微生物学报  2024, Vol. 64 Issue (9): 3124-3140   DOI: 10.13343/j.cnki.wsxb.20240110.
http://dx.doi.org/10.13343/j.cnki.wsxb.20240110
中国科学院微生物研究所，中国微生物学会

文章信息

杨婷, 邸倩南, 丁加研, 那立欣. 2024
YANG Ting, DI Qiannan, DING Jiayan, NA Lixin.
中药活性成分通过调控肠道菌群改善2型糖尿病的作用研究进展
Research progress in the role of active components of traditional Chinese medicine in ameliorating type 2 diabetes mellitus by regulating gut microbiota
微生物学报, 64(9): 3124-3140
Acta Microbiologica Sinica, 64(9): 3124-3140

文章历史

收稿日期：2024-02-22
网络出版日期：2024-04-20
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引用本文
杨婷, 邸倩南, 丁加研, 那立欣. 中药活性成分通过调控肠道菌群改善2型糖尿病的作用研究进展[J]. 微生物学报, 2024, 64(9): 3124-3140.
Yang Ting, Di Qiannan, Ding Jiayan, Na Lixin. Research progress in the role of active components of traditional Chinese medicine in ameliorating type 2 diabetes mellitus by regulating gut microbiota[J]. Acta Microbiologica Sinica, 2024, 64(9): 3124-3140.
中药活性成分通过调控肠道菌群改善2型糖尿病的作用研究进展
杨婷1 , 邸倩南2 , 丁加研1 , 那立欣1,2     
1. 上海中医药大学 研究生院, 上海 201203;
2. 上海健康医学院 健康与公共卫生学院, 上海 201318
收稿日期：2024-02-22；接受日期：2024-04-16；网络出版日期：2024-04-20
基金项目：国家自然科学基金(81872614)
摘要：2型糖尿病(type 2 diabetes mellitus, T2DM)是慢性代谢疾病之一，因高患病率成为当今全球性公共健康难题。肠道菌群在T2DM的发生和发展中发挥重要作用，通过调节肠道菌群治疗T2DM已经成为当前研究的焦点。近年来，已有研究表明中药在改善T2DM的同时使肠道菌群发生变化，但中药是否通过调控肠道菌群发挥药理作用尚不明确。中药富含的多种活性成分是中药发挥药理作用的关键。因此，本文系统总结了中药多糖类、生物碱类、黄酮类、皂苷类及其他类活性成分调节肠道菌群干预T2DM的研究进展，旨在为中药预防和治疗T2DM作用提供更充分的理论依据，这对加速中药现代化具有重要意义。
关键词：2型糖尿病    肠道菌群    中药活性成分    调控    药理作用    
Research progress in the role of active components of traditional Chinese medicine in ameliorating type 2 diabetes mellitus by regulating gut microbiota
YANG Ting1 , DI Qiannan2 , DING Jiayan1 , NA Lixin1,2     
1. Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;
2. College of Public Health, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China
Received: 22 February 2024; Accepted: 16 April 2024; Published online: 20 April 2024
*Corresponding author: NA Lixin, E-mail: nlxshktz@163.com.
Foundation item: This work was supported by the National Natural Science Foundation of China (81872614)
Abstract: Type 2 diabetes mellitus (T2DM) stands as a chronic metabolic disorder posing a challenge to global public health, owing to its widespread prevalence. The intricate interplay between gut microbiota and the onset and progression of T2DM, along with the potential therapeutic benefits of modulating gut microbiota, has emerged as a focal point in contemporary research. Recent studies have underscored the capacity of traditional Chinese medicine to ameliorate T2DM by inducing alterations in gut microbiota. Nevertheless, the precise mechanisms underlying the pharmacological actions of traditional Chinese medicine via gut microbiota regulation remain elusive. The diverse bioactive compounds in traditional Chinese medicine play pivotal roles in eliciting its pharmacological effects. This article systematically reviews the advancements in the research concerning the modulation of gut microbiota for T2DM intervention by a spectrum of bioactive components in traditional Chinese medicine, encompassing polysaccharides, alkaloids, flavonoids, saponins, and other compounds. The objective of this review is to furnish a comprehensive theoretical framework supporting the preventive and therapeutic potential of traditional Chinese medicine in T2DM management, thereby significantly contributing to the modernization of traditional Chinese medicine.
Keywords: type 2 diabetes mellitus (T2DM)    gut microbiota    active components of traditional Chinese medicine    regulation    pharmacological effects    

糖尿病是以高血糖为标志的慢性疾病，截至2021年，全球患糖尿病人数达到5.366亿，预计到2045年将增至7.832亿[1]。糖尿病主要包括1型糖尿病(type 1 diabetes mellitus, T1DM)、2型糖尿病(type 2 diabetes mellitus, T2DM)和妊娠期糖尿病(gestational diabetes mellitus, GDM)，其中T2DM最常见，约占糖尿病人群比例的90%− 95%[2]。在《黄帝内经》中，T2DM属于“消渴”范畴，中医理论将多味中药配伍组成的中药方剂用于治疗消渴，这些方剂一直被沿用至今[3]。常见的消渴方、玉女煎在临床试验中能改善T2DM患者血糖，其疗效优于注射胰岛素和口服二甲双胍[4-6]。在临床上，常见的T2DM治疗药物包括胰岛素促分泌剂(如磺脲类)、胰岛素增敏剂(如双胍类、格列酮类)和葡萄糖苷酶抑制剂(如阿卡波糖、伏格列波糖)，这些药物不仅价格高昂，而且易造成不良反应和耐药性，这些问题亟待解决[7]。相比之下，中药价格低廉、安全性好，有望为T2DM新药开发提供新的来源。因此，探索中药改善T2DM的作用机制对推动糖尿病治疗的新方法和开发糖尿病治疗新药具有重要意义。

流行病学研究表明，与正常人相比，T2DM患者的肠道菌群结构不仅发生显著变化[8-9]，而且这种变化与T2DM胰岛素分泌不足、胰岛素抵抗、低度炎症等发病机制存在相关性[10-13]。肠道菌群对T2DM的影响已成为当前研究领域的热点。肠道菌群的结构和多样性的改变能直接或间接影响肠道菌群分泌的功能分子和代谢产物水平，如短链脂肪酸(short-chain fatty acid, SCFA)、脂多糖(lipopolysaccharide, LPS)、胆汁酸(bile acid, BA)和支链氨基酸(branched-chain amino acids, BCAAs)等[14-16]。因此，探究如何调节肠道菌群组成和恢复肠道菌群代谢物水平对改善T2DM具有至关重要的意义。

中药活性成分是中药发挥药理作用的关键物质，研究发现中药活性成分可改变T2DM患者肠道菌群丰度和种类，恢复肠道屏障功能，并间接影响肠菌代谢产物的产生[17-18]。因此，中药活性成分改善T2DM的作用与中药调控肠道菌群之间存在一定相关性，但仍有大部分活性成分的作用机制尚不明确，亟须探索。因此本文主要总结了T2DM人群肠道微生物群的特征、中药活性成分对肠道菌群的调节作用以及中药活性成分协同肠道菌群改善T2DM的效应，这或许能为未来中药活性成分-肠道菌群-T2DM的防治策略提供理论依据。

1 T2DM的肠道菌群特征

元基因组研究显示，成人肠道的大部分微生物群属于5个门，分别是厚壁菌门(Firmicutes)、拟杆菌门(Bacteroidetes)、变形菌门(Proteobacteria)、放线菌门(Actinobacteria)和梭杆菌门(Fusobacteria)，其中约90%的细菌种类属于Firmicutes和Bacteroidetes[19]。早在2010年就有研究提出患T2DM的人群肠道菌群与正常人群在门水平上存在显著差异[20]。通过对T2DM患者肠道菌群分析发现，与正常人相比，T2DM患者肠道菌群多样性降低，并且T2DM的发生与Firmicutes/Bacteroidetes比率升高有关[21]。总结发现，T2DM肠道菌群结构变化集中在Firmicutes、Bacteroidetes、Proteobacteria、Actinobacteria、Fusobacteria和疣微菌门(Verrucomicrobia)。如表 1所示，T2DM人群Firmicutes门中殊异韦荣氏球菌(Veillonella dispar)、丁酸梭菌(Clostridium butyricum)、栖粪杆菌属(Faecalibacterium)、罗斯拜瑞氏菌属(Roseburia)、戴阿利斯特菌属(Dialister)和韦氏布劳特氏菌(Blautia wexlerae)等菌属丰度降低，而Firmicutes菌门的韦荣氏球菌属(Veillonella)、乳杆菌属(Lactobacillus)、链球菌属(Streptococcus)、人罗斯拜瑞氏菌(Roseburia hominis)、黏液真杆菌(Eubacterium limosum)、坏齿韦荣氏球菌(Veillonella denticariosi)、布劳特氏菌属(Blautia)、瘤胃球菌属(Ruminococcus)等菌属的丰度升高[22-28]。Bacteroidetes门中辨野氏卟啉单胞菌(Porphyromonas bennonis)、普雷沃氏菌属(Prevotella)、普通拟杆菌(Bacteroides vulgatus)、啮齿拟杆菌(Bacteroides rodentium)等菌的丰度显著升高，而别样杆菌属(Alistipes)、拟杆菌属(Bacteroides)菌属丰度降低[22-24, 26, 29-30]。Actinobacteria门中双歧杆菌(Bifidobacterium)和Verrucomicrobia门中阿克曼氏菌(Akkermansia)有益菌减少[22, 24, 26]。Proteobacteria门中变化主要为埃希氏菌属(Escherichia)、志贺氏菌属(Shigella)和幽门螺杆菌(Helicobacter pylori)等致病菌增加[23, 26-27, 31]。以上研究表明，T2DM肠道菌群特征表现为菌群组成改变，其中有益菌比例减少而致病菌比例增多。

表 1. 2型糖尿病患者的肠道菌群特征 Table 1. Characterization of gut microbiota in type 2 diabetes mellitus patients
Types of phylum Microbiota with increased abundance in T2DM Microbiota with decreased abundance in T2DM
Firmicutes Roseburia hominis[22], Eubacterium[23], Peptostreptococcus[23], Veillonella denticariosi[24], Blautia[24], Ruminococcus[24], Eubacterium limosum[25], Veillonella[26], Lactobacillus[26], Streptococcus[26] Coprobacillus unclassified[22], Veillonella dispar[22], Clostridium butyricum[23], Faecalibacterium[24], Enterococcus faecium[25], Blautia lineages[25], Roseburia[24, 26], Dialister[26], Flavonifractor[26], Faecalibacterium prausnitzii[26], Clostridium sensu stricto1[27], Blautia wexlerae[28]
Bacteroidetes Porphyromonas bennonis[22], Paraprevotella unclassified[22], Prevotella copri[29], Bacteroides vulgatus[29], Bacteroides rodentium[29], Bacteroides xylanisolvens[29], Prevotella[30] Bacteroides[24], Alistipes[26]
Proteobacteria Desulfovibrio piger[23], Escherichia[26-27], Shigella[26-27], Enterobacteriaceae[27], Helicobacter pylori[31] Haemophilus[26]
Actinobacteria Collinsella[26] Bifidobacterium longum[22], Bifidobacterium[24]
Verrucomicrobiota − Akkermansia[24], Akkermansia muciniphila[26]
Fusobacteria Fusobacterium[24] −
− indicates no record.
表选项

T2DM患者肠道菌群的分布特点吸引了大量研究关注，尤其是肠菌分泌的功能分子和代谢物对T2DM的作用进行的研究。肠道内有益菌Akkermansia muciniphila不仅能分泌外囊泡和蛋白质Amuc_1100来改善胰岛素抵抗和肠道屏障功能，还能促进SCFA的产生来促进胰岛素分泌[32-35]。SCFA是由肠道菌群将膳食纤维、抗酶解淀粉分解产生的代谢产物之一，SCFA在体内能增加糖原合成及SCFA可能通过胰高血糖素样肽1 (glucagon-like peptide-1, GLP-1)介导的胰岛素分泌增加来调节血糖浓度[36]。Bifidobacterium属中Bifidobacterium longum、短双歧杆菌(Bifidobacterium breve)、青春双歧杆菌(Bifidobacterium adolescentis)能促进SCFA产生、增强胰岛素敏感性、减少肝脂肪变性、促进肝糖原合成，同时恢复T2DM肠道菌群稳态[37-41]。丁酸盐作为SCFA之一，能抑制肝脏组蛋白去乙酰化酶(histone deacetylase, HDAC)活性和促进胰岛素受体底物-1的过度乙酰化，从而改善减少糖异生和胰岛素抵抗[42]。Faecalibacterium prausnitzii是主要的丁酸盐产生菌之一，其代谢产生的微生物抗炎分子和胞外囊泡可以通过调节紧密连接蛋白的表达来恢复T2DM的肠道屏障结构和功能[43-44]。研究指出体内高BCAAs水平与T2DM患病率和胰岛素抵抗有关，Prevotella copri能参与BCAAs的生物合成[45-47]。迪氏副拟杆菌(Parabacteroides distasonis)产生的代谢物烟酸是一种重要的生物活性分子，它通过激活肠道G蛋白偶联受体109a (G protein coupled receptor, GPR109a)来增强肠道屏障功能，从而改善T2DM的胰岛素抵抗[13]。此外，Parabacteroides distasonis的另一种代谢物吲哚丙烯酸，可激活芳烃受体(aryl hydrocarbon receptor, AhR)信号通路，增加白细胞介素-22 (interleukin-22, IL-22)的表达水平和增强肠道屏障相关蛋白的表达，从而减少肠道菌群紊乱引起的炎症，最终改善胰岛素抵抗[48]。Blautia wexlerae能调节氨基酸相关代谢和碳水化合物代谢，从而改善肥胖诱导的T2DM小鼠脂肪堆积、胰岛素抵抗、葡萄糖耐量受损指标[28]。细菌LPS又称内毒素，存在于革兰氏阴性细菌的外膜中[49]。研究发现LPS能通过激活Toll样受体和诱发炎症，从而促进胰岛素抵抗[50-51]。作为已知的产LPS菌，Helicobacter pylori在T2DM患者中增加可能会通过增加LPS加重宿主病情[52-53]。

2 中药活性成分调控肠道菌群改善T2DM的作用进展

中药或中药方剂由于成分复杂、作用机制不明确，在T2DM药物开发中受到限制。中药活性成分是中药的特征成分，不仅能用于鉴定药材品质好坏，还是中药发挥药理作用的关键[54]。目前已知的具有改善T2DM的中药活性成分包括多糖类、生物碱、黄酮类、皂苷类和萜类，它们能降低血糖水平、增加胰岛素敏感性和降低炎症水平[55-56]。如表 2所示，这些成分会引起肠道微生物变化、增加有益菌和减少有害菌，所以肠道菌群在中药活性成分改善T2DM中发挥的作用值得探索。

表 2. 中药活性成分调控肠道菌群改善2型糖尿病及主要作用机制 Table 2. Active ingredients of traditional Chinese medicine (TCM) regulate gut microbiota to improve type 2 diabetes mellitus and their main mechanism
Active components of TCM Subject investigated Administration route and dosage Changes in gut microbiota Main mechanism
Ganoderma lucidum polysaccharides[57] Male Sprague-Dawley (SD) rats (HFD+STZ) 400 mg/(kg·d), ig; Blautia, Dehalobacterium, Parabacteroides, Bacteroides↑; Aerococcus, Ruminococcus, Corynebactrium, Proteus↓ Restoring amino acid metabolism, carbohydrate metabolism, inflammatory levels, and nucleic acid metabolism in the body
Polygonatum rhizoma polysaccharide[58] Male db/db mice 1.0 g/(kg·d), ig Turicibacter, Ruminococcus↑; Lachnospiraceae, Romboutsia↓ Regulating the expression of genes involved in liver glucose storage and utilization, and promoting hepatic glycogen formation
Astragalus membranaceus polysaccharides[59-60] Male C57BL/6J mice (HFD+STZ); Male db/db mice 400 mg/(kg·d) and 600 mg/(kg·d), ig Akkermansia, Faecalibaculum, Bifidobacterium, Romboutsia, Allobaculum, Lactobacillus, Prevotellaceae_UCG-001, Oscillospiraceae_UCG-005↑; Escherichia, Shigella, Odoribacter, Lachnoclostridium, Lachnospiraceae_UCG-006, Lachnospiraceae_A2↓ Promoting SCFA production to activate G protein-coupled receptors 41/43 (GPCR41/43), thereby indirectly stimulating GLP-1 secretion and restoring intestinal barrier function
Lycium barbarum Polysaccharide[61-63] Male C57BL/6J mice (HFD+STZ) 50 mg/(kg·d), 100 mg/(kg·d) and 200 mg/(kg·d), ig Bacteroides, Ruminococcaceae_UCG-014, Intestinimonas, Mucispirillum, Ruminococcaceae_UCG-009, Allobaculum↑; Dubosiella, Romboutsia↓ Promoting the production of SCFA to stimulate peptide YY (PYY) and GLP-1 secretion, enhancing the activity of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and mitigating inflammation
Coix seed polysaccharides[64-65] ICR male mice (HFD+STZ) 24 mg/(kg·d), ig Lactobacillus, Akkermansia, Bacteroides, Bifidobacterium↑ Activating the IGF1/PI3K/AKT signaling pathway to decrease blood glucose levels, elevating SCFA levels, and increasing the expression of tight junction proteins for intestinal barrier repair
Cordyceps militaris polysaccharide[66] Male C57BL/6J mice (HFD+STZ) 400 mg/(kg·d), ig Allobaculum, Alistipes, Lachnospiraceae_NK4A136_ group, Muribaculaceae↑; Enterococcus, Ruminococcus_ torques_group↓ Inhibiting the TLR4/NF-κB pathway and enhancing the expression of intestinal tight junction proteins
Dendrobium officinale polysaccharide[67-68] Male C57BL/6J mice (HFD+STZ) 200 mg/(kg·d), ig Parabacteroides distasonis, Parabacteroides, Ruminococcus, Dorea, Allobaculum, Bifidobacterium, Lactobacillus↑; Helicobacter pylori↓ Activating intestinal GPR109a and indirectly upregulating the expression of tight junction proteins through the LPS/TLR4/TRIF/NF-κB axis to repair the intestinal barrier
Fructus mori polysaccharide[69] Male C57BL/6J mice (HFD+STZ) 600 mg/(kg·d), ig Allobaculum, Bifidobacterium↑; Escherichia, Shigella↓ Suppressing the activation of the TLR4/MyD88/NF-κB pathway to alleviate intestinal inflammation and oxidative stress levels, thereby indirectly promoting the expression of tight junction proteins for intestinal barrier restoration
Berberine[54, 70-73] Male SD rats (HFD+STZ); Male GK rats; Male Zucker Diabetic Fatty (ZDF) rats 100 mg/(kg·d) and 200 mg/(kg·d), ig Faecalibacterium, Roseburia, Clostridium, Clostridium XIVa, Ruminococcus 2, Dorea, Parabacteroides, Paraprevotella, Butyricimonas, Alistipes, Gemmiger, Butyricicoccus, Coprococcus, Bacteroides, Oscillospira, Akkermansia, Aggregatibacter, Eubacterium↑; Helicobacter pylori, Prevotella copri↓ Promoting the production of SCFA to activate the bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and stimulating the secretion of GLP1/2, while concurrently suppressing lipopolysaccharide (LPS) production and inflammation
1-deoxynojirimycin[74, 75] Male C57BL/6J mice (HFD+STZ) 20 mg/(kg·d), ig Akkermansia, Bifidobacterium, Lactobacillus↑; Enterococcaceae, Lachnospiraceae↓ Inhibiting the expression of suppressor of cytokine signaling 3 (SOCS3) and the activity of the TLR4/NF-κB signaling pathway, while also enhancing the expression of claudin and the ratio of phosphorylated insulin receptor substrate 1 (p-IRS1) to IRS1
Myricetin[76] Male C57BL/6J mice (HFD+STZ) 75 mg/(kg·d), ig Alistipes, Lachnospiraceae UCG-006, Odoribacter, Alloprevotella, Bacteroidales S24-7, Bacteroides, Delftia, Faecalibaculum, Lachnospiraceae_NK4A136 group, Ruminiclostridium 9↑; Corynebacterium 1, Erysipelotrichaceae_uncultured, Lactobacillus↓ Elevating the levels of superoxide dismutase (SOD)
Luteolin[77] Male Kunming mice (HFD+STZ) 100 mg/(kg·d), ig Lactobacillus, Alloprevotella, Alistipes, Bacteroides, Ruminiclostridium, Brevundimonas, Pseudomonas↑ Regulating aberrant glucose metabolism via the peroxisome proliferator-activated receptor (PPAR) signaling pathway
licochalcone A[78] Male C57BL/6J mice (HFD+STZ) 35 mg/(kg·d), ig Bifidobacterium, Turicibacter, Blautia, Faecococcus↑; Enterococcus, Dorea, Arachnococcus↓ −
Pelargonidin-3-O-glucoside[79] Male db/db mice 150 mg/(kg·d), ig Bacteroidales, Prevotella↑; Firmicutes↓ Enhancing SCFA levels and safeguarding intestinal barrier integrity
Lycium barbarum flavonoids[80] Male C57BL/6J mice (HFD+STZ) 100 mg/(kg·d) and 200 mg/(kg·d), ig Bacteroidales_S24−7_group, Lachnospiraceae, Ruminococcaceae, Clostridiales_vadinBB60_group, Allobaculum, Turicibacter, Coriobacteriaeceae, Enterococcus↓ Enhancing overall organismal glucose and lipid metabolic functions
Epigallocatechin-3-Gallate[81] Male db/db mice 100 mg/(kg·d), ig Lactobacillus gasseri, Lactobacillus intestinalis, Lactobacillus reuteri, Christensenellaceae↑; Enterobacteriaceae, Proteobacteria↓ −
Polygonatum sibiricum saponin[82-83] ICR male mice (HFD+STZ) 1.0, 1.5, and 2.0 g/(kg·d), ig Lactobacillus, Lachnospiraceae_NK4A136 _group, Intestinimonas, Bifidobacterium↑; Firmicutes, Enterococcus, Enterobacteriaceae, Clostridium perfringens↓ Regulating both carbohydrate and amino acid metabolism
Ginsenoside compound K[84-85] Male db/db mice diabetic patients and healthy subjects 40 mg/(kg·d), ig Lactobacillaceae, Akkermansiaceae, Lachnospirace, Ruminococcaceae, Alistipes, Parabacteroides↑; Bacteroidaceae, Enterococcaceae↓ Activating the gut microbiota-bile acid-TGR5 pathway to enhance GLP-1 secretion
Ginsenoside Rb1[86] Male KKAy rats (HFD) 200 mg/(kg·d), ig Bacteroides, Parasutterella, Marvinbryantia, Erysipelatoclostridium↑; Firmicutes/Bacteroidetes, Helicobacter, Alistipes, Prevotellaceae_unclassified, Odoribacter, Roseburia, Mucispirillum, Coprococcus, Anaeroplasma↓ Reducing the levels of metabolites such as alpha-linolenic acid, oleic acid, arachidonic acid, palmitic acid, stearic acid, and others
Ginsenoside Rd[87] Male SD rats (HFD+STZ) 300 mg/(kg·d), ig Enterococcus, SMB53, rc4-4, Turicibacters, Ruminococcus↑; Lactobacillus helveticus, Clostridium celatum↓ Activating the Akt pathway to enhance glycogen synthesis and suppress hepatic gluconeogenesis
Ginsenoside Rg1[88] Male SD rats (HFD+STZ) 100 mg/(kg·d), ig Lachnospiraceae_NK4A136_ group, Lachnoclostridium↑; Lactobacillus↓ −
Ginsenoside Rg5[89] Male db/db mice 90 mg/(kg·d), ig Bacteroidales↑; Firmicutes, Proteobacteria↓ Restoring the intestinal barrier and reducing systemic levels of LPS
Ginsenoside T19[90] Male C57BL/6J mice (HFD+STZ) 30 mg/(kg·d) and 60 mg/(kg·d), ig Probacillus, Streptococcus, Lactobacillus, Ruminococcus, Anaerotruncus, Roseburia, Coprococcus, Lachnospiraceae↑; Firmicutes/Bacteroidetes↓ Activating the AMP-activated protein kinase (AMPK) and phosphoinositide 3-kinase (PI3K) signaling pathways
Astragalus saponins[91] Male SD rats (HFD+STZ) 80 mg/(kg·d), ig Bifidobacterium, Ruminococcaceae_UCG-014↑; Lactobacillus, Turicibacter↓ Elevating the expression levels of hepatic IRS-1, PI3K, PDK1, and phosphorylated AKT (p-AKT), while diminishing the protein expression levels of phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β), thereby ameliorating glucose and lipid metabolism associated with T2DM and insulin resistance
Astragaloside Ⅳ[92] Male Kunming mice (HFSD+STZ) 25, 50, and 100 mg/(kg·d), ig Anaerobacter, Romboutsia, Alkalibacteria, Canadidatus stoquefichus, Oligobacterium, Brautella, Erysipelatoclostridum↑; Bacteroides, Oscillibacter, Parabacteroides, Roseburia, Muribaculum↓ Elevating butyrate levels and activating the PI3K/Akt signaling pathway to diminish hepatic gluconeogenesis and glycogenolysis, while enhancing glycogen synthesis and fatty acid synthesis
Andrographolide[93] Male db/db mice 150 mg/(kg·d), ig Akkermansia, Prevotella, Adlercreutzia↑; Odoribacter, Alistipes, Dehalobacterium, Defluviitalae, Oscillospira, Parabacteroides↓ Restoring the intestinal barrier and lowering systemic levels of LPS
Curcumin[94] Male SD rats (HFD+STZ) 200 mg/(kg·d), ig Bacteroidea, Bifidobacterium↑; Firmicutes, Enterobacterales↓ Increasing Occludin and ZO-1 expression levels to preserve intestinal barrier integrity, thereby reducing LPS production and ameliorating insulin resistance
HFD: High fat die; HFSD: High fat/high sugar diet; STZ: Streptozotocin; ig: Intragastric gavage; − indicates no record; ↑ indicates increase; ↓ indicates decrease.
表选项

2.1 多糖类

多项动物试验表明，中药多糖作为肠道菌群的营养源，可促进有益菌的生长、抑制有害菌的生长和改变肠道菌群组成。如灵芝多糖能上调T2DM大鼠肠道副拟杆菌属(Parabacteroides)和拟杆菌属(Bacteroides)丰度，下调Ruminococcus和Corynebactrium丰度，并调节宿主-微生物共代谢，以改善T2DM[57]。Chen等[58]也发现黄精多糖能调节db/db小鼠肝脏中有关葡萄糖代谢基因的表达，并下调肠道菌群丰富度至正常水平。多项动物试验揭示多糖对T2DM的积极影响与促进SCFA产生有关，同时还能抑制LPS的生成，修复肠道屏障受损，改善T2DM胰岛素抵抗。如黄芪多糖、枸杞多糖和薏苡仁多糖能上调T2DM小鼠肠道粪小杆菌属(Faecalibaculum)、别样棒菌属(Allobaculum)、Akkermansia、Bifidobacterium和Lactobacillus等有益菌丰度，促进SCFA产生以间接促进GLP-1分泌和修复肠道屏障[59-65]；而冬虫夏草多糖、铁皮石斛多糖和桑葚多糖能上调T2DM小鼠中Allobaculum、Alistipes、Bifidobacterium等有益菌，下调Helicobacter pylori、Escherichia和Shigella等致病菌的丰度，并抑制LPS/Toll样受体4 (Toll-like receptor 4, TLR4)/核转录因子(nuclear transcription factor, NF-κB)途径间接改善胰岛素抵抗和修复肠道屏障[66-69]。中药多糖对T2DM的改善作用与肠道菌群密切相关。铁皮石斛多糖和桑葚多糖能显著降低T2DM小鼠血糖水平，而干预伪无菌T2DM小鼠时，几乎无治疗效果，这表明肠道菌群是二者改善T2DM中重要的参与者[68-69]。因此，肠道菌群的存在对中药多糖的干预效果起着重要的调节作用，这一发现为中药多糖在治疗T2DM方面的应用提供了更加科学的依据。

2.2 生物碱类

小檗碱、1-脱氧野尻霉素是具有改善T2DM活性的代表性生物碱类成分，均能调节肠道菌群结构和修复肠道屏障。曾有研究发现，小檗碱对伪无菌T2DM小鼠的治疗效果弱于普通T2DM小鼠，这个结果揭示肠道菌群是小檗碱发挥药理作用的重要部位[70-71]。研究发现小檗碱能增加T2DM大鼠体中丁酸盐水平、降低LPS水平、改善肠道炎症并保护肠道屏障，这与肠道中Helicobacter pylori、Prevotella copri等产LPS致病菌丰度降低，Roseburia、Akkermansia和Bifidobacterium产丁酸菌丰度增加有关[54, 72]。此外，小檗碱促进次级胆汁酸产生，增加Bacteroides和颤螺菌属(Oscillospira)丰度，并激活结肠L细胞G蛋白偶联胆汁酸受体5 (takeda G protein-coupled receptor 5, TGR5)受体以促进GLP-1/2的分泌[73]。1-脱氧野尻霉素是桑叶、桑白皮的主要成分，可增加T2DM小鼠中Akkermansia、Bifidobacterium和Lactobacillus等有益菌的丰度，降低肠球菌科(Enterococcaceae)和毛螺菌科(Lachnospiraceae)的丰度[74-75]。

2.3 黄酮类

黄酮类化合物是中药中广泛存在的一类物质且对肠道菌群具有调控作用，如杨梅素、木犀草素可增加有益菌丰度，降低致病菌丰度，从而降低血糖水平并抑制T2DM小鼠的炎症反应[76-77]。甘草的黄酮类成分之一甘草查尔酮A可降低T2DM小鼠胰岛素抵抗指数以及血糖和血脂水平，这可能与促进Bifidobacterium、Turicibacter、Blautia和Faecococcus等有益菌生长，抑制Enterococcus、Arachnococcus等有害菌生长有关[78]。覆盆子中的天竺葵素-3-O-葡萄糖苷具有改善T2DM作用，并显著上调Bacteroidales丰度，降低Firmicutes门丰度，促进SCFA产生并增强肠道屏障的完整性[79]。枸杞总黄酮可降低T2DM小鼠肠道中瘤胃球菌科(Ruminococcaceae)、苏黎世杆菌属(Turicibacter)、Lachnospiraceae、Allobaculum和Enterococcus的丰度以改善糖脂质代谢和抑制促炎因子的产生[80]。表没食子儿茶素没食子酸酯是广泛存在于自然界的黄酮类成分，其维持T2DM小鼠葡萄糖稳态的效应与肠道Lactobacillus丰度呈正相关[81]。

2.4 皂苷类

据报道，皂苷是治疗T2DM的有效生物活性化合物，调控肠道菌群和调节肠菌-宿主共代谢水平可能是其发挥作用的关键途径。黄精皂苷能调节T2DM小鼠碳水化合物和氨基酸代谢，增加肠道中Lactobacillus、Lachnospiraceae_ NK4A136_group和鼠肠单胞菌属(Intestinimonas)的丰度[82-83]。目前已知，具有改善T2DM功效的人参皂苷中，人参皂苷K、人参皂苷Rb、人参皂苷Rb1、人参皂苷Rg1和人参皂苷Rg5能调节肠道菌群[84-89]。人参皂苷Rb1能上调T2DM小鼠Bacteroides和副萨特氏菌属(Parasutterella)丰度，下调臭气杆菌属(Odoribacter)、粪球菌属(Coprococcus)和Helicobacter pylori等菌丰度，以及调节脂肪酸代谢，而对伪无菌T2DM小鼠的改善作用减弱[86]。人参皂苷Rg5能改善T2DM小鼠高血糖和恢复T2DM小鼠肠道菌群组成，但对于伪无菌T2DM小鼠，其对高血糖、内毒素血症、炎症的改善作用则会减弱[89]。这2项结果揭示人参皂苷Rb1和人参皂苷Rg5在一定程度上能通过调控肠道微生物群来改善T2DM。人参皂苷T19能改善T2DM小鼠的肠道菌群紊乱情况，并提高Lachnospiraceae、Lactobacillus、Ruminococcus等菌属的相对丰度，其中Lachnospiraceae丰度与葡萄糖和脂质水平呈负相关[90]。此外，黄芪皂苷均能调节肠道微生物群落结构，并激活磷脂酰肌醇-3-激酶/蛋白激酶B (phosphatidylinositol-3-kinase/protein kinase B, PI3K/Akt)信号通路以减少肝葡萄糖的产生和糖原分解，并增加糖原合成和脂肪酸合成，从而控制T2DM葡萄糖和脂质稳态[91]。

2.5 其他活性成分

其他类别的中药活性成分方面，萜类成分黄芪甲苷可以调节T2DM小鼠肠道菌群组成，例如增加厌氧杆菌属(Anaerobacter)、龙包茨氏菌属(Romboutsia)、Alkalibacteria的丰度，降低Odoribacter、Parabacteroides、Roseburia和鼠杆状菌属(Muribaculum)的丰度[92]。穿心莲内酯是穿心莲的特征萜类成分，能调节T2DM小鼠肠道微生物群组成，增加有益菌Akkermansia的丰度，以及增加SCFA水平[93]。姜黄素是存在于姜黄、莪术等植物中的二酮类化合物，可以修复糖尿病大鼠肠黏膜屏障、降低血清炎症因子水平、改善内毒素血症，并增加Bacteroidetes/Firmicutes比值和Bifidobacterium的丰度[94]。

3 中药活性成分与肠道有益菌联合改善T2DM的协同效应

现有研究发现，益生菌与抗糖尿病药物具有协同改善T2DM病理指标的作用[95]。T2DM患者连续16周服用小檗碱联合Bifidobacterium后，空腹血糖和糖化血红蛋白水平降低，表明Bifidobacterium具有增强小檗碱降血糖作用的潜力[96]。芒果苷联合Lactobacillus reuteri 1-12使用可增加Lactobacillus acidophilus、Lactobacillus murinus等有益菌丰度，这与肠道中的自诱导因子-2 (autoinducer-2, AI-2)表达增加有关[97]。此外，甘草酸联合Lactobacillus能显著提高甘草酸在体内的口服生物利用度，从而增强甘草酸对T2DM的改善作用[98-99]。在T2DM患者肠道中有益菌往往减少，因此探索合适的益生菌与中药活性成分联合补充方案，对增强中药活性成分对T2DM的疗效具有重要意义。这些研究结果为中药与益生菌联合应用改善T2DM方面提供了更为科学的依据。

4 总结与展望

T2DM的发生发展与肠道菌群之间有重要联系，因此从调节肠道菌群的角度出发对于防治T2DM具有重要意义。中药活性成分能调节肠道菌群结构，恢复菌群平衡，以达到改善T2DM的目的。同时，部分中药活性成分生物利用度低却仍能发挥一定的功效，这可能与肠道菌群代谢作用有关。因此靶向肠道菌群的中药给药方式可能会成为一个未来的研究热点。

然而，肠道菌群是一个复杂的、动态平衡的微生物群体，在体内的分布和生存状态受多种因素的影响，如饮食习惯、精神状态、生活环境。然而中药调节菌群紊乱防治糖尿病的相关研究尚存有空白和局限性。具体表现在以下方面：(1) 随着肠道菌群与T2DM关系研究的不断深入，肠道菌群研究开始转向多组学技术，如16S rRNA基因测序联合代谢组学、16S rRNA基因测序联合蛋白组学等，而大量中药活性成分涉及肠道菌群运用多组学技术的研究仍然很少。(2) 中药活性成分多种多样，其对T2DM的调控作用可能与一些特异菌有关，而这些特异菌是否与中药活性成分干预T2DM作用有关还待确认。(3) 动物和人类的代谢系统之间存在各种差异，然而目前大量中药活性成分对T2DM的肠道微生物群和粪便代谢物的变化研究仍然局限在动物模型中，针对T2DM人群研究相对较少。(4) 大部分中药活性成分对T2DM肠道菌群的机制研究不够深入，仍局限在肠道局部，而有关肠-肝轴、脑-肠轴的机制研究较少。

因此，未来应加强有关中药活性成分在肠道菌群方面的多组学研究和中药活性成分临床研究，深入理解中药改善T2DM的作用机制，以及加强对糖尿病人群中特定肠道微生物群及其分子功能的探索，以期为开发新的治疗策略提供科学依据和丰富中医药现代化研究的内容，并提升中医药在现代医学领域中的地位和应用价值。

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中药活性成分通过调控肠道菌群改善2型糖尿病的作用研究进展
杨婷 , 邸倩南 , 丁加研 , 那立欣