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益气养阴化浊通络方调控肠道菌群-LPS/Caspase-11/GSDMD通路改善糖尿病肾病的机制研究
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| 篇名： | 益气养阴化浊通络方调控肠道菌群-LPS/Caspase-11/GSDMD通路改善糖尿病肾病的机制研究 |
| TITLE： | Mechanism of Yiqi yangyin huazhuo tongluo formula in ameliorating diabetic kidney disease by regulating the gut microbiota-LPS/Caspase-11/GSDMD pathway |
| 摘要： | 目的 基于肠道菌群-脂多糖（LPS）/胱天蛋白酶11（Caspase-11）/消皮素D（GSDMD）通路探讨益气养阴化浊通络方改善糖尿病肾病（DKD）的作用机制。方法采用高脂高糖饮食联合小剂量链脲佐菌素腹腔注射的方法建立DKD小鼠模型。将成模小鼠随机分为模型组、二甲双胍组（阳性对照，200mg/kg）和益气养阴化浊通络方组（32.4g/kg，以生药量计），每组10只；另取10只小鼠作为对照组。每天灌胃药液/生理盐水1次，连续8周。末次给药后，检测小鼠糖脂代谢与肾功能指标，观察肾脏及结肠组织病理形态学变化，检测肾脏、结肠内容物及血清中LPS含量，通过16SrRNA高通量测序对结肠内容物进行肠道菌群分析，并检测结肠组织中闭合蛋白（Occludin）、闭锁小带蛋白1（ZO-1）及肾脏组织中Caspase-11、GSDMD蛋白表达。结果与对照组相比，模型组小鼠血清中空腹血糖、甘油三酯、总胆固醇、血清肌酐、血尿素氮及尿液中尿微量白蛋白水平，各样本中LPS含量，以及肾脏组织中Caspase-11、GSDMD蛋白表达水平均显著升高（P＜0.05）；结肠组织中ZO-1、Occludin蛋白表达水平和肠道菌群Chao1、Ace指数均显著降低（P＜0.05），厚壁菌门/拟杆菌门比值异常升高；肾脏和结肠组织均发生了明显的病理形态学改变，肾脏过碘酸希夫阳性面积百分比显著升高（P＜0.05）。与模型组相比，益气养阴化浊通络方组小鼠糖脂代谢及肾功能相关指标（除总胆固醇外），各样本中LPS含量，肾脏组织中Caspase-11、GSDMD蛋白表达水平均显著降低（P＜0.05）；结肠组织中ZO-1蛋白表达水平、肠道菌群Ace指数均显著升高（P＜0.05）；肠道菌群中双歧杆菌属、粪杆菌属和阿克曼氏菌属等有益菌的相对丰度升高；肾脏和结肠组织的病理形态学损伤得到改善。结论益气养阴化浊通络方改善DKD的机制可能与重塑肠道菌群、修复肠道黏膜屏障、减少LPS入血，继而抑制肾脏Caspase-11/GSDMD介导的细胞焦亡有关。 |
| ABSTRACT： | OBJECTIVE To explore the mechanism of Yiqi yangyin huazhuo tongluo formula in ameliorating diabetic kidney disease （DKD） based on the gut microbiota-lipopolysaccharide （LPS）/Caspase-11/gasdermin D （GSDMD） pathway.METHODS A DKD mouse model was established by high-fat and high-sugar diet combined with intraperitoneal injection of low-dose streptozotocin. The successfully modeled mice were randomly divided into model group， metformin group （positive control， 200 mg/kg） and Yiqi yangyin huazhuo tongluo formula group （32.4 g/kg， calculated as crude drug dosage）， with 10 mice in each group； another 10 mice were set as the control group. Mice were intragastrically administered with corresponding drug solutions or normal saline once a day for 8 consecutive weeks. After the last administration， serum glycolipid metabolism indicators and urinary renal function indicators of mice were determined； the pathological and morphological changes of renal and colonic tissues were observed； LPS contents in renal tissues， colonic contents and serum were detected. 16S rRNA high-throughput sequencing was performed for gut microbiota analysis of colonic contents. The protein expressions of Occludin and zonula occludens-1 （ZO-1） in colonic tissues as well as Caspase-11 and GSDMD in renal tissues were detected.RESULTS Compared with the control group， the model group exhibited significantly elevated levels of serum fasting blood glucose， triglyceride， total cholesterol， serum creatinine， blood urea nitrogen and microalbumin， LPS contents in each sample， as well as protein expressions of Caspase-11 and GSDMD in renal tissues （ P ＜0.05）. The protein expressions of ZO-1 and Occludin in colonic tissues， together with Chao1 and Ace indices of gut microbiota， were markedly decreased （ P ＜0.05）， and the ratio of Firmicutes to Bacteroidetes was abnormally increased. Obvious histopathological changes were observed in renal and colonic tissues； the percentage of PAS-positive area in kidney was markedly increased （ P ＜0.05）. Compared with the model group， the Yiqi yangyin huazhuo tongluo formula group showed remarkable reductions in glycolipid metabolism and renal function-related indicators（except total cholesterol）， LPS contents in various samples， and renal protein expressions of Caspase-11 and GSDMD （ P ＜0.05）. The protein expression level of ZO-1 in colonic tissues and the Ace index of gut microbiota were significantly increased （ P ＜0.05）， and the relative abundance of beneficial genera including Bifidobacterium ， Faecalibaculum and Akkermansia in the gut microbiota was elevated.CONCLUSIONS The mechanism by which Yiqi yangyin huazhuo tongluo formula ameliorates DKD may be related to reshaping gut microbiota， repairing intestinal mucosal barrier， reducing LPS translocation into blood， and further inhibiting Caspase-11/GSDMD-mediated pyroptosis in kidney. |
| 期刊： | 2026年第37卷第19期 |
| 作者： | 侯紫君；李颖利；郭克磊；王艺圆；黄诗雨；张璐嘉；卞华 |
| AUTHORS： | HOU Zijun，LI Yingli，GUO Kelei，WANG Yiyuan，HUANG Shiyu，ZHANG Lujia，BIAN Hua |
| 关键字： | 益气养阴化浊通络方;糖尿病肾病;肠道菌群;LPS/Caspase-11/GSDMD通路;细胞焦亡 |
| KEYWORDS： | Yiqi yangyin huazhuo tongluo formula;Diabetic kidney disease;gut microbiota;LPS/Caspase-11/GSDMD pathway;pyroptosis |
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