Gegen Qinlian Decoction (GQD), a traditional Chinese medicine (TCM) formula, has long been used for the treatment of common metabolic diseases, including type 2 diabetes mellitus. However, the main limitation of its wider application is ingredient complexity of this formula. Thus, it is critically important to identify the major active ingredients of GQD and to illustrate mechanisms underlying its action. Here, we compared the effects of GQD and berberine, a hypothetical key active pharmaceutical ingredient of GQD, on a diabetic rat model by comprehensive analyses of gut microbiota, short-chain fatty acids, proinflammatory cytokines, and ileum transcriptomics. Our results show that berberine and GQD had similar effects on lowering blood glucose levels, modulating gut microbiota, inducing ileal gene expression, as well as relieving systemic and local inflammation. As expected, both berberine and GQD treatment significantly altered the overall gut microbiota structure and enriched many butyrate-producing bacteria, including Faecalibacterium and Roseburia, thereby attenuating intestinal inflammation and lowering glucose. Levels of short-chain fatty acids in rat feces were also significantly elevated after treatment with berberine or GQD. Moreover, concentration of serum proinflammatory cytokines and expression of immune-related genes, including Nfkb1, Stat1, and Ifnrg1, in pancreatic islets were significantly reduced after treatment. Our study demonstrates that the main effects of GQD can be attributed to berberine via modulating gut microbiota. The strategy employed would facilitate further standardization and widespread application of TCM in many diseases.
?研究问题：鉴定中药复方葛根芩连汤中通过调节肠道菌群治疗2型糖尿病的关键活性成分，并阐明其可能的作用机制。?研究方法：本研究中，我们以自发2型糖尿病GK大鼠为动物模型，共设置5组，包括正常Wistar大鼠组（N组）、糖尿病模型组（D组）、二甲双胍治疗组（M组）、葛根芩连汤治疗组（GQD组）和小檗碱治疗组（BBR组），实验共干预12周，期间持续监测体重及随机血糖变化情况。干预结束后，通过OGTT实验评估各组大鼠的葡萄糖耐量改善状况；利用16S rRNA基因扩增子测序评估药物干预后，大鼠的肠道菌群多样性及菌群结构的变化情况，并进一步检测各实验组大鼠粪便短链脂肪酸的变化，进行组间比较分析；利用回肠转录组测序，比较药物干预前后大鼠的肠道功能改变，通过生物信息学分析挖掘葛根芩连汤和小檗碱治疗2型糖尿病的潜在机制；利用Luminex液相芯片检测各组大鼠的血清细胞因子水平，评估系统性炎症水平的改善情况；利用实时荧光定量PCR，检测各组大鼠胰岛局部炎症缓解状况。?主要结果1：二甲双胍、葛根芩连汤以及小檗碱治疗均可显著降低GK大鼠的血糖及胰岛素抵抗水平。?主要结果2：葛根芩连汤和小檗碱治疗均可显著改变GK大鼠的肠道菌群结构，促进其向正常菌群结构恢复，显著富集包括Faecalibacterium、Roseburia和Gemmiger等菌属在内的多种产丁酸细菌，增加乙酸、丙酸和丁酸等短链脂肪酸含量。?主要结果3：葛根芩连汤和小檗碱治疗可显著下调回肠免疫相关基因的表达，并上调糖脂代谢相关基因表达，从而调控GK大鼠的肠道黏膜免疫，提高脂质和碳水化合物的代谢能力。?主要结果4：糖尿病GK大鼠的系统性炎症水平及胰岛局部炎症水平在药物治疗后显著降低。





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