Berberine Alleviates Non-alcoholic Steatohepatitis Through Modulating Gut Microbiota Mediated Intestinal FXR Activation.
Berberine Alleviates Non-alcoholic Steatohepatitis Through Modulating Gut Microbiota Mediated Intestinal FXR Activation.
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小檗碱通过调节肠道微生物群介导的肠道 FXR 激活减轻非酒精性脂肪性肝炎
DOI：
10.3389/fphar.2021.750826
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Shu X;Li M;Cao Y;Li C;Zhou W;Ji G;Zhang L
小檗碱是一种从多种属中分离出来的天然植物生物碱，具有抗炎、抗肥胖和保护肝脏的特性，是治疗非酒精性脂肪性肝炎（NASH）的有希望的药物。Farnesoid X受体（FXR）是一种胆汁酸受体，也是NASH的药物靶点，然而，小檗碱调节FXR的潜在机制尚不清楚。在本研究中，我们给小鼠喂食了12周的高脂肪饮食，间歇用葡萄糖聚糖硫酸钠（0.5%的饮用水）饮食来诱导NASH，并通过口服灌胃给小鼠服用小檗碱（100 mg/kg /天），再持续4周。我们证明，施用小檗碱可减轻NASH小鼠肝脏脂肪变性和炎症细胞浸润。我们采用16S核糖体DNA测序技术筛选肠道菌群结构，并采用超高效液相色谱-串联质谱分析确定胆汁酸谱。结果表明，小檗碱可调节肠道生态失调，特别是增加梭菌属、乳酸杆菌科和拟杆菌属的相对丰度。小檗碱调节的微生物群与胆汁酸脱偶联和转化有关，这与小檗碱处理后胆汁酸种类（例如去氧胆酸，熊去氧胆酸）的改变是一致的。对小檗碱治疗有反应的BA物种是已知的FXR激动剂，因此我们通过定量Real - Time-PCR和western blot检测FXR通路，发现小檗碱上调肠道FXR和成纤维细胞生长因子15 （FGF15）的表达，FGF15的分泌进一步抑制肝脏脂肪生成和核因子κ b的激活。而小檗碱的有益作用在FXR基因敲除小鼠中减弱。我们的研究结果表明，小檗碱通过调节肠道微生物群和胆汁酸代谢的相互作用以及随后的肠道FXR激活来缓解NASH。
Berberine is a natural plant alkaloid isolated from a diverse range of genera, it obtains anti-inflammatory, anti-obesity, and hepatoprotective properties, and is a promising agent for non-alcoholic steatohepatitis (NASH). Farnesoid X receptor (FXR) is a bile acid receptor and a drug target for NASH, however, the underlying mechanisms of berberine on regulating FXR are still unknown. In the present study, we feed mice with a 12-week high-fat diet with interval dextran sulfate sodium (0.5% in drinking water) diet to induce NASH, and treat the mice with berberine (100 mg/kg per day) via oral gavage for additional 4 weeks. We demonstrate that administration of berberine alleviates steatosis and infiltration of inflammatory cells in the liver of NASH mice. We apply 16S ribosomal DNA sequencing to screen the structure of gut microbiota, and ultra-performance liquid chromatography-tandem mass spectrometry analysis to determine the bile acid profiles. The results show that berberine modulates gut dysbiosis, and specifically increases the relative abundance of Clostridiales, Lactobacillaceae, and Bacteroidale. Berberine modulated microbiomes are associated with bile acid de-conjugation and transformation, which are consistent with the altered bile acid species (e.g., deoxycholic acid, ursodeoxycholic acid) upon berberine treatment. BA species that respond to berberine treatment are known FXR agonists, thus we performed quantitative Real Time-PCR and western blot to examine the FXR pathway, and find that berberine up-regulates intestinal FXR and fibroblast growth factor 15 (FGF15) expression, and the secretion of FGF15 further inhibits lipogenesis and nuclear factor-κB activation in the liver. Whereas the beneficial effects of berberine are blunted in FXR knockout mice. Our results reveal that berberine alleviates NASH by modulating the interplay of gut microbiota and bile acid metabolism, as well as the subsequent intestinal FXR activation.
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