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Hepatology
Original research
Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites
  1. Xiang Zhang1,
  2. Olabisi Oluwabukola Coker1,
  3. Eagle SH Chu1,
  4. Kaili Fu1,
  5. Harry C H Lau1,
  6. Yi-Xiang Wang2,
  7. Anthony W H Chan3,
  8. Hong Wei4,5,
  9. Xiaoyong Yang6,
  10. Joseph J Y Sung1,
  11. Jun Yu1
  1. 1 State Key Laboratory of Digestive Disease, Institute of Digestive Disease and The Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
  2. 2 Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong SAR, China
  3. 3 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
  4. 4 Department of Precision Medicine, Sun Yat-Sen University First Affiliated Hospital, Guangzhou, Guangdong, China
  5. 5 Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China
  6. 6 Department of Comparative Medicine and Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA
  1. Correspondence to Jun Yu, Institute of Digestive Disease and The Department of Medicine and Therapeutics, Chinese University of Hong Kong, New Territories, Hong Kong; junyu{at}cuhk.edu.hk

Abstract

Objective Non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is an increasing healthcare burden worldwide. We examined the role of dietary cholesterol in driving NAFLD–HCC through modulating gut microbiota and its metabolites.

Design High-fat/high-cholesterol (HFHC), high-fat/low-cholesterol or normal chow diet was fed to C57BL/6 male littermates for 14 months. Cholesterol-lowering drug atorvastatin was administered to HFHC-fed mice. Germ-free mice were transplanted with stools from mice fed different diets to determine the direct role of cholesterol modulated-microbiota in NAFLD–HCC. Gut microbiota was analysed by 16S rRNA sequencing and serum metabolites by liquid chromatography–mass spectrometry (LC–MS) metabolomic analysis. Faecal microbial compositions were examined in 59 hypercholesterolemia patients and 39 healthy controls.

Results High dietary cholesterol led to the sequential progression of steatosis, steatohepatitis, fibrosis and eventually HCC in mice, concomitant with insulin resistance. Cholesterol-induced NAFLD–HCC formation was associated with gut microbiota dysbiosis. The microbiota composition clustered distinctly along stages of steatosis, steatohepatitis and HCC. Mucispirillum, Desulfovibrio, Anaerotruncus and Desulfovibrionaceae increased sequentially; while Bifidobacterium and Bacteroides were depleted in HFHC-fed mice, which was corroborated in human hypercholesteremia patients. Dietary cholesterol induced gut bacterial metabolites alteration including increased taurocholic acid and decreased 3-indolepropionic acid. Germ-free mice gavaged with stools from mice fed HFHC manifested hepatic lipid accumulation, inflammation and cell proliferation. Moreover, atorvastatin restored cholesterol-induced gut microbiota dysbiosis and completely prevented NAFLD–HCC development.

Conclusions Dietary cholesterol drives NAFLD–HCC formation by inducing alteration of gut microbiota and metabolites in mice. Cholesterol inhibitory therapy and gut microbiota manipulation may be effective strategies for NAFLD–HCC prevention.

  • dietary factors
  • fatty liver
  • nonalcoholic steatohepatitis
  • intestinal microbiology
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2019-319664

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    Footnotes

    • XZ and OOC are co-first authors.

    • Contributors XZ and OOC were involved in study design, conducted the experiments and drafted the paper; EC, KF, HCHL and Y-XW performed the experiments; AWHC determined the histology; HW provided germ-free animal; XY and JJYS commented and revised the manuscript; JY designed, supervised the study and wrote the paper.

    • Funding This project was supported by research funds from Guangdong Natural Science Foundation (2018B030312009), RGC Collaborative Research Fund (C4041-17GF, C7026-18G, C7065-18G), RGC Theme-based Research Scheme Hong Kong (T12-703/19 R), CUHK direct grant for research, Vice-Chancellor's Discretionary Fund CUHK.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval All animal studies were performed in accordance with guidelines approved by the Animal Experimentation Ethics Committee of the Chinese University of Hong Kong and the Third Military Medical University.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.