基于肠道菌群和代谢组学探讨疏肝化滞方对糖尿病合并 代谢相关脂肪性肝病的影响

doi:10.19871/j.cnki.xfcrbzz.2025.03.006

摘要/Abstract

摘要： 目的探讨疏肝化滞方对糖尿病（diabetes mellitus,DM）合并代谢相关脂肪性肝病（metabolic fatty liver disease,MAFLD）的疗效及作用机制。方法斑马鱼实验预测疏肝化滞方的功效。18只小鼠随机分为空白对照组、模型组（DM合并MAFLD模型）和疏肝化滞方组,每组6只,其中,疏肝化滞方组是给予DM合并MAFLD小鼠疏肝化滞方治疗4周。对比每组小鼠血糖（blood glucose,BG）、血脂、肝功能、C反应蛋白（C-reactive protein,CRP）、C肽、肝脏脂多糖（lipopolysaccharide,LPS）、活性氧（reactive oxygen species,ROS）、胞外信号调节激酶（extracellular signal-regulated kinase,ERK）、c-Jun氨基末端激酶（c-jun N-terminal kinase,JNK）、微管相关蛋白1轻链3B（microtubule associated protein 1 light chain 3B,LC3B）、P38丝裂原激活蛋白激酶（P38 mitogen activated protein kinase,P38）、自噬蛋白P62（autophagy protein P62, P62）的表达水平以及肝脏病理、肠道菌群和代谢组学的差异。DM合并MAFLD小鼠又随机分为阳性对照组和粪菌移植组,每组5只,阳性对照组给予双歧杆菌灌胃4周,粪菌移植组给予疏肝化滞方治疗后小鼠的粪便悬液灌胃4周,检测两组小鼠的BG、血脂、肝功能、LPS、肝脏病理和肠道菌群。结果斑马鱼实验结果显示疏肝化滞方具有降血脂、降血糖的功效。疏肝化滞方能够降低DM合并MAFLD小鼠的BG、血脂、肝功能、CRP、C肽、肝脏LPS、ERK、JNK、P38、P62的表达水平,升高肝脏LC3B的表达水平,改善肝脏脂质沉积。疏肝化滞方治疗后小鼠的肠道菌群以厚壁菌门、真杆菌目、梭菌纲、毛螺菌科、颤杆菌克属和假黄酮菌属等为优势菌群,与代谢物单甘油酯、甘油二酯、甘油三酯呈负相关。粪菌移植实验结果显示,与阳性对照组相比,粪菌移植组小鼠的血糖、血脂、肝功能、LPS水平差异无统计学意义。肠道萨特氏菌属、粪杆菌属、Candidatus_Amulumruptor和拟杆菌属的相对丰度增加,埃希氏菌属、乳杆菌属、副拟杆菌属和阿克曼菌属的相对丰度减少。结论疏肝化滞方可能是通过调节MAPK信号通路及自噬、重塑肠道菌群、改善代谢、降低LPS和炎症因子水平等多通路、多靶点来发挥对DM合并MAFLD的治疗作用。

关键词: 疏肝化滞方, 糖尿病, 代谢相关脂肪性肝病, 肠道菌群, 代谢组学

Abstract: Objective To explore the efficacy and mechanism of Shugan huazhi decoction in diabetes mellitus（DM）with metabolic fatty liver disease (MAFLD). Method Zebrafish experiments were used to predict the efficacy of Shugan huazhi decoction. 18 mice were randomly divided into normal control group, model group (DM with MAFLD model), and Shugan huazhi decoction group. The Shugan huazhi decoction group was treated with Shugan huazhi decoction for 4 weeks in DM combined with MAFLD mice. The expression levels of blood glucose(BG), blood lipids, liver function, C-reactive protein (CRP), C-peptide, liver lipopolysaccharide (LPS), reactive oxygen species (ROS), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), microtubule associated protein 1 light chain 3B (LC3B), P38 mitogen activated protein kinase (P38), autophagy protein P62 (P62), as well as differences in liver pathology, gut microbiota, and metabolomics were compared in each group. DM with MAFLD mice were randomly divided into positive control group and fecal microbiota transplantation group. The positive control group was treated with bifidobacteria, while the fecal microbiota transplantation group was treated with the fecal suspension of Shugan huazhi decoction group. The BG, blood lipid, liver function, LPS, liver pathology and gut microbiota of two groups were detected. Result The result of zebrafish experiment showed that Shugan huazhi decoction has the effect of decreasing blood lipids and BG. After the treatment of Shugan huazhi decoction, the expression levels of BG, blood lipids, liver function, CRP, C-peptide, liver LPS, ERK, JNK, P38 and P62 were decreased, the expression level of liver LC3B was increased, and the liver lipid deposition was improved in DM with MAFLD mice. The gut microbiota was dominated by Firmicutes, Eubacterales, Clostridia, Lachnospiraceae, Oscillibacter, and Pseudoflavonifractor, which were negatively correlated with metabolites monoglycerides, diglycerides, and triglycerides. The result of fecal microbiota transplantation experiment showed that the levels of BG, blood lipids, liver function, and LPS were decreased compared with the positive control group, but there was no statistical difference between the two groups. The relative abundance of Parasottella, Faecalibaculum, Candidatus-Amulumdisruptor, and Bacteroides were increased, while the relative abundance of Escherichia, Lactobacillus, Parabteroides, and Akkermansia were decreased. Conclusion The therapeutic effect of Shugan huazhi decoction in DM with MAFLD may be achieved by multiple pathways and targets, such as regulating the MAPK signaling pathway, autophagy and gut microbiota, improving metabolism, and reducing the levels of LPS and inflammatory factors.

Key words: Shugan huazhi decoction, Diabetes mellitus, Metabolic fatty liver disease, Gut microbiota, Metabonomics

中图分类号:

R587.1

刘星, 梁煊, 李斌, 张立佳, 李美雨希, 李欣悦, 张朕, 王岩. 基于肠道菌群和代谢组学探讨疏肝化滞方对糖尿病合并代谢相关脂肪性肝病的影响[J]. 新发传染病电子杂志, 2025, 10(3): 29-39.

Liu Xing, Liang Xuan, Li Bin, Zhang Lijia, Li Meiyuxi, Li Xinyue, Zhang Zhen, Wang Yan. Effects of Shugan huazhi decoction in diabetes mellitus with MAFLD based on gut microbiota and metabonomics[J]. Electronic Journal of Emerging Infectious Diseases, 2025, 10(3): 29-39.

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