Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites
Zhang X, Coker OO, Chu ES, Fu K, Lau HCH, Wang YX, Chan AWH, Wei H, Yang X, Sung JJY, Yu J
Gut · 716 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- Case-control study (indexed by PubMed)
- Studied in
- People, plus animal or lab work
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Independent funding
- Government
- Natural Science Foundation of Guangdong Province
- University or hospital
- Chinese University of Hong Kong
- Government
- Guangdong Natural Science Foundation
- Government
- RGC Collaborative Research Fund
- University or hospital
- Vice-Chancellor's Discretionary Fund CUHK
- Government
- RGC Theme-based Research Scheme Hong Kong
- University or hospital
- CUHK direct grant for research
- Grants
- Natural Science Foundation of Guangdong Province (2018B030312009)
Based on 7 listed funder(s).
Publication
- Published
- 2020-07-21 · Gut · vol. 70 · issue 4 · pp. 761–774
- Publisher
- BMJ
- Cited
- 870 citations · more than 100% of similar papers · 27.7× the field average
- Impact
- Top 10% most cited in its field
- References
- 44 works
- Access
- Open access (hybrid journal) · CC-BY-NC
- Research areas
- Gut microbiota and health · Liver Disease Diagnosis and Treatment · Metabolomics and Mass Spectrometry Studies
- Keywords
- Steatohepatitis, Gut flora, Dysbiosis, Fatty liver, Internal medicine, Cholesterol, Steatosis, Dyslipidemia, Endocrinology, Atorvastatin, Taurocholic acid, Biology, Bile acid, Medicine, Immunology, Diabetes mellitus, Disease
- MeSH
- animals, mice, inbred c57bl, mice, carcinoma, hepatocellular, liver neoplasms, disease progression, cholesterol, dietary, case-control studies, male, non-alcoholic fatty liver disease, gastrointestinal microbiome, fecal microbiota transplantation, atorvastatin
11 authors
From HK, CN, US
- Xiang ZhangChinese University of Hong Kong; Chinese University of Hong Kong, Shenzhen
- Olabisi Oluwabukola CokerChinese University of Hong Kong; Chinese University of Hong Kong, Shenzhen
- Eagle SH ChuChinese University of Hong Kong; Chinese University of Hong Kong, Shenzhen
- Kaili FuChinese University of Hong Kong; Chinese University of Hong Kong, Shenzhen
- Harry Cheuk-Hay LauChinese University of Hong Kong; Chinese University of Hong Kong, Shenzhen
- Yi-Xiang WangChinese University of Hong Kong
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC).
Community trust
Loading…
How much do you trust this study's findings?
Comments
Sign in to rate, comment on or flag this study.Sign inSomething wrong here?
Flag this study if its information, labels or funding look wrong. An editor reviews every flag.
Sign in to rate, comment on or flag this study.Sign inEducational information about published research. Not medical advice, and not a recommendation to start or stop anything.