小檗碱通过调节肠道菌群治疗2型糖尿病
Berberine Treats Type 2 Diabetes by Regulating Gutmicrobiota
DOI:10.12677/acm.2024.1472096,PDF,HTML,XML,下载: 23浏览: 36科研立项经费支持
作者:白 雪,卿 岚:西安医学院含光校区研工部,陕西 西安;朱路阳,王 婷,赵 媛*:陕西省人民医院老年病科,陕西 西安
关键词:小檗碱(BBR)2型糖尿病(T2DM)肠道菌群Berberine (BBR)Type 2 Diabetes Mellitus (T2DM)Gut Microbiota
摘要:2型糖尿病(T2DM)及其并发症是一种严重威胁人们生活质量的公共卫生问题。肠道菌群的调节在T2DM的治疗已得到广泛认可,已有证据表明肠道菌群对葡萄糖代谢有影响,通过调节肠道菌群治疗糖尿病具有重要临床应用前景。小檗碱(BBR)是黄连的主要成分,通过调节肠道菌群可降糖、降脂,以及减重和抗炎,被认为是治疗T2DM的潜在药物之一。
Abstract:Type 2 diabetes mellitus (T2DM) and its complications are major public health problems that seriously affect the quality of human life. The regulation of gut microbiota has been widely recognized in T2DM treatment. There have been evidences that gut microbiota has an impact on glucose metabolism, and the regulation of gut microbiota in diabetes treatment has an important clinical application prospect. Berberine (BBR), the main component of Coptischinensis, is considered as one of the potential strategies in T2DM treatment by regulating gut microbiota, which can reduce blood sugar, blood lipid, weight loss and anti-inflammatory.
文章引用:白雪, 卿岚, 朱路阳, 王婷, 赵媛. 小檗碱通过调节肠道菌群治疗2型糖尿病[J]. 临床医学进展, 2024, 14(7): 922-927. https://doi.org/10.12677/acm.2024.1472096

1. 前言

T2DM是全球重大的公共卫生问题,我国T2DM发病率位居世界首位。T2DM是以血糖升高为主要表现的慢性代谢性疾病,其主要病理生理机制包括胰岛素抵抗和胰岛β细胞分泌障碍[1]。近年来越来越多研究发现T2DM的发生发展可能与肠道菌群失调紧密相关,T2DM患者的肠道菌群结构较健康对照组存在差异,通过调节肠道菌群有望成为治疗T2DM的新靶点[2][3]。目前药物与肠道菌群的相互作用已成为国内外研究热点。BBR又名黄连素,可通过调节肠道菌群、肠道代谢物及肠道免疫从而降糖、降脂以及减重和抗炎[4][5]。本文旨在阐明BBR通过调节肠道菌群治疗T2DM的机制,为T2DM的治疗的新途径寻找理论依据。

2. 肠道菌群在T2DM中的作用

2.1. 肠道菌群与T2DM相互影响

肠道菌群是一组主要栖息于肠道的微生物,占人体微生物90%,大部分是厌氧菌,主要可分为厚壁菌门(乳酸菌属、肠球菌属、芽孢杆菌属等)、拟杆菌门、变形菌门(β变形杆菌属)、放线菌门(双歧杆菌属)、梭杆菌门和疣微球菌门(嗜粘蛋白阿克曼菌属)[6]-[8]。肠道菌群对维持机体健康至关重要,其紊乱会导致多种疾病的发生[3]。研究发现其发挥降糖作用可能是通过降低炎症因子水平、调节氧化应激、脂质和葡萄糖代谢等[9]。糖尿病前期患者存在胰岛素抵抗、慢性低度炎症、高甘油三酯血症和超重,并有肠道菌群的异常,最显著的是梭状芽孢杆菌属和嗜粘蛋白阿克曼菌属丰度的降低[10][11]。研究发现T2DM患者相比于健康人群,肠道菌群中双歧杆菌属、梭状芽孢杆菌属和厚壁菌门数量减少明显,拟杆菌门和β变形杆菌属数量增加明显[3][8]。同时也有研究表明T2DM患者肠道菌群失调会导致革兰氏阴性菌比例上升,产生更多脂多糖(LPS),诱导T2DM患者持续性、低度全身炎症[12]。由肠道菌群产生的肠道代谢物,如三甲胺-n-氧化物(TMAO)、短链脂肪酸(SCFAs)、支链氨基酸(BCAAs)、胆汁酸(BAs)、维生素和芳香氨基酸(AAAs)与T2DM的发病机制有关。研究发现短链脂肪酸减少会降低肠道抗炎能力、减弱其受体激活能力,从而导致胰岛功能受损、胰岛素敏感性降低和胰岛素抵抗[8];芳香族氨基酸浓度升高会增加T2DM风险[7][13]。因此,肠道菌群紊乱可能诱发或加重T2DM,同时T2DM也会导致肠道菌群紊乱,二者相互影响。

2.2. 口服降糖药对肠道菌群的调节

目前治疗T2DM的方法包括生活方式干预和使用药物治疗。临床上常用的药物主要有磺脲类、格列奈类、双胍类、噻唑烷二酮类、α-葡萄糖苷酶抑制剂、二肽基肽酶-4 (DPP-4)抑制剂、胰高血糖素样肽1 (GLP-1)激动剂和钠–葡萄糖转运蛋白-2 (SGLT2)抑制剂等几种类别[1],它们分别作用于不同靶点,研究表明部分降糖药物可以通过调节肠道菌群从而改善葡萄糖代谢和能量平衡,其机制主要包括降低炎症因子水平、增加短链脂肪酸含量及降低芳香族氨基酸含量等[14]。二甲双胍不仅可以通过增加外周组织对葡萄糖摄取和利用、增加胰高血糖素样肽-1,而且可以通过增加胆汁酸水平来调节肠道菌群,研究发现口服二甲双胍后肠道菌群中大肠杆菌属、梭状芽孢杆菌属及双歧杆菌属丰度增加,肠杆菌属丰度减少[14],同时二甲双胍可降低酪氨酸和苯丙氨酸等芳香氨基酸的浓度从而发挥降糖作用[15][16]。阿卡波糖是一种α-葡萄糖苷酶抑制剂,通过延缓葡萄糖吸收来降低餐后血糖水平,同时可降低炎症因子和增加短链脂肪酸水平[19]。研究发现口服阿卡波糖后肠道菌群中乳酸菌属和双歧杆菌属丰度明显增加[14][17]-[19]。GLP-1受体激动剂能增加胰岛素的分泌,并能抑制胰高糖素的含量,延迟胃排空时间,加快饱腹感,使体重下降,并减少低血糖的危险[14][17][18]。有研究发现,肠道菌群可通过肠道神经系统的一氧化氮信号传导通路调控GLP-1的敏感性[14],进一步支持调节肠道菌群可能成为治疗T2DM提供新途径。

3. BBR对肠道菌群的作用

BBR是一种生物碱,属于异喹啉类,分子式为C20H18NO4。可从多种植物中提取,包括芒柄菊科、小檗科、芒柄菊科和罂粟科,是传统中药中的一种重要化合物[6]。由于口服BBR的生物利用度极低,可以很容易地到达肠道并与肠道菌群相互作用,BBR可以调节肠道菌群的组成和代谢,同时肠道菌群也可以调节BBR在肠道中的代谢。肠道菌群能够合成三甲胺、短链脂肪酸、胆汁酸和支链氨基酸等维持正常生理功能所必需的代谢物,BBR可以通过调节肠道菌群的丰度来调节这些代谢物[20]。研究发现BBR会降低肠道中产生支链氨基酸的细菌如梭状芽孢杆菌属、链球菌属及鞭毛菌属丰度,同时增加产生短链脂肪酸的细菌如经黏液真杆菌属、拟杆菌属及罗氏菌属丰度[20][21]。肠道屏障功能减退会诱发肠道炎症及代谢性疾病的发生。BBR可以通过抑制核因子κB (NF-κB)和促炎性细胞因子(如TNF-α、IL-1β、IL-6等)的表达和活性降低血管和肠道中炎症因子和趋化因子,通过激活AMPK通路和调节特定转录因子(如Sp1、AP-1等)的活性促进肠道紧密连接蛋白(ZO-1和闭塞蛋白)的表达,从而增加结肠粘液层的厚度从而改善肠道屏障功能[22][23];同时BBR也可以通过增加短链脂肪酸含量和减少脂多糖含量,改善肠道屏障功能[22]。P-糖蛋白(P-glycoprotein)介导的药物外排是BBR在肠道吸收差的重要因素,研究表明短链脂肪酸能抑制P-糖蛋白的活性,BBR诱导短链脂肪酸增加可以抑制P-糖蛋白的表达和活性[22][23],进一步增加BBR的吸收利用。

4. BBR对T2DM肠道菌群的调节机制

4.1. BBR通过改变肠道菌群的丰度调节血糖

BBR最重要的功能之一是改变肠道菌群的组成。丝状温度敏感蛋白Z (FtsZ)是一种介导肠道细菌细胞分裂的蛋白质。有研究表明,BBR通过抑制丝状温度敏感蛋白Z的组装功能从而阻止细菌的细胞分裂,对条件致病菌群(肠球菌属、肠杆菌属等)和致病菌群 (大肠杆菌属、沙门氏菌属等)具有抑菌活性,同时对致病菌群有明显抑制活性,同时增强有益菌群(双歧杆菌属、乳酸杆菌属和嗜粘蛋白杆菌属等)的丰度,从而改善血糖血脂水平[21][24]

4.2. BBR改善胆汁酸和氨基酸代谢

胆汁酸是人体内胆固醇代谢的主要产物,它不仅参与脂质和脂溶性维生素的吸收、运输和分布,还可以作为一种信号分子,通过激活法尼醇X受体(FXR)和跨膜G蛋白偶联受体5(TGR5)增强能量代谢和抑制肠道内细菌过度增殖,增加T2DM的胰岛素敏感性从而降低血糖[9][21][24];同时BBR可通过提高双歧杆菌属、梭状芽孢杆菌属的活性等有益菌群活性从而促进胆汁酸的分解,增强其通过肠道的排泄。此外,BBR可下调肠道菌群和血清中的酪氨酸、色氨酸和苯丙氨酸含量,表明BBR可以通过降低芳香氨基酸含量来降低血糖[21][24]

4.3. BBR调节肠道免疫

脂多糖是革兰氏阴性菌细胞壁的一种重要成分。BBR可显著降低变形菌门中脱硫弧菌属、阴沟肠杆菌复合群等革兰氏阴性菌的丰度,抑制脂多糖生成,调节肠道通透性,减轻胰岛素抵抗,有效改善代谢性内毒素血症[25]。BBR还可通过降低脂多糖和炎症介质(IL-1、IL-6等)的水平,阻断Toll样受体和核因子-kB的生物合成,改善肠道和内脏脂肪组织炎症水平,促进胰岛素信号转导和葡萄糖代谢,从而降低血糖[5][21][25]

4.4. BBR促进肠道GLP-1分泌

研究表明BBR可通过增加肠道菌群中拟杆菌门和厚壁菌门的丰度,促进结肠近端细胞的数量增加,提高血浆GLP-1、GLP-2的表达[21]。动物实验结果表明BBR可提高血浆中GLP-1和食欲素A,上调下丘脑GLP-1受体的表达,对胰岛素抵抗和肥胖等多种代谢紊乱具有有益作用,从而诱导肠道–脑轴微生物群的调节,改善小鼠的能量代谢发挥降糖作用[22]

4.5. BBR与其他药物的相互作用

研究表明BBR与二甲双胍联合应用可以减少肠道菌群对二甲双胍的降解,增加其口服生物利用度[26]。水苏糖是一种在豆科、唇科植物中普遍存在的一种四糖类物质,可被肠道中的双歧杆菌、乳杆菌等有益菌所吸收,从而促进细菌的繁殖,同时也可抑制产气型产酸梭菌等致病菌的生长,调节人体肠道内微生态平衡。BBR与水苏糖联合应用可以通过调节糖尿病大鼠结肠中的microRNA和基因表达来改善葡萄糖代谢和肠道菌群紊乱[27][28];一项随机双盲对照试验纳入了409名T2DM患者,分为益生菌组、BBR组、益生菌联合BBR组和安慰剂组共4组,与安慰剂组和益生菌组相比,益生菌联合BBR组和BBR组的糖化血红蛋白明显降低,且益生菌联合BBR组糖化血红蛋白降低更显著,这表明益生菌可以增强BBR通过调节肠道菌群降血糖作用[5][29];另一项研究将带有Leptin基因突变型小鼠随机分为对照组、BBR处理组和BBR合成物(BBR、谷维素和维生素B6按30:4.8:1比例混合)处理组3组,喂养4周后发现BBR组和BBR合成物组与对照组相比血糖血脂水平明显降低,肠道菌群中拟杆菌门和厚壁菌门的相对丰度增加,且BBR合成物组血糖血脂水平降低更显著[5][30]。表明BBR联合其他药物在T2DM治疗具有重要应用前景。

5. 结论

肠道菌群在T2DM的发生发展中具有重要作用,BBR可以通过多种作用机制调节肠道菌群从而改善T2DM,可能是一种潜在的治疗T2DM的药物。

基金项目

陕西省自然科学基础研究计划面上项目(2022JM-586)。

NOTES

*通讯作者。

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