CJLIS (Traditional Chinese Medicine)
中药调节肠道微生物群治疗痛风研究进展
1.黑龙江中医药大学,黑龙江 哈尔滨 150040;2.黑龙江中医药大学附属第一医院,黑龙江 哈尔滨 150040
摘要:肠道微生物群代谢产物及微生物群结构与痛风发病密切相关,中药可作为肠道微生态调节剂,对肠道微生物群结构及代谢起调节作用,从而延缓发病、改善病情、提高患者生活质量。本文主要探讨中医药调节肠道微生物群治疗痛风研究进展,从中医药治疗痛风优势、中医药调节肠道微生物群防治痛风作用机制出发,为临床治疗痛风扩展思路。
关键词:痛风;肠道微生物群;中医药;相互作用;综述
中图分类号:R259 文献标识码:A 文章编号:2095-5707(2024)02-0249-05
DOI:10.3969/j.issn.2095-5707.202306025 开放科学(资源服务)标识码(OSID):
Research Progress in the Regulation of Gut Microbiota in TCM in the Treatment of Gout
ZHAI Yi1, TONG Ying2
(1. Heilongjiang University of Chinese Medicine, Harbin 150040, China; 2. First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China)
Abstract: Gut microbiota metabolites and their structural are closely related to the occurrence of gout. TCM can be regarded as an ideal intestinal microecological regulator, which plays a role by affecting the structure and metabolism of intestinal microflora in patients, and apparents advantages in delaying the onset, improving the condition, and improving the quality of life.This article mainly discusses the research progress of TCM regulating the intestinal microbiota in the treatment of gout, from the advantages of TCM in treatment of gout, and expanding the ideas for the clinical treatment of gout.
Keywords: gout; gut microbiota; TCM; interaction; review
痛风是由嘌呤代谢障碍、血尿酸水平过高导致单钠尿酸盐结晶沉积于关节和非关节结构引起的代谢性炎症性疾病[1],分为高尿酸血症、尿酸钠晶体沉积、尿
酸钠晶体沉积急性炎症反应、晚期痛风4个阶段[2]。调
查数据显示,中国成人痛风加权患病率为3.2%,随年龄增长呈上升趋势[3]。国内外治疗痛风主要以抗炎药物
及降尿酸盐为主,能有效减轻关节炎症、疼痛,降低尿酸,但长期使用易引发不良反应,如胃肠道反应、肾功能不全、别嘌呤醇超敏反应综合征伴嗜酸性粒细胞增多、药疹及心血管风险等[4]。
随着多组学技术的发展,肠道微生物群(gut microbiota,GM)与痛风相关性研究不断增加,干预
GM或将成为治疗痛风新靶标。中药富有多糖、多酚、生物碱、萜类等药效活性成分[5],能有效改善痛风病情,减少不良反应[6]。多项研究表明,中药在控制不良反应[7]、改善关节症状[8]、降低复发率[9]等方面均优于
西药,可广泛用于痛风的预防和治疗。本文对中药调控GM改善痛风症状相关研究进行综述,以期为临床治疗痛风提供参考。
1 肠道微生物群引发痛风的作用机制
GM是由细菌、真菌、病毒组成的复杂群落。细菌以拟杆菌门和厚壁菌门为主,其次为变形菌门、梭杆菌门、软壁菌门、放线菌门、疣微菌门[10],根据作用
机制不同可分为生理性菌群、机会致病菌和过路菌。研究表明,GM主要通过影响嘌呤及尿酸代谢,诱导炎症反应介导痛风[11]。
1.1 肠道微生物群改变
GM改变与痛风尿酸盐、嘌呤降解及炎症发生密切
相关。Chu等[12]使用宏基因组分析发现,与健康人相比,痛风患者粪便中普雷沃菌属、梭杆菌属和拟杆菌属相对丰度增加,而肠杆菌科细菌和产丁酸盐菌种相
对丰度降低;Guo等[13]观察35例痛风患者粪便,发现其中拟杆菌、木糖降解拟杆菌富集,粪大肠杆菌、产丁酸梭菌及假小链双歧杆菌减少。一项结合微生物组及代谢组的研究显示,痛风患者肠道拟杆菌、卟啉单胞菌科、红球菌、丹毒梭菌等条件致病菌增加,乙酸
盐、琥珀酸盐等代谢物含量也发生了改变[14]。
1.2 影响尿酸与嘌呤代谢
GM通过影响尿酸及嘌呤代谢参与痛风发生发展。尿酸是人类嘌呤代谢终产物,人体内嘌呤核苷酸水解为
次黄嘌呤和鸟嘌呤,次黄嘌呤经黄嘌呤氧化酶(XOD)催化形成黄嘌呤,鸟嘌呤脱氨形成黄嘌呤,随后氧化
形成尿酸[15]。正常人体每天产生约700 mg尿酸,其中
2/3由肾脏排出,1/3经肠道排出[16]。肠上皮细胞尿酸转运体负责将尿酸从血液转运至肠腔,被肠道菌群分
解或直接排出体外[17]。
研究表明,GM能够分解尿酸,Lim等[18]研究发现,拟杆菌属肠型1中富集5-羟基异尿酸水解酶,可将尿酸分解为尿囊素。痛风患者肠杆菌科相对丰度降低,
可导致尿酸降解功能障碍、尿酸蓄积[12]。粪球菌可通过产生短链脂肪酸促进尿酸排泄,而高尿酸血症患者粪球菌属相对丰度降低,影响血清尿酸代谢,导致尿
酸升高[19]。Yamada等[20]研究发现,加氏乳杆菌PA-3细胞外嘌呤酶活性较高,可将核苷转化为嘌呤碱基,
减少肠道嘌呤吸收。Yu等[21]研究发现,高尿酸血症模型大鼠乳酸杆菌属、链球菌属等丰度减少,使嘌呤吸收和尿酸分解效率降低;变形杆菌属丰度增加,加速将嘌呤转化为尿酸。
1.3 诱发炎症反应
GM代谢产物脂多糖(LPS)增加和SCFAs产生减少可导致痛风发作。研究表明,痛风急性发作时,单钠尿酸盐结晶激活巨噬细胞和单核细胞NOD样受体热蛋白结构域相关蛋白3炎症小体,释放白细胞介素
(IL) -1β,引起急性炎症反应[1]。SCFAs主要由乙酸盐、丙酸盐和丁酸盐组成,是膳食纤维在肠道细菌厌氧发酵过程中的代谢产物,具有维持肠道稳态、控制
炎症、增强屏障等功能[22]。Park等[23]研究发现,与急性状态相比,20名痛风患者在恢复过程中SCFAs产生
属增加、乙酸盐水平升高、炎症相关属减少。Vieira
等[24]予痛风小鼠乙酸盐,发现其可诱导中性粒细胞凋亡,从而抑制单钠尿酸盐晶体的炎症反应,改善痛风小鼠急性炎症。丁酸盐可通过抑制Ⅰ类组蛋白去乙酰化酶降低单钠尿酸盐诱导的炎症因子水平,发挥抗炎作用[25]。
LPS是革兰阴性菌细胞壁的主要成分,GM改变使肠道通透性增加,LPS通过肠道进入循环系统引发炎症反应[26]。研究发现,痛风幼鹅血清LPS水平显著高于健康幼鹅,且与变形菌门丰度呈正相关,说明菌群失调导致肠源性内毒素进入血液循环[27]。该研究还发现
痛风幼鹅肠道和肾脏同时存在炎症紊乱,表明LPS/ TLR4/MyD88炎症信号通路被激活,导致肠道和肾脏发生炎症反应。
2 中药与肠道微生物群互相调节
中药经口服进入肠道,通过与GM直接接触发生化学反应调节肠道菌群紊乱,维持肠道菌群平衡[28]。如桑黄乙醇提取物可增加乳酸杆菌有益菌丰度[29]、姜黄素可抑制志贺埃希氏菌和拟杆菌过度生长[30]。
此外,GM也可将中药化学成分转化为具有不同生物利用度和生物活性或毒性的代谢产物[31]。中药提取
物中存在极性化合物,其亲脂性差、生物利用度低, GM可对其进行转化,如氧化、还原、重排等,使其变成较小极性或亲脂性更高的分子,提高药物成分生物利用度[31]。中药及其汤剂富含糖苷类化合物(如三萜
苷和黄酮苷),因氢键数多、极性表面积大和分子柔顺性弱,导致肠渗透性差,限制糖苷类吸收[32],GM可通过催化去糖基化产生次生糖苷和/或苷元,增加肠道对药物有效成分吸收[33],也可通过乙酰化和酯化将具有
毒性的乌头碱(一种二脂双萜生物碱)代谢为苯甲酰乌头碱和酯乌头碱,以减轻毒性[34]。
3 中药调节肠道微生物群治疗痛风
中药通过改善肠道菌群组成、调节炎症因子、增加SCFA、减少LPS恢复肠屏障功能,维持GM多样性,降低尿酸,控制炎症,治疗痛风。
3.1 改善肠道微生物群结构
研究表明,单味中药、中药成分或中药复方均可调控GM组成。孟博文等[35]发现,健脾泄浊法通过增
加乳酸杆菌及双歧杆菌数量、减少拟杆菌数量改善肠道微生态失衡;Lin等[36]发现,予痛风性关节炎小鼠四
妙汤可使幽门螺杆菌属、普雷沃氏菌属丰度降低,阿克曼西亚属和厌氧菌属丰度增加;Wang等[37]发现,改
良白虎汤能调节急性痛风性关节炎大鼠乳酸杆菌、瘤胃球菌科、普雷沃氏菌丰度;贾二涛等[38]发现,痛风患者经慈苓化浊颗粒治疗后,瘤胃球菌属富集。Gao等[39]研究发现,中药复方CoTOL可降低接种XOD粪
链球菌的肥胖高尿酸血症小鼠血清尿酸水平、增加阿克曼菌丰度、降低拟杆菌及普雷沃菌属丰度。
此外,中药对肠道有害菌或条件致病菌具有抑制作用。如四妙汤能抑制痛风性关节炎小鼠克雷伯菌、普雷沃氏菌、志贺氏菌和肠球菌等致病菌生长[40]; H方案和T方案中药汤剂均可抑制致病菌的繁殖,帮助患者恢复肠道水平[41]。
3.2 保护肠黏膜屏障
肠黏膜屏障包括肠道黏膜上皮、肠道菌群、黏液等,由机械屏障、化学屏障、生物屏障和免疫屏障组成,具有防止肠腔内有害物质和病原体进入血液循环,维持机体内环境稳态的功能[42]。痛风发作时,肠黏膜屏
障作用降低、肠道通透性增加致使细菌和内毒素易位,出现炎症反应,加重痛风症状。肠黏膜上皮和细胞间紧密连接构成的机械屏障是肠黏膜屏障中最重要部分,肠道紧密连接蛋白(ZO)-1和闭锁蛋白是重要的紧密连接
蛋白,有助于维持肠黏膜完整性,维持肠黏膜屏障功能[30]。研究发现,在尿酸氧化酶基因敲除小鼠中,ZO-1
和闭锁蛋白表达显著下降,二胺氧化酶、血清D-乳酸、
内毒素水平升高,表明肠道屏障受损,肠道通透性增强,同时,其血清及肠道肿瘤坏死因子(TNF)-α、IL-6升高,表明肠屏障受损可能与尿酸诱导的炎症有关[43]。
王雨等[44]发现,维药菊苣提取物喂养高尿酸血症大鼠能改善其肠道菌群结构,降低血清LPS水平、肠道β-防御素1水平,促进肠道分泌型免疫球蛋白A分
泌,减少致病菌,增加有益菌,综合调节肠黏膜屏障,维护肠道内稳态。
祛浊通痹汤是治疗痛风经验方,由土茯苓、绵萆薢、姜黄、玉米须、薏苡仁、豨莶草、姜黄、桑寄生、延胡索、佛手等组成,可通过增加ZO-1、闭锁蛋白等
紧密连接相关蛋白表达,增强肠道屏障功能,抑制肠道炎症,改善肠道尿酸排泄,从而改善痛风症状[45]。Song等[46]将祛浊通痹汤治疗小鼠GM移植到尿酸酶敲除小鼠肠道内,表现出相同的治疗作用。
研究发现,铁皮石斛六方(铁皮石斛、黄柏、苍术、牛膝、薏苡仁)可通过抑制LPS/TLR4/NF-κB信号通路,减少IL-6、IL-8和TNF-α分泌,改善肾脏炎症,其作用可能与维持肠黏膜屏障功能有关,肠道菌群失衡导致肠黏膜屏障受损,进而增加LPS吸收,激活TLR4/NF-κB信号通路,诱发肾脏炎症反应[47]。石斛超微粉可以保护肠黏膜屏障[48]。姜黄素可增加ZO-1、闭锁蛋白和claudin-1表达水平,保持肠道屏障功能完整性,防止LPS易位,减少炎症[49]。
3.3 调节肠道微生物群代谢产物研究表明,改良白虎汤可增加痛风性关节炎大鼠普雷沃菌科丰度,增加SCFAs合成[37];祛浊通痹汤可促进产SCFAs细菌及丁酸的产生,恢复肠道屏障功能,抑制肠道炎症因子产生[45]。
石斛超微粉也可减少进入体循环LPS含量[48]。姜黄素可以减少LPS循环水平,防止肠道细菌易位,增强肠道屏障,降低炎症反应[30]。
4 结语
痛风表现为嘌呤代谢紊乱、尿酸堆积及关节炎症反应,这与GM组成及其代谢产物失调有关,痛风患者GM中有益菌减少、致病菌增多,中药治疗可改善痛风中肠道菌群失调现象,增加有益菌、抑制致病菌,有效防治痛风。此外,中药也可通过保护肠黏膜屏障、调节GM代谢产物减轻炎症,达到防治痛风目的,但其作用机制有待进一步研究。
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