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于君团队:膳食胆固醇影响肠道菌群及其代谢物,驱动脂肪肝相关肝癌

创作:Vicky审核:何才高2020-07-24

①长期高脂高胆固醇(HFHC)饲喂使小鼠依次发生脂肪肝、脂肪性肝炎、纤维化和肝癌(HCC);
②肠道菌群组成随疾病进展改变,4个OTU逐渐增加,多个梭菌属OTU富集,而双歧杆菌属和拟杆菌属等在HFHC小鼠和高胆固醇患者中缺乏;
③膳食胆固醇诱导菌群代谢物改变,牛磺胆酸增加、3-吲哚丙酸减少,促进了肝细胞的脂质积累和增殖;
④粪菌移植试验证实胆固醇诱导的菌群失调可促进上述肝脏病变和炎症。

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主编推荐语

非酒精性脂肪性肝病(NAFLD)是一类代谢疾病,可从脂肪肝进展至脂肪性肝炎,进一步导致肝硬化甚至肝细胞癌(HCC),胆固醇被认为是疾病发展过程中主要的脂毒性分子。Gut杂志最新发表了来自香港中文大学于君团队的研究,以小鼠为模型研究了膳食胆固醇在NAFLD及其相关HCC发生发展过程中的作用和机制,表明高脂高胆固醇饮食可通过改变肠道菌群的组成和代谢物,驱动NAFLD-HCC的发生发展,降胆固醇药物和肠道菌群干预或是有效的预防策略。

延伸导读

本研究的原文信息和链接出处,以及相关解读和评论文章。欢迎读者朋友们推荐!
Gut
[IF:19.819]
Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites
膳食胆固醇通过调控肠道菌群和代谢物驱动脂肪肝相关肝癌
10.1136/gutjnl-2019-319664
07-21, Article
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.