Salvia-Nelumbinis naturalis extract protects mice against MCD diet-induced steatohepatitis via activation of colonic FXR-FGF15 pathway
Salvia-Nelumbinis naturalis extract protects mice against MCD diet-induced steatohepatitis via activation of colonic FXR-FGF15 pathway
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丹参-荷花提取物通过激活结肠 FXR-FGF15 通路保护小鼠免受 MCD 饮食诱导的脂肪性肝炎
DOI：
10.1016/j.biopha.2021.111587
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发表时间：
2021-04-14
影响因子：
7.5
通讯作者：
Ji, Guang
中科院分区：
文献类型：
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作者：
Li, Chunlin;Zhou, Wenjun;Ji, Guang
丹参莲子方（SNN）是一种中药方剂，已被证实对治疗非酒精性脂肪性肝炎（NASH）有效，但其潜在机制仍不清楚。在这里，我们发现，4 周的 SNN 给药可减轻 C57BL/6 小鼠蛋氨酸胆碱缺乏 (MCD) 饮食诱导的肝脏脂肪变性和炎症，以及血清丙氨酸转氨酶 (ALT) 水平的增加。粪便 16S rDNA 测序表明，SNN 改变了肠道微生物群的结构，并部分逆转了肠道菌群失调。同时，我们使用液相色谱结合三重四极杆质谱 (UPLC-TQMS) 为基础的代谢组学分析了粪便 BA 谱，发现 SNN 调节了粪便 BA 谱，主要增加了与微生物组相关的 BA 种类（例如去甲脱氧胆酸），进而激活了法尼醇 X 受体 (FXR)-成纤维细胞生长因子 15 (FGF15) 信号通路存在于结肠中，但不在回肠中。肠道 FXR-FGF15 信号传导的激活伴随着肝蛋白激酶 B (PKB/Akt) 磷酸化的增加，以及 NF-kappa B 磷酸化 p-65 亚基的减少，导致肝脏 CD68 阳性巨噬细胞以及炎症细胞因子 IL-1 β 和 TNF-α 表达减少。我们的研究结果建立了SNN治疗、肠道菌群、BA谱和NASH之间的联系，这可能有助于揭示SNN对NASH有益作用背后的机制，从而为SNN的临床应用提供证据。
Salvia-Nelumbinis naturalis (SNN) formula is a traditional Chinese medicine prescription, and has been confirmed to be effective in treating non-alcoholic steatohepatitis (NASH), but the underlying mechanisms are still unknown. Here we showed that 4-week SNN administration alleviated methionine-choline-deficiency (MCD) diet-induced hepatic steatosis and inflammation as well as serum levels of alanine transaminase (ALT) increase in C57BL/6 mice. Fecal 16S rDNA sequencing indicated that SNN altered the structure of gut microbiota and partially reversed the gut dysbiosis. Simultaneously, we analyzed the fecal BA profile using liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQMS) -based metabolomics, and found that SNN modulated fecal BA profile, predominantly increased the microbiomes related BA species (e.g. nordeoxycholic acid) which in turn, activated farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling pathway in the colon but not the ileum. The activation of intestinal FXR-FGF15 signaling was accompanied by increase of liver protein kinase B (PKB/Akt) phosphorylation, and decrease of p-65 subunit of NF-kappa B phosphorylation, resulting in less liver CD68 positive macrophages, and inflammatory cytokine IL-1 beta and TNF-alpha expression. Our results established the link between SNN treatment, gut microbiota, BA profile and NASH, which might shed light into the mechanisms behind the beneficial effects of SNN on NASH, thus provide evidence for the clinical application of SNN.