yeoh; Benoit Chassaing; Xia Xiao; Piu Saha; Rodrigo Aguilera Olvera; John D Lapek; Limin Zhang; Wei-Bei Wang; Sijie Hao; Michael D Flythe; David J Gonzalez; Patrice D Cani; Jose R Conejo-Garcia; Na Xiong; Mary J Kennett; Bina Joe; Andrew D Patterson; Andrew T Gewirtz; Matam Vijay-Kumar Journal: Cell Date: 2018-10-18 Impact factor: 41.582