目的 探讨鞣花酸对阿尔茨海默病（AD）治疗的可能作用机制。方法 取24只SPF级APP/PS1双转基因小鼠随机分为模型组、石杉碱甲（0.1 mg·kg^-1）组和鞣花酸高、低剂量（50、20 mg·kg^-1）组，每组6只，另外选取6只SPF级3月龄C57BL/6J野生型小鼠作为对照组，连续ig给药60 d。采用Morris水迷宫实验观察各组小鼠的空间学习记忆能力，各组随机处死后通过苏木精-伊红（HE）染色观察结肠组织形态，免疫组化分析紧密连接蛋白1（ZO-1）、Claudin-1蛋白的表达，16S rRNA测序检测各组小鼠肠道菌群多样性和优势物种分布情况。结果 在定位巡航实验中，与对照组比较，模型组逃避潜伏期延长（P＜0.01）；与模型组比较，鞣花酸高、低剂量组和石杉碱甲组逃避潜伏期明显缩短（P＜0.01）。在空间探索实验中，模型组小鼠在平台象限内的停留时间和穿越平台的次数较对照组均显著减少（P＜0.01）；石杉碱甲组和鞣花酸低、高剂量组的小鼠在平台象限内停留时间较模型组小鼠均显著延长（P＜0.01），穿越平台的次数显著增加（P＜0.05、0.01）。与对照组相比，模型组和低剂量鞣花酸组的结肠组织形态差异较大；石杉碱甲组和高剂量鞣花酸组结肠组织形态差异较小。对照组ZO-1、Claudin-1蛋白表达强阳性，与对照组相比，模型组表达量显著下降（P＜0.01） ；与模型组相比，石杉碱甲组和鞣花酸组表达量显著上升（P＜0.01）。模型组小鼠的菌群丰度和多样性明显低于对照组小鼠，经高剂量鞣花酸处理的AD小鼠菌群丰富度和多样性的缺陷均有所改善。与对照组相比，AD模型小鼠拟杆菌门丰度显著降低，厚壁菌门、促炎相关变形菌门丰度异常升高；经鞣花酸干预后，失衡的厚壁菌门、拟杆菌门丰度得到有效回调，变形菌门丰度显著下降。在属水平上，模型组乳杆菌属本底丰度已上升；经鞣花酸干预后，促炎相关杜氏杆菌属丰度降低，同时乳杆菌属、异普氏菌属丰度进一步升高。结论 鞣花酸可以通过调节紧密蛋白的表达，增强肠道的屏障功能，降低肠道通透性，改善肠道微生态结构，对AD发挥改善作用。

Objective To explore the possible mechanism of ellagic acid in treatment of Alzheimer’s disease (AD). Method Twentyfour SPF-grade APP/PS1 double-transgenic mice were randomly divided into four groups: Model group, huperzine A (0.1 mg·kg^-1) group, and high- and low-dose ellagic acid groups (20, 50 mg·kg^-1), with six mice in each group. Additionally, six SPF-grade 3-monthold C57BL/6J wild-type mice were selected as the control group. All groups received intragastric administration for 60 consecutive days. Spatial learning and memory abilities were assessed using the Morris water maze test. After random sacrifice, colonic tissue morphology was examined by hematoxylin-eosin (HE) staining, expression of tight junction proteins ZO-1 and Claudin-1 was analyzed via immunohistochemistry, and intestinal microbiota diversity and dominant species distribution were evaluated by 16S rRNA sequencing. Results In the place navigation test, compared to the control group, the escape latency in the model group was significantly prolonged (P<0.01); Compared to the model group, escape latency was significantly shortened in both the high- and low-dose ellagic acid groups and the huperzine A group (P<0.01). In the spatial probe test, the time spent in the target quadrant and the number of platform crossings were significantly reduced in the model group compared to the control group (P<0.01). The time spent in the target quadrant and the number of platform crossings were significantly increased in the huperzine A group and both ellagic acid dose groups compared to the model group (P<0.05 or 0.01). Compared to the control group, significant morphological differences were observed in the colon tissues of the model group and the low-dose ellagic acid group; However, fewer differences were noted in the huperzine A and high-dose ellagic acid groups. Strong positive expression of ZO-1 and Claudin-1 proteins was observed in the control group, while their expression levels were significantly decreased in the model group (P<0.01). Compared to the model group, expression levels were significantly elevated in the huperzine A and ellagic acid groups (P<0.01). Microbial richness and diversity in the model group were markedly lower than those in the control group; Treatment with high-dose ellagic acid improved microbial richness and diversity in AD mice. Compared to the control group, the abundance of Bacteroidetes was significantly reduced in AD model mice, while Firmicutes and pro-inflammatory Proteobacteria were abnormally increased. Following ellagic acid intervention, the imbalanced abundances of Firmicutes and Bacteroidetes were effectively restored, and the abundance of Proteobacteria significantly decreased. At the genus level, baseline abundance of Lactobacillus had already increased in the model group; After ellagic acid treatment, the abundance of pro-inflammatory Desulfovibrio decreased, while that of Lactobacillus and Allobaculum further increased. Conclusion Ellagic acid can improve AD by regulating tight junction protein expression, enhancing intestinal barrier function, reducing intestinal permeability, and improving gut microbiota structure.

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黑龙江省自然科学基金联合引导项目（LH2022H068）；中国博士后科学基金资助课题（2015M581496）；黑龙江中医药大学研究生创新科研项目（2022yjscx012，2019yjscx011，2024yjsc027）；黑龙江省卫生健康委科研课题（20220202080996）；黑龙江省中医药科研课题（ZHY2025-180）