【目的】 探讨附子理中丸对腹泻型肠易激综合征（IBS-D）大鼠的治疗作用及其对核因子 κB（ NF-κB）/神经源性基因 Notch同源蛋白1（Notch1）/环氧化酶-2（COX-2）信号通路的调控机制。【方法】 将40只SD大鼠随机分为正常组、模型组、中药 组和西药组。除正常组，其他各组大鼠构建IBS-D模型。成功造模后，中药组大鼠每日给予附子理中丸方水煎液灌胃，西药 组大鼠每日给予匹维溴铵片溶液灌胃，模型组和正常组大鼠给予等体积生理盐水灌胃，连续给药21 d。观察各组大鼠一般状 态、排便情况、内脏敏感性，测定血清异硫氰酸荧光素-葡聚糖（FITC-dextran）、脂多糖（LPS）、连蛋白（Zonulin）水平以评价 肠道通透性，测定小肠推进率，采用酶联免疫吸附分析（ELISA）法检测结肠组织白细胞介素8（ IL-8）、单核细胞趋化蛋白1 （MCP-1）、闭合蛋白（Claudin）、闭锁小带蛋白 1（ZO-1）、咬合蛋白（Occludin）、前列腺素 E2（PGE2）含量，实时荧光定量聚 合酶链反应（PCR）法检测结肠组织NF-κB、Notch1、COX-2的mRNA表达水平，蛋白质免疫印迹（Western Blot）法检测结肠组 织 NF-κB、Notch1、COX-2的蛋白表达水平。【结果】 与模型组比较，中药组大鼠各指标变化如下：排便状况明显改善，表 现为排便频率、稀便率和粪便含水量显著降低（P＜0.05）；内脏敏感性降低，表现为各压力下AWR评分显著降低（P＜0.05）； 肠道通透性改善，表现为血清 FITC-dextran、LPS、Zonulin含量显著降低（P＜0.05）；小肠推进率降低（P＜0.05）；结肠组织 炎症因子（IL-8、MCP-1、PGE2）含量显著降低（P＜0.05）；结肠组织紧密连接蛋白（Claudin、ZO-1、Occludin）水平显著升高 （P＜0.05）；结肠组织NF-κB、Notch1、COX-2的mRNA和蛋白表达水平均显著降低（P＜0.05）。中药组上述各指标水平与西 药组比较，差异均无统计学意义（P＞0.05）。【结论】 附子理中丸能有效改善IBS-D大鼠的肠道功能紊乱、内脏高敏感性和肠 道通透性增加，其机制可能与抑制NF-κB/Notch1/COX-2信号通路激活、减轻肠道炎症反应、增强肠黏膜屏障功能有关。

Objective To investigate the therapeutic effect of Fuzi Lizhong Pills on rats with diarrhea-predominant irritable bowel syndrome （IBS-D） and its regulatory mechanism on the nuclear factor-kappa B（NF- κB）/Notch homolog 1（Notch1）/cyclooxygenase-2（COX-2） signaling pathway. Methods Forty SD rats were randomly divided into a normal group，a model group，a Chinese medicine group，and a western medicine group. Except for the normal group，IBS-D models were established in the other groups. After successful modeling，rats in the Chinese medicine group received daily gavage of Fuzi Lizhong Pills decoction，rats in the western medicine group received daily gavage of pinaverium bromide solution，while rats in the model and normal groups received equal volumes of saline，for 21 consecutive days. The general state，defecation status，and visceral sensitivity of rats in each group were observed. Serum levels of fluorescein isothiocyanate-dextran （FITC-dextran），lipopolysaccharide （LPS）， and zonulin were measured to assess intestinal permeability. The small intestinal propulsion rate was determined. The contents of interleukin-8 （IL-8）， monocyte chemoattractant protein-1 （MCP-1）， Claudin， zonula occludens-1（ZO-1），Occludin，and prostaglandin E2（PGE2） in colon tissue were detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expression levels of NF- κB，Notch1，and COX-2 in colon tissue were measured by real-time quantitative polymerase chain reaction （PCR）. The protein expression levels of NF- κB，Notch1，and COX-2 in colon tissue were detected by Western Blot. Results Compared with the model group， rats in the Chinese medicine group showed significantly improved defecation status [manifested as significantly reduced defecation frequency， loose stool rate， and fecal water content （P＜0.05）]， reduced visceral hypersensitivity [manifested as significantly lower abdominal withdrawal reflex （AWR） scores at various pressures （P＜0.05）]， improved intestinal permeability [manifested as significantly decreased serum levels of FITCdextran， LPS， and zonulin （P＜0.05）]， decreased small intestinal propulsion rate （P＜0.05）， significantly reduced contents of inflammatory factors （IL-8， MCP-1， PGE2） in colon tissue （P＜0.05）， significantly increased levels of tight junction proteins （Claudin， ZO-1， Occludin） in colon tissue （P＜0.05）， and significantly decreased mRNA and protein expression levels of NF-κB，Notch1，and COX-2 in colon tissue （P＜ 0.05）. There were no statistically significant differences in the levels of all aforementioned indicators between the Chinese medicine group and the western medicine group （P＞0.05）. Conclusion Fuzi Lizhong Pills can effectively improve intestinal dysfunction，visceral hypersensitivity，and increased intestinal permeability in IBS-D rats. The mechanism may be related to inhibiting the activation of the NF-κB/Notch1/COX-2 signaling pathway，alleviating intestinal inflammation，and enhancing the intestinal mucosal barrier function.

R285.5

佛山市卫生健康局医学科研课题（编号：20220432）；广东省中医药局科研项目（编号：20233019，20251135）；广州市基础与应 用基础研究基金项目（编号：2024A04J3302）