黄芩-黄连药对及其活性成分治疗溃疡性结肠炎作用机制

Mechanisms of the couplet medicines of baical skullcap root and golden thread and their active constituents in the treatment of ulcerative colitis

摘要

溃疡性结肠炎（UC）是一种慢性非特异性肠道炎症性疾病，以腹痛、腹泻、黏液脓血便、里急后重为主要临床表现，并伴随营养不良和营养风险，严重影响患者生活质量。中医将溃疡性结肠炎归入“痢疾”“肠澼”等范畴，认为湿热为贯穿溃疡性结肠炎始终的重要病理因素，主要治则是清热燥湿。黄芩、黄连均是清热解毒燥湿药，二者配伍应用首见于葛根芩连汤，后世多用于湿热泄泻、痢疾等治疗中，是治疗溃疡性结肠炎的高频药对。黄芩、黄连药对可通过多种途径发挥抗炎、抗氧化、调节肠道屏障和菌群等作用，其主要活性成分包括黄芩素、黄芩苷、汉黄芩苷、小檗碱等，能够显著缓解临床症状、促进黏膜愈合并改善预后。从中医配伍理论出发，结合现代研究进展，系统阐述黄芩-黄连药对治疗溃疡性结肠炎的药效物质基础和药理机制，以期为黄芩、黄连药对的临床应用和治疗溃疡性结肠炎中药新药研发提供依据。

Abstract

Ulcerative colitis (UC) is a chronic non-specific intestinal inflammatory disease. In clinic, UC is manifested as abdominal pain, diarrhea, mucous purulent bloody stools and tenesmus, usually accompanied by malnutrition and nutritional risks and seriously affecting the quality of life of patients. In traditional Chinese medicine (TCM), it is classified under categories such as "dysentery" and "Chang Pi" (ancient TCM term for dysentery), with damp-heat as a consistent and critical pathological factor throughout the disease course, and clearing heat and removing dampness as its primary therapeutic principle. Baical skullcap root and golden thread are both commonly used Chinese herbs for clearing heat, resolving toxicity, and eliminating dampness. They were first used in combination in Gegen Qinlian Decoction, and have since been widely used in the treatment of damp-heat diarrhea and dysentery, making them the commonly used couplet medicines for UC. Modern studies have shown that the couplet medicines have multiple effects such as anti-inflammation, anti-oxidation, regulation of the intestinal barrier, and modulation of gut microbiota. Their main active components include baicalein, baicalin, wogonoside, and berberine, which can significantly alleviate clinical symptoms, promote mucosal healing, and improve prognosis. Based on the theory of Chinese herbal compatibility and recent research progress, this article systematically reviews the pharmacodynamic material basis and pharmacological mechanisms of the couplet medicines of baical skullcap root and golden thread in the treatment of UC, and discusses their limitations and future perspectives, aiming to provide a reference for their clinical application and the development of new Chinese medicines for the treatment of ulcerative colitis.

关键词

溃疡性结肠炎 / 药对 / 黄芩 / 黄连 / 活性成分 / 炎症 / 肠道菌群 / 机制

Key words

ulcerative colitis / couplet medicines / baical skullcap root / golden thread / active constituents / inflammation / gut microbiota / mechanism

溃疡性结肠炎（ulcerative colitis，UC）是一种慢性非特异性肠道炎症性疾病，以腹痛、腹泻、黏液脓血便、里急后重为主要临床表现，并伴随营养不良和营养风险。中年、青年群体的发病率高^[1]。中医作为补充和替代医学重要分支，在溃疡性结肠炎治疗中应用广泛，可显著缓解患者临床症状，提高患者生活质量，临床疗效显著。中医认为溃疡性结肠炎归属于“痢疾”“便血”“肠澼”等范畴，湿热蕴肠证是临床常见证型之一。药对是中药配伍的最小单元，是方剂应用的精华与核心。黄芩-黄连药对源自《伤寒杂病论》中葛根芩连汤，用治太阳阳明合病致邪热下利。黄芩、黄连性味苦寒，寒以清热，苦能坚阴，二者清热燥湿、协同增效，历来同用以治疗湿热泄泻、痢疾等证。本文从不同层面黄芩、黄连药对配伍理论出发，并结合国内外研究，总结黄芩、黄连药对活性成分及其复方可能的防治溃疡性结肠炎作用机制，以期为后期研究和临床运用提供理论基础。

1 配伍理论研究

1.1 基于用药经验配伍研究

《证治汇补·痢疾》曰：“肠澼者，谓湿热积于肠中，即今之痢疾也”，故古代医家治痢选方如葛根芩连汤、黄芩汤、白头翁汤、承气汤、芍药汤等，多以清利之药涤荡胃肠。董建华^[2]认为溃疡性结肠炎活动期病机为脾胃本虚，湿热为患，善用黄芩、黄连等苦寒之品燥湿祛邪，并主张燥润相济，毋损阴津。王庆国^[3]认为溃疡性结肠炎常呈寒热错杂、虚实互见之证，常用黄芩、黄连、败酱草等，化裁柴胡桂枝干姜汤、半夏泻心汤、援绝神丹等寒温并用、辛开苦降甘调共治。现代生活中嗜食生冷厚腻损伤脾胃运化，酿湿生热，蕴结于肠，戕害脏腑气血阴阳，变生他证，导致反复难愈。黄芩、黄连药对配伍补益药或温里药，以寒热并用、攻补兼施，治疗溃疡性结肠炎寒热错杂、虚实并见之证。

1.2 药对药效优化研究

中药活性成分是中药发挥疗效的物质基础，黄芩、黄连配伍后煎出活性成分的变化是揭示配伍机制的关键。黄芩、黄连共煎后，黄芩苷、黄芩苷元、小檗碱和黄连碱的浓度因相变作用显著降低，伴随形成黄芩苷与小檗碱占比65%的沉淀复合物^[4]。沉淀复合物在治疗溃疡性结肠炎小鼠方面优于黄芩苷和小檗碱^[5]。黄芩、黄连共煎时Cmax、AUC显著降低，t_1/2、T_max明显延长，表明配伍共煎的相态变化促使有效成分的释放更加平稳持久^[4]。不同配伍比例的小檗碱和黄芩苷抑制的条件致病菌菌谱存在差异。中医认为“合渣服用”可有效提高疗效，黄芩、黄连配伍共煎后，掩蔽苦味基团，减轻对肠道非致病菌的抑制作用，配伍共煎减毒矫味增效，“和合”黄芩、黄连苦寒之性^[6]。

2 治疗溃疡性结肠炎的作用机制研究

2.1 炎症级联调控

2.1.1 NF-κB

NF-κB通路与溃疡性结肠炎密切相关。研究^[7]表明黄芩、黄连共煎靶向TLR4/NF-κB、TLR-4/TRIF、TNFR-1/NF-κB信号级联反应，抑制炎症介质的表达，缓解肠道炎症。黄芩素通过结合MD-2，阻断TLR4/MyD88通路^[8]。小檗碱可以抑制EIF2AK2的二聚化，从而阻断其自磷酸化活化后触发的NF-κB、AKT、JNK和NLRP3等多种炎症通路的激活^[9]。

2.1.2 MAPKs

过量ROS、IL-1β、TNF-α等炎症介质异常激活MAPKs（ERK、p38、JNK等），促进肠道炎症进展。黄芩苷通过对ROS/MAPKs的调控减轻炎症级联和氧化应激^[10]。研究^[11]报道黄芩苷-正丁酯衍生物具有p-ERK抑制剂和活性氧清除剂的双重效果。

2.1.3 JAK/STAT

溃疡性结肠炎患者中IL-6、IL-23、IFN-γ等促炎因子驱动JAK激酶磷酸化，激活STAT转录因子，导致肠黏膜屏障受损和免疫异常。葛根芩连汤通过调控IL-6/JAK2/STAT3信号级联及p-STAT3转录功能，重塑小鼠结肠炎模型Treg/Th17稳态^[12]。IL-6家族成员OSM对小檗碱抑制STAT/AKT/ERK的磷酸化具有主导作用^[13]。

2.1.4 PI3K/AKT

TLR4通过串扰机制激活PI3K并磷酸化下游靶蛋白AKT，继而激活NF-κB，加剧肠道炎症。葵洁元汤可通过抑制TLR4，阻断该信号通路，促进抗氧化酶生成，恢复肠黏膜屏障损伤^[14]。研究^[15]发现小檗碱可能靶向IRGM1抑制PI3K/AKT/mTOR信号通路，下调细胞因子的表达，缓解炎症反应。

2.1.5 NLRP3

过量ROS导致TXNIP、NLRP3与NEK7结合，招募下游靶蛋白ASC、Pro-Caspase-1，组装成NLRP3炎症小体，加剧炎症及细胞焦亡。黄连素通过调控ROS/TXNIP/NLRP3通路，调节有益菌阿克曼菌和短链脂肪酸产生菌丰度^[16]。小檗碱通过氢键与NEK7的121-精氨酸（R121）残基结合，特异性阻断NEK7/NLRP3的相互作用，从而抑制NLRP3炎症小体的激活及炎症因子的释放，发挥抗炎活性^[17]。

2.2 抗氧化

溃疡性结肠炎患者体内ROS/RNS的产生与清除失衡，氧化损伤标志物（如MDA、MPO、LPO）积累，抗氧化酶（如SOD、CAT、GSH）活性下降。干姜黄芩黄连人参汤通过PINK1/Parkin恢复线粒体自噬^[18]。黄芩提取物调节GPX4/ACSL4轴抑制铁死亡^[19]。葛根芩连汤恢复Nrf2/NQO1/HO-1的内源性抗氧化调控作用，改善模型大鼠结肠组织病理损伤和形态结构^[20]。

2.3 调节肠道黏膜屏障

肠黏膜屏障由黏液层、肠上皮细胞的紧密连接构成。溃疡性结肠炎患者肠上皮细胞过度凋亡，导致坏死性凋亡、焦亡通路激活，诱发炎症。芍药汤通过上调Muc2、Tff3、ZO-1和Occludin表达，维持肠黏膜屏障完整性^[21]。葛根芩连汤通过双向调节Notch信号通路，恢复溃疡性结肠炎小鼠肠上皮的再生和稳态^[22]，其中活性成分汉黄芩苷通过抑制MLCK和p-MLC2的表达，防止紧密连接断裂^[23]。汉黄芩素调控AhR/CYP1A1/IL-22通路，上调ZO-1、Occludin的表达，促进肠上皮再生与屏障修复^[24]。

2.4 调节肠道微生态

2.4.1 调节肠道菌群

宿主对自身肠道菌群免疫耐受的异常是溃疡性结肠炎发病的核心机制之一。溃疡性结肠炎患者肠道菌群失调，其特征为有益共生菌群显著减少，致病菌相对增加。葛根芩连汤通过激活PPAR-γ通路，抑制iNOS合成，从而抑制大肠杆菌过度增殖^[25]。经黄芩、黄连药对治疗的BALB/c小鼠粪菌移植增强黄芩、黄连药对抗炎、抗氧化应激和调节肠道菌群的能力，抗生素处理组经治疗后和模型组细胞因子（IL-1β、TNF-α、IL-6）、氧化应激水平（SOD、MDA、GSH）无显著差异^[26]。

2.4.2 菌群-宿主互作

短链脂肪酸（short-chain fatty acids，SCFAs）依赖肠道菌群代谢产生，激活TGR5，抑制组蛋白去乙酰化酶活化，缓解炎症，促进黏膜屏障修复。溃疡性结肠炎患者肠黏膜组织和粪便中SCFAs产生菌及SCFAs显著低于健康人群。黄连多糖和小檗碱联用增加SCFAs产生菌丰度，提高SCFAs含量，激活AhR/IL-22通路，缓解炎症反应，修复紧密连接，保护C57BL/6J小鼠肠黏膜屏障^[27]。

胆汁酸依赖肝肠循环“合成-分泌-重吸收”，通过FXR/TGR5/S1PR2等通路调控，共同维持稳态，其失衡与溃疡性结肠炎密切相关。黄芩、黄连药对通过调控Nrf2/ROS/TXNIP/NLRP3抑制氧化应激和炎症反应，调节FXR/SHP/CYP7A1和TGR5，调控胆汁酸信号通路，重塑肝肠循环胆汁酸稳态，促进肠黏膜屏障功能恢复^[28]。

2.5 免疫调节

2.5.1 调控巨噬细胞

肠黏膜M1型巨噬细胞保护宿主免受病原体侵害，M2型巨噬细胞维持宿主对自身肠道微生态的耐受，溃疡性结肠炎患者巨噬细胞M1/M2失衡，M1型巨噬细胞过度极化。黄连素通过调节TSC1 mRNA m6A的修饰，增强并稳定TSC1的表达，介导TSC1/ERK通路抑制M1极化、介导TCS1/mTORC1/CEBPβ通路促进M2极化^[29]。小檗碱通过AKT/SOCS/NF-κB信号通路抑制M1巨噬细胞极化，其作用在AKT1 siRNA和SOCS1 siRNA的RAW264.7细胞中被抑制^[30]。

2.5.2 调节CD4⁺ T细胞

在溃疡性结肠炎患者中，维持免疫耐受的Treg降低， 发挥免疫功能的Th1、Th17过度活化，持续推动黏膜炎症及屏障破坏。大量临床和实验证据支持中医药调节溃疡性结肠炎免疫失衡的作用。芍药汤通过调节IL-6/STAT3信号通路恢复溃疡性结肠炎大鼠Th17/Treg平衡^[31]。葛根芩连汤调控IL-6/JAK2/STAT3通路和磷酸化STAT3的转录功能，重塑Treg/Th17平衡^[12]小檗碱通过苦味信号通路促进簇状细胞分泌IL-25以维持肠黏膜屏障完整性和Th1/Th2/Th17稳态^[32]。

3 小结

黄芩、黄连作为经典药对组合，药简效专，历来用于治疗湿热泄泻、痢疾。黄芩、黄连药对活性成分黄芩素、黄芩苷、汉黄芩苷、小檗碱等成分发挥主要作用。黄芩、黄连药对通过共煎和合七情、兼洽性味，减毒矫味增效，通过调节NF-κB、MAPKs、JAK、PI3K、AKT、NLRP3等通路调控炎症反应、氧化应激，调节AhR、Notch通路促进肠道黏膜修复，调节FXR、TGR5等通路调节胆汁酸、短链脂肪酸代谢，维持菌群-宿主稳态，为宿主提供能量和营养，维持免疫平衡，抑制致病菌定植，调节巨噬细胞极化、CD4⁺ T细胞分化，抑制过度免疫反应，维持免疫耐受。

尽管目前对黄芩、黄连治疗溃疡性结肠炎机制的研究取得了一定进展，但仍有多个方面的问题有待进一步探索。黄芩、黄连配伍比例、配伍后活性成分的比例及其作用的研究仍较少；多数研究集中在单味药及单个成分的作用机制上，对药对配伍及多成分协同作用研究较少；当前研究主要集中于细胞和动物模型，作用机理虽有初步揭示，但缺乏充分的临床证据和网络药理学、生物信息学与转录组学、蛋白组学、代谢组学等多组学整合系统研究验证。

黄芩、黄连药对配伍比例在古籍不同方剂中有多个记载，在探究药物有效物质、药理活性、临床疗效、制剂技术、毒性实验及不良反应研究的同时，加强不同配伍比例对其活性成分及其代谢的影响研究，使黄芩、黄连药对更广泛应用于临床。

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基金资助

2023年江苏省中医肛肠疾病临床医学创新中心重点项目(GCCXZX-2021)

2022年江苏省自然科学基金项目(BK20221178)

江苏省研究生实践创新计划项目(SJCX25_1042)