目的 从肠黏膜屏障和CRH信号通路的角度，探讨枳术丸（生白术/麸炒白术）治疗功能性消化不良（FD）的药 效作用机制。方法 将108只SD雄性大鼠，随机分为空白组、模型组、阳性对照（莫沙必利）组、益生菌组、枳 术丸（生白术入药）组、枳术丸（麸炒白术入药）组、生白术组、麸炒白术组以及麸炒枳实组，共 9组。除空白 组以外，其它各组均采取过度疲劳、饮食失节和夹尾刺激相结合的方式建立功能性消化不良脾虚证模型。造 模成功后，各组按照莫沙必利6.25 mg·kg-1，益生菌0.83 g·kg-1，枳术丸（生/麸炒白术）10.5 g·kg-1，生/麸炒白术 单味饮片水提物 7.0 g·kg-1，麸炒枳实单味饮片水提物 3.5 g·kg-1的剂量灌胃给药，共 14 d。测定大鼠胃排空速 率、肠推进速率，采用酶联免疫吸附测定法（ELISA）检测血清中组胺（HIS），白细胞介素 6（IL-6），干扰素 α （IFN-α）的水平；采用 Western Blot 法检测下丘脑中 CRH、CRHR1、CRHR2 蛋白表达水平，以及肠中 CRH、 CRHR1、CRHR2、Occludin、β-Catenin、Claudin 1、E-Caderin的蛋白表达水平；采用Rt-PCR法检测大鼠肠中 胰蛋白酶（Tryptase）和蛋白酶激活受体 2（Par-2）mRNA 相对表达量。结果 与空白组比较，模型组大鼠胃排空 速率和肠推进速率均明显下降（P＜0.01），血清中 IFN-α，IL-6 的含量明显上升（P＜0.01）；下丘脑和肠中 CRH，CRH-R1 的表达水平明显升高，CRH-R2 的表达水平明显降低（P＜0.01）；肠中 β-Catenin、Claudin 1、E-Caderin、Occludin 的蛋白表达水平明显降低（P＜0.01）；肠中的 Par-2，Trptase 的 mRNA 表达明显升高 （P＜0.01）。各给药组上述指标均得到不同程度的改善，其中枳术丸（麸炒白术入药）组较枳术丸（生白术入药） 组作用更好（P＜0.05，P＜0.01）；麸炒白术单味饮片组作用强于生白术单味饮片组（P＜0.05，P＜0.01）；相较 于单味饮片，枳术丸（麸炒白术入药）组的药效作用更明显（P＜0.05，P＜0.01）。结论 枳术丸对功能性消化不 良的治疗作用可通过 CRH信号通路和维持肠黏膜屏障完整性，抑制炎症反应而实现。白术炮制后对功能性消 化不良的治疗作用增强，枳术丸中配以麸炒白术组方治疗功能性消化不良更合理。

Objective To understand the mechanism of Zhizhu Wan in the treatment of functional dyspepsia（FD），we evaluated the pharmacodynamic mechanism of Zhizhu Wan （raw Atractylodis Macrocephalae Rhizoma /bran-fried Atractylodis Macrocephalae Rhizoma）in the treatment of FD from the perspective of intestinal mucosal barrier and CRH signaling pathway. Methods Totally 108 male SD rats were randomly divided into nine groups：the normal group，the model group， positive control group （mosapride）， probiotics group （PB）， Zhizhu Wan （raw Atractylodis Macrocephalae Rhizoma used as medicine in the formula， RW）group， Zhizhu Wan （bran-fried Atractylodis Macrocephalae Rhizoma used as medicine in the formula， BW）group， raw Atractylodis Macrocephalae Rhizoma （RAM）group， bran-fried Atractylodis Macrocephalae Rhizoma （BAM）group， and bran-fried Aurantii Fructus Immaturus （BAF）group. Except for the blank control group， rats in other groups were treated with combining stimulation of excessive fatigue，dietary disorders，and tail-clamping to establish FD and spleen deficiency syndrome models. After successful modeling，each group was intragastrically administrated with mosapride（6.25 mg·kg-1），PB （0.83 g·kg-1），PAF（3.5 g·kg-1），PAM（7.0 g·kg-1），RAM（7.0 g·kg-1），RW（10.5 g·kg-1）and PW（10.5 g·kg-1） for 14 days. Gastric emptying rate and intestinal propulsion rate were measured. The serum levels of histamine（HIS）， interleukin-6（IL-6）and interferon alpha（IFN-α）were determined by enzyme-linked immunosorbent assay（ELISA）. Western Blotting was used to detect the expression levels of CRH， CRHR1 and CRHR2 in hypothalamus and CRH， CRHR1， CRHR2， Occludin， β-Catenin，Claudin 1 and E-Caderin in intestines. The relative mRNA expression levels of Tryptase and protease-activated receptor-2 （Par-2） in rat intestines were determined by real-time fluorescence quantitative polymerase chain reaction（Rt-PCR）. Results Compared with the blank group，the levels of gastric emptying rate and intestinal propulsive rate assessment in the model group were significantly decreased（P＜ 0.01）. The levels of IFN- α and IL-6 in serum were significantly increased（P＜0.01）. The expression levels of CRH and CRH-R1 in hypothalamus and intestines were significantly increased，while the expression level of CRH-R2 was significantly decreased（P＜0.01）. The protein expression levels of β-Catenin，Claudin 1，E-Caderin and Occludin in intestines were significantly decreased（P＜0.01）. The mRNA expressions of Par-2 and Trptase in intestines were significantly increased（P＜0.01）. The above indexes in each administration group were improved to different degrees. Compared with RAM group，BAM group showed better improvement in the above indexes（P＜0.05，P＜0.01）. The improvement effect of BW group was stronger than that of RW group（P＜0.05，P＜0.01）. Compared with single herb， the pharmacodynamic effect of BW group was more obvious（P＜0.05，P＜0.01）. Conclusion The therapeutic effect of Zhizhu Wan on FD can be achieved by maintaining the integrity of intestinal mucosal barrier，regulating CRH signaling pathway and inhibiting inflammatory response. After processing，the therapeutic effect of Atractylodis Macrocephalae Rhizoma on FD was enhanced. It was more reasonable to use bran-fried Atractylodis Macrocephalae Rhizoma in Zhizhu Wan.

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国家自然科学基金项目（81803726）；辽宁省博士启动基金项目（20180540012）；辽宁省自然科学基金面上项目（2022-MS-334）； 第五批全国中医临床优秀人才研修项目（国中医药人教函[2022]1 号）；“兴辽英才计划”医学名家项目（YXMJ-MZY-08）；辽宁省优秀中医临床 人才培养项目（辽卫办发〔2021〕29号）；大连医科大学附属第二医院院内培育项目（dy2yynpy202218）