目的 探讨枳术宽中胶囊（Zhizhu Kuanzhong Capsule，ZZKZ）对葡聚糖硫酸钠（dextran sulfate sodium，DSS）诱导的溃疡性结肠炎（ulcerative colitis，UC）及伴随抑郁样行为的治疗作用及其机制。方法 采用超高效液相色谱-离子阱-静电场轨道阱质谱（UPLC-LTQ/Orbitrap-MS）分析ZZKZ中的主要成分。小鼠自由饮用3.5% DSS溶液建立UC模型，给予药物干预7 d，采用苏木素-伊红（hematoxylin-eosin，HE）和阿利新蓝-过碘酸-雪夫（Alcian blue-periodic acid-Schiff，AB-PAS）染色评估结肠组织病理损伤及黏液分泌情况；采用旷场实验和糖水偏好实验评估抑郁样行为；采用16S rRNA测序和血清非靶向代谢组学分析肠道菌群与血清代谢物变化，结合网络药理学预测靶点和通路，并通过分子对接、分子动力学模拟、qRT-PCR和Western blotting实验进行验证。结果 与模型组比较，ZZKZ显著减轻UC小鼠的结肠缩短（P＜0.05、0.01），降低疾病活动指数（disease activity index，DAI）评分（P＜0.01），提高旷场实验运动总距离、平均运动速度和糖水偏好指数（P＜0.05、0.01），减少结肠组织和脑组织炎症因子表达（P＜0.05、0.01），缓解肠道组织病理损伤和海马神经元损伤（P＜0.01）。16S rRNA测序结果显示，ZZKZ能够降低有害菌的丰度，升高有益菌的丰度，逆转肠道菌群失调。血清非靶向代谢组学分析结果显示，ZZKZ能够调控代谢途径，逆转脂质、色氨酸和胆汁酸代谢紊乱。网络药理学分析预测Janus激酶2（Janus kinase 2，JAK2）/信号转导和转录激活蛋白3（signal transducer and activator of transcription 3，STAT3）为相关通路，ZZKZ中熊果酸、白术内酯I、橙皮素和异鼠李素与其靶标蛋白表现出显著的结合亲和力，可能是其发挥疗效的主要活性成分。Western blotting结果显示，与模型组比较，ZZKZ显著上调UC小鼠肠道紧密连接蛋白-1（zonula occludens-1，ZO-1）、Occludin和Claudin-1表达（P＜0.05、0.01），并抑制JAK2和STAT3的磷酸化（P＜0.05）。结论 ZZKZ可能通过调节肠道菌群、代谢途径及抑制JAK2/STAT3通路，缓解UC及伴随的抑郁样行为。

Objective To investigate the therapeutic effect and mechanism of Zhizhu Kuanzhong Capsule (枳术宽中胶囊, ZZKZ) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) and associated depressive-like behaviors. Methods The main components in ZZKZ were analyzed using UPLC-LTQ/Orbitrap-MS. UC model was established by freely drinking 3.5% DSS solution in mice, and drug intervention was given for 7 d. Hematoxylin-eosin (HE) and Alcian blue-periodic acid Schiff (AB-PAS) staining were used to evaluate the pathological damage and mucus secretion of colon tissue. Depressive like behavior was evaluated using open field experiments and sugar water preference experiments. 16S rRNA sequencing and serum untargeted metabolomics were used to analyze changes in gut microbiota and serum metabolites. Network pharmacology was used to predict targets and pathways, which were validated through molecular docking, molecular dynamics simulation, qRT-PCR and Western blotting experiments. Results Compared with model group, ZZKZ significantly reduced colon shortening in UC mice (P < 0.05, 0.01), decreased disease activity index (DAI) score (P < 0.01), increased total distance, average exercise speed in open field experiments and sugar preference index (P < 0.05, 0.01), reduced the expressions of inflammatory factors in colon and brain tissues (P < 0.05, 0.01), and alleviated intestinal tissue pathological damage and hippocampal neuron damage (P < 0.01). 16S rRNA sequencing results showed that ZZKZ could reduce the abundance of harmful bacteria, increase the abundance of beneficial bacteria, and reverse the imbalance of gut microbiota. The results of serum non-targeted metabolomics analysis showed that ZZKZ could regulate metabolic pathways, reverse lipid, tryptophan and bile acid metabolism disorders. Network pharmacology analysis predicted that Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) was related pathway, ursolic acid, atractylenolide I, hesperetin and isorhamnetin in ZZKZ showed significant binding affinity with their target proteins, which may be the main active ingredients for their therapeutic effects. Western blotting results showed that compared with model group, ZZKZ significantly upregulated the expressions of zonula occludin-1 (ZO-1), Occludin and Claudin-1 in colon of UC mice (P < 0.05, 0.01), and inhibited the phosphorylation of JAK2 and STAT3 (P < 0.05). Conclusion ZZKZ may alleviate UC and associated depressive like behavior by regulating gut microbiota, metabolic pathways and inhibiting JAK2/STAT3 pathway.

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湖北省自然科学基金中医药创新发展联合基金资助项目（2025AFD569）