Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites.

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.

• Authors: Xiang Zhang, Olabisi Oluwabukola Coker, Eagle Sh Chu, Kaili Fu, Harry C H Lau, Yi-Xiang Wang, Anthony W H Chan, Hong Wei, Xiaoyong Yang, Joseph J Y Sung, Jun Yu
• Journal: Gut (Gut) Vol. 70 Issue 4 Pg. 761-774 (04 2021) ISSN: 1468-3288 [Electronic] England
• PMID: 32694178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Cholesterol, Dietary
• Atorvastatin

Topics

• Animals
• Atorvastatin (pharmacology)
• Carcinoma, Hepatocellular (etiology, prevention & control)
• Case-Control Studies
• Cholesterol, Dietary
• Disease Progression
• Fecal Microbiota Transplantation
• Gastrointestinal Microbiome (drug effects)
• Liver Neoplasms (etiology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (complications, prevention & control)