2025, Vol. 41
http://dx.doi.org/10.13345/j.cjb.240996
中国科学院微生物研究所、中国微生物学会主办
中国科学院微生物研究所、中国微生物学会主办
文章信息
- 杨德仪, 林靖涵, 王涛, 刘宏伟
- YANG Deyi, LIN Jinghan, WANG Tao, LIU Hongwei
- 中药调控肠道菌群代谢产物干预疾病研究进展
- Advances in the regulation of gut microbiota metabolites by traditional Chinese medicine in the treatment of diseases
- 生物工程学报, 2025, 41(6): 2236-2255
- Chinese Journal of Biotechnology, 2025, 41(6): 2236-2255
- CSTR: 32114.14.j.cjb.240996
- DOI: 10.13345/j.cjb.240996
-
文章历史
- Received: December 24, 2024
- Accepted: February 20, 2025
- Published: February 21, 2025
引用本文
|
杨德仪, 林靖涵, 王涛, 刘宏伟. 中药调控肠道菌群代谢产物干预疾病研究进展[J]. 生物工程学报, 2025, 41(6): 2236-2255.
YANG Deyi, LIN Jinghan, WANG Tao, LIU Hongwei. Advances in the regulation of gut microbiota metabolites by traditional Chinese medicine in the treatment of diseases[J]. Chinese Journal of Biotechnology, 2025, 41(6): 2236-2255.
中药调控肠道菌群代谢产物干预疾病研究进展
1. 中国科学院微生物研究所 微生物组与微生态技术研究室, 北京 1001012;
2. 中国科学院大学 医学院, 北京 100049
2. 中国科学院大学 医学院, 北京 100049
摘要：中药在预防和治疗疾病、改善机体健康方面发挥重要作用。中药化学组成复杂，调控途径和网络多样，极大阻碍了中药作用机理的阐明。人是由人体细胞与微生物组成的超级“共生体”。肠道菌群作为人体核心共生微生态系统，被称为人体的“第二基因组”和新的“器官”。肠道菌群稳态的变化在整体、系统层面上影响宿主健康和疾病进展。富含多糖、多酚等化学成分的中药可以调节肠道菌群代谢物，通过调控代谢产物及免疫信号介导的“肠-肝轴” “肠-脑轴”等通路防治疾病。本文综述了中药调控肠道菌群代谢产物与改善疾病的因果相关性和作用机制进展，为全面阐明中药治病防病作用机理和基于中药开发创新药物提供了指导和见解。
关键词：中药 肠道微生物 肠道菌群代谢产物 代谢性疾病
Advances in the regulation of gut microbiota metabolites by traditional Chinese medicine in the treatment of diseases
1. The Laboratory of Microbiome and Microecological Technology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China;
2. Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
2. Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
Abstract: Traditional Chinese medicine (TCM) plays an important role in preventing and treating diseases and improving human health. However, the complex bioactive components and regulation of signaling pathway and network restrict the elucidation of the mechanisms of action of TCM. A human being is regarded as a super "symbiont" composed of body cells and commensal microorganisms. Gut microbiota is the core commensal microorganism system of a human body, being considered as "the second genome" and the new "organ". Alterations in gut microbiota reflect the state of body health and progression of diseases. Recent investigations have revealed that the TCM rich in polysaccharides and polyphenols can modulate gut microbiota metabolites to rehabilitate gut homeostasis, thus ameliorating diseases via regulating gut-liver axis or gut-brain axis. This review summarizes the causal relationship and mechanisms of action of TCM in the treatment of diseases from the perspective of gut microbiota metabolites. Our findings are expected to provide new insights into the mechanisms of TCM in preventing and treating diseases and guidance for TCM-based drug discovery in the future.
Keywords:
traditional Chinese medicine (TCM) gut microbiota gut microbiota metabolites metabolic disease
中医是在中国古代唯物论和辩证法思想的指导下逐渐形成的传统医学理论体系，是研究人体生理病理以及疾病诊断和防治的一门科学[1-2]。中医具有整体观念和辨证论治的基本特点。整体观念强调统一性和完整性，人体作为有机整体，与自然环境相互适应[3]。辨证论治是对疾病诊断和处理的基本原则，辨证是分析、辨认疾病的证候，论治是治疗疾病的时机、方法和手段[4]。中药(traditional Chinese medicine, TCM)是指以中医药理论为指导，用于预防和治疗疾病的天然药物及其加工品，包括植物药、动物药、矿物药及部分化学生物制品类药物，具有康复与保健作用[5]。目前，越来越多的研究表明中药在各类疾病的治疗，尤其是在西方医学难以治愈的糖尿病、心血管疾病等复杂疾病的治疗中具有良好的效果，其多靶点、多层面的药理作用也随着网络药理学及多组学技术的发展被逐渐阐明。
人体是由自身细胞与共生微生物细胞构成的“超级生物体”。肠道菌群编码300万个基因，是人体编码基因的150倍，肠道共生微生物的基因组与宿主基因组构成总的基因组，发挥代谢和免疫功能[6]。肠道菌群及其代谢产物已被证明与代谢性疾病、免疫性疾病和肿瘤等多种疾病的发生发展密切相关，被视作疾病诊断、预防和治疗的潜在靶点[7-13]。肠道微生物的结构和功能随宿主健康状况的变化而变化，即在不同疾病或同种疾病的不同阶段下宿主的肠道微生物状态往往不同。肠道菌群通过单独或协同作用产生各种各样的代谢产物，直接或间接作用于下游信号通路，影响宿主稳态维持和疾病转归，而宿主健康状况的改变又会进一步反过来影响肠道菌群的结构和功能。肠道微生物与人体健康的共生关系密切、互作机制复杂，在系统和整体层面影响机体代谢、免疫等生理过程，这与中药治病防病的基本特点相适应。肠道微生物作为机体的一部分，可反映宿主整体的健康状况，并受多种因素影响；根据对肠道微生物的动态监测，可以适时调整干预策略，以获得更好的临床收益[14-16]。因此，肠道微生物具有作为中医药防治疾病重要靶点的先决优势。
肠道菌群受遗传背景、年龄、生存环境、饮食、药物等因素动态调控，其中药物对肠道菌群的影响尤为显著。中药及其活性物质与肠道微生物之间存在复杂的相互作用。一方面，中药直接作用于肠道菌群，影响菌群代谢产物的生成；另一方面，肠道菌群可通过复杂的生物转化对药物进行分解代谢或修饰，介导还原、脱羧、水解等反应发生及特定代谢物产生，从而改变药物的药效学、药动学和毒理学特征[17-18]。近年来，肠道微生物产生的多种代谢物及其功能逐渐被揭示，相关代谢产物作为机体代谢反应的信号分子和底物，与宿主生理、病理等过程密切相关[19]。中药天然药物中含有多糖、三萜糖苷、黄酮皂苷、多酚和生物碱等口服吸收差的活性物质，这些活性成分发挥作用的机制如何，一直是困扰中药现代化研究的科学难题。因此，本文将聚焦中药调控肠道菌群代谢物的产生，进而改善疾病进程的最新研究进展，以期为全面阐明中药防治疾病的机理机制提供思路和见解。
1 短链脂肪酸短链脂肪酸(short chain fatty acid, SCFAs)由结肠内厌氧菌发酵未消化吸收的碳水化合物(如抗性淀粉、纤维素等)产生，主要包括乙酸、丙酸和丁酸等。SCFAs可抑制组蛋白脱乙酰酶(histone deacetylases, HDAC)，激活G蛋白偶联受体(G-protein coupled receptors, GPCRs)，作为信号分子和能量代谢的底物影响宿主生理活动，具有调节代谢、调节T细胞功能、维持肠道免疫稳态、抗肿瘤、保护神经系统和心血管系统等作用[20-23]。
中药的单个组分和复方具有调节SCFAs产生的功能。黄芪多糖(Astragalus polysaccharides, APS)增加脱硫弧菌(Desulfovibrio vulgaris)的丰度，进一步促进乙酸的产生，抑制肝脏脂肪酸合酶(fatty acid synthase, FASN)和CD36蛋白的表达，进而改善非酒精性脂肪肝(nonalcoholic fatty liver disease, NAFLD)症状[24]。茯苓菌核中分离得到的水不溶性多糖(water insoluble polysaccharide, WIP)干预瘦素缺陷型ob/ob小鼠后，可促进毛螺菌科(Lachnospiracea)和梭菌属(Clostridium)等丁酸产生菌的生长，提高肠道中的丁酸产量，改善肠道屏障功能，激活肠道过氧化物酶体增殖物激活受体-γ (peroxisome proliferator-activated receptor γ, PPAR-γ)通路，进而改善糖脂代谢异常[25]。甘蔗叶来源的多酚类物质(sugarcane leaves-derived polyphenols, SLP)可以缓解肥胖小鼠的糖脂代谢紊乱，富集嗜黏蛋白阿克曼氏菌(Akkermansia muciniphila)和产酸拟杆菌(Bacteroides acidifaciens)，促进丁酸、丙酸、异戊酸等SCFAs以及脱氧胆酸、石胆酸等次级胆汁酸的产生，是治疗代谢综合征的潜在益生元[26]。中药复方葛根芩连汤(Gegen Qinlian decoction, GQD)可以促进SCFAs产生菌生长，如阿克曼氏菌属(Akkermansia)、拟杆菌属(Bacteroides)、梭菌属(Clostridium)、瘤胃球菌属(Ruminococcus)和考拉杆菌属(Phascolarctobacterium)，抑制HDAC和核因子-κB (nuclear factor-κB, NF-κB)信号通路，减轻肠道黏膜炎症反应，进而缓解腹泻[27]。而另一项研究则证实GQD及其关键组分小檗碱可以富集丁酸产生菌，如粪杆菌属(Faecalibacterium)和罗氏菌属(Roseburia)，促进肠道丁酸产生，下调促炎因子和免疫相关基因(包括Nfkb1、Stat1和Ifnrg1)的表达，发挥改善糖尿病的作用[28]。类似地，小檗碱可富集SCFAs产生菌抑制大鼠内脏高敏感性和小神经胶质细胞活化，改善肠易激综合征[29]。从葛根中提取纯化的均质多糖(Radix Puerariae thomsonii polysaccharide, RPP-2)可调节肠道弗林蒂杆菌属(Flintibacter)、丁酸球菌属(Butyricicoccus)和颤杆菌克属(Oscillibacter)及其代谢产物脂多糖、胆汁酸和SCFAs的丰度，通过调节炎症、葡萄糖代谢和肝脂肪变性改善NAFLD[30]。目前，在多种疾病中中药及其活性组分可通过影响肠道菌群介导的SCFAs的产生影响疾病预后，具体内容见表 1。
表 1 中药及活性组分调控短链脂肪酸干预疾病
Table 1 TCM and/or active ingredients regulate SCFAs to manage diseases
| TCM and/or active ingredients | Disease model | Changes in gut microbiota composition (vs. model group) | Changes in SCFAs levels (vs. model group) |
References | |
| Astragalus polysaccharides (APS) extracted from Astragalus mongholicus | High-fat diet (HFD)- fed mice |
↑: Desulfovibrio, Parabacteroides, Acetatifactor, Alistipes | ↑: Acetic acid | [24] | |
| Water insoluble polysaccharide from the sclerotium of Poria cocos | ob/ob (leptin deficiency) mice |
↑: Lachnospiracea, Alloprevotella, Parabacteroides, Clostridum Ⅳ, Ruminococcus, Bacteroides ↓: Megamonas, Proteus |
↑: Butyric acid | [25] | |
| Gegen Qinlian decoction | Bacterial diarrheal piglets | ↑: Akkermansia, Bacteroides, Clostridium, Ruminococcus, Phascolarctobacterium, Escherichia, Desulfovibrio ↓: Methanobrevibacter, Oscillospira, Prevotella |
↑: Acetic acid, propionic acid, butyric acid | [27] | |
| Gegen Qinlian decoction and its major active ingredient berberine | Goto-Kakizaki (GK) rats | ↑: Faecalibacterium, Roseburia, Clostridium XIVa, Ruminococcus_2, Dorea | ↑: Acetic acid, propionic acid, butyric acid | [28] | |
| Berberine | Visceral hypersensitivity rats | ↑: Akkermansia, Bacteroides, Lachnoclostridium, Anaerostipes | ↑: Acetic acid, propionic acid, total SCFAs ↓: Isobutyric acid, valeric acid |
[29] | |
| α-d-1, 3-glucan from Radix Puerariae thomsonii | HFD-induced non-alcoholic fatty liver disease (NAFLD) mice | ↑: Phocea, Ruthenibacterium, Flavonifractor, Oscillibacter, Flintibacter, Butyricicoccus | ↑: Butyric acid, propionic acid | [30] | |
| Forsythiaside A | CCl4-induced liver fibrosis mice | ↑: Prevotellaceae_UCG-001, Ruminococcus_1, Bacteroides ↓: Mucispirillum, Lactobacillus |
↑: Acetic acid, propionic acid, isobutyric acid, butyric acid, caproic acid | [31] | |
| TCM and/or active ingredients | Disease model | Changes in gut microbiota composition (vs. model group) | Changes in SCFAs levels (vs. model group) |
References | |
| Forsythin extract in Forsythia leaves | HFD-fed mice | ↑: Ruminococcaceae_UCG-001, Romboutsia ↓: Akkermansia |
↓: Propionic acid, butyric acid, valeric acid, caproic acid, total SCFAs | [32] | |
| Triterpenoids from Ganoderma lucidum | d-gal induced Alzheimer’s disease rats | ↑: Firmicutes, Verrucomicrobia ↓: Actionbacteria, Proteobacteria, Tenericutes, TM7 |
↑: Acetic acid, isobutyric acid, isovaleric acid, propionic acid, butyric acid, valeric acid | [33] | |
| Cistanche deserticola polysaccharide | Postmenopausal osteoporosis mice | ↑: Desulfovibrionales, Lactobacillales ↓: Bacteroides |
↑: Acetic acid | [34] | |
| Fuzi polysaccharides | Cyclophosphamide induced immunosuppressed mice | ↑: Rhodospirillales, Ruminococcaceae_UCG-013, Mollicutes_RF39, Ruminococcus_1, Christensenellaceae_R-7_group, Muribaculaceae ↓: Helicobacter, Anaerotruncus, Faecalibacterium, Lachnospira, Erysipelotrichaceae_UCG-003, Mucispirillum, Mycoplasma |
↑: Acetic acid, propionic acid, isobutyric acid, n-butyric acid | [35] | |
| Moutan Cortex polysaccharide | High-fat and high-sugar diet combined with streptozotocin (STZ) induced diabetic kidney disease rats | ↑: Ruminococcaceae_UCG-014, Muribaculaceae_unclassified, Lactobacillus, Akkermansia | ↑: Acetic acid, propionic acid, butyric acid ↓: Isovaleric acid |
[36] | |
| Schisandra chinensis polysaccharides | Antibiotic-associated diarrhea rats | ↑: Blautia, Intestinibacter, Lachnospiraceae_UCG-008 ↓: Ruminococcus_1, Ruminococcaceae_UCG-014, Erysipelatoclostridium |
↑: Acetic acid, propionic acid, butyric acid, total SCFAs | [37] | |
| Bletilla striata oligosaccharides | HFD-fed mice | ↑: Caproiciproducens, Parvibacter, Eubacterium nodatum group, Marvinbryantia, Butyricicoccus, Coriobacteriaceae_UCG-002, Blautia, Erysipelatoclostridium, Faecalibaculum ↓: Lachnospiraceae NC2004 group, Treponema_2, Enterococcus, Ruminococcus_1, Bifidobacterium |
↑: Acetic acid ↓: Propanoic acid, valeric acid |
[38] | |
| Polygonatum kingianum polysaccharides | HFD-fed rats | ↑: Bacteroides, Oscillibacter, SCFAs-producing bacteria ↓: Lactobacillus, Psychrobacter |
↑: Acetic acid, propionic acid, butyric acid, total SCFAs | [39] | |
| Flos Abelmoschus manihot extract | DSS-induced colitis mice | ↑: Lachnospiraceae, Alistipes, Lactobacillus, Bilophila, Desulfovibrio ↓: Bacteroides |
↑: Acetic acid, butyric acid | [40] | |
| TCM and/or active ingredients | Disease model | Changes in gut microbiota composition (vs. model group) | Changes in SCFAs levels (vs. model group) |
References | |
| Limonitum decoction | Castor oil induced diarrhoea mice | ↑: norankˍf_Bacteroidales_S24-7_group, Lactobacillus, Lachnospiraceae_NK4A136_group, norankˍf_Lachnospiraceae ↓: Bacteroides, Klebsiella, Lachnoclostridium, Akkermansia, Parabacteroides |
↑: Acetic acid, propionic acid, isobutyric acid, butyric acid, valeric acid | [41] | |
| Chaihu Shugan formula | The simulator of the human intestinal microbial ecosystem (SHIME®) technology platform | ↑: Bifidobacterium, Bacteroidaceae, Rikenellaceae, Acidaminococcaceae ↓: Opportunistic pathogenic Escherichia coli |
↑: Acetic acid, propionic acid, butyric acid ↓: Branched SCFAs (isobutyric acid, isovaleric acid, isocaproate acid) |
[42] | |
| Huanglian Wendan decoction | Para-chlorophenylalanine (PCPA)-induced insomnia rats | ↑: Oscillospira, Helicobacter, Roseburia, Bifidobacterium ↓: Lactobacillus |
↑: Acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, capric acid, isohexanoic acid | [43] | |
| Yishen Qingli Heluo granule | 5/6 nephrectomized rats | ↑: SCFAs-producing bacteria (i.e., Lactobacillaceae, Lactobacillus and Lactobacillus gasseri) | ↑: Total SCFAs, acetic acid, butyric acid | [44] | |
| Bufei Jianpi formula | Repeated cigarette smoke inhalation and lipopolysaccharide (LPS) injection induced chronic obstructive pulmonary disease (COPD) rats | ↑: Firmicutes ↓: Oscillospira, Lactobacillus, Allobaculum, Clostridiaceae, Treponema |
↑: Acetic acid, propionic acid, butyric acid | [45] | |
| Xiexin Tang | Type 2 diabetes mellitus (T2DM) rats | ↑: Alloprevotella, Barnesiella, [Eubacterium] Ventriosum group, Lachnospiraceae_UCG-001, Papillibacter, Prevotellaceae_NK3B31_group ↓: Blautia, Adlercreutzia |
↑: Acetic acid, propionic acid, isobutyric acid, butyric acid | [46] | |
| Jiang Tang San Hao formula | HFD combined with streptozotocin injection induced T2DM mice | ↑: Bacteroides, Prevotella, Parabacteroides ↓: Clostridium, Lactobacillus, Oscillibacter |
↑: Acetic acid, propionic acid, butyric acid | [47] | |
| Jiangu granule | Postmenopausal osteoporosis rats | ↑: Prevotella ↓: Ruminococcus, Bacteroides, Blautia, Coprococcus |
↑: Isobutyric acid, butyric acid, isovaleric acid | [48] | |
| Zhengganxifeng decoction | Spontaneously hypertensive rats | ↑: SCFAs-producing bacteria | ↑: Acetic acid, propionic acid, butyric acid | [49] | |
| Shenling Baizhu powder | A lard diet in a fatigued state induced diarrhea belonging to spleen qi deficiency mice | ↑: Lactobacillus | ↑: Acetic acid, butyric acid, valeric acid | [50] | |
| TCM and/or active ingredients | Disease model | Changes in gut microbiota composition (vs. model group) | Changes in SCFAs levels (vs. model group) |
References | |
| Qiong-Yu-Gao | Cisplatin-induced acute kidney injury mice | ↑: Akkermansia, Faecalibaculum, Bifidobacterium, Lachnospiraceae_NK4A136_group | ↑: Acetic acid, butyric acid | [51] | |
| Naoxintong capsule | HFD-fed rats | ↓: [Ruminococcus] gauvreaui group, Collinsella, Romboutsia (genus), Romboutsia ilealis (species) | ↑: Acetic acid, propionic acid, butyric acid, total SCFAs | [52] | |
| Naoxintong capsule | Early-stage atherosclerosis mice | ↑: Akkermansia, Faecalibacterium, Prevotella ↓: Actinobacteria |
↑: Acetic acid, isobutyric acid, isovaleric acid, total SCFAs | [53] | |
| Triphala | HFD-induced NAFLD rats | ↑: Ligilactobacilli, Akkermansia, Ruminococcus ↓: Actinobacteria |
↑: Acetic acid, propionic acid, butyric acid, isobutyric acid, isovaleric acid, total SCFAs | [54] | |
| Xiao Cheng Qi decoction | Loperamide-induced slow-transit constipation mice | ↑: Lactobacillus, Prevotellaceae_UCG-001, Prevotellaceae_NK3B31_group, Muribaculaceae, Roseburia ↓: Desulfovibrio, Tuzzerella, Lachnospiraceae_NK4A136_group |
↑: Acetic acid, propionic acid, isobutyric acid, butyric acid, valeric acid, total SCFAs | [55] | |
| Yunpi Tongbian Fang | Loperamide-induced slow-transit constipation rats | ↑: Romboutsia ↓: Lactobacillus |
↑: Acetic acid, propionic acid, butyric acid | [56] | |
| Qingyi decoction | Severe acute pancreatitis-associated acute lung injury mice | ↑: Bacteroides, Roseburia, Parabacteroides, Prevotella, Akkermansia ↓: Escherichia, Enterococcus, Enterobacter, Peptostreptococcus, Helicobacter |
↑: Propionic acid, butyric acid | [57] | |
| Gu-Ben-Fang- Xiao decoction |
Asthma in remission stage mice | ↑: Lachnospiraceae, Bifidobacteriaceae, Verrucomicrobiaceae, Peptococcacea, Anaeroplasmataceae, f_unclassified_p_Firmicutes ↓: Alistipes, Rikenellaceae |
↑: Acetic acid, propionic acid, total SCFAs | [58] | |
| Wu-tou decoction | Adjuvant-induced arthritis rats | ↑: Lactobacillus, Oscillospira ↓: Akkermansia, Bacteroides, Prevotella, Enterococcus, Dorea, Jeotgalicoccis |
↑: Acetic acid, propionic acid, butyric acid, valeric acid, hexanoic | [59] | |
| Ganoderma meroterpene derivative | HFD-fed ApoE−/− mice | ↑: Parabacteroides, Akkermansia, Roseburia | ↑: Propionic acid, butyric acid, 2-methylbutyate | [60] | |
| Shouhuitongbian | HFD-fed mice; db/db mice | ↑: Akkermansia, Parabacteroides ↓: Desulfovibrio, Lachnoclostridium |
↑: Isobutyric acid, isovaleric acid, 2-methylbutyric acid | [61] | |
肠道微生物不仅可以转化和合成脂类物质，也可以分解膳食来源的脂质，产生具有宿主调节特性的次生代谢物，这些脂质代谢物通过影响宿主代谢途径和调节免疫功能，影响宿主的生理健康[62]。研究表明，肥胖及糖尿病患者和小鼠肠道中毛螺菌科(Lachnospiraceae)共生菌Fusimonas intestine可以产生反油酸酯(elaidate)等反式不饱和长链脂肪酸，损伤肠道上皮屏障，促进代谢性内毒素血症，加重饮食诱导的肥胖表型，这表明肠菌脂质代谢的变化与疾病进展存在因果关系[63]。
花生四烯酸(arachidonic acid, AA)是全顺式- 5, 8, 11, 14-二十碳四烯酸，是一种ω-6多不饱和脂肪酸，主要存在于人类细胞膜的磷脂和免疫细胞的脂滴中[64]。游离的AA在环氧合酶(cyclooxygenase, COX)、脂氧合酶(lipoxygenases, LOX)、细胞色素酶P450 (cytochrome P450, CYP450)和脂肪酰胺水解酶(fatty acid amide hydrolase, FAAH)作用下产生多种AA衍生物，具有调节机体免疫、炎症、创伤、情绪和代谢等功能[65]，是多种疾病的潜在治疗靶点。酒精性脂肪肝小鼠肠道中大量增加的真菌季也蒙迈耶氏酵母(Meyerozyma guilliermondii)可将花生四烯酸代谢成前列腺素E2，进而加剧疾病症状，而茯苓多糖干预可抑制M. guilliermondii及其衍生物前列腺素E2的产生，改善酒精性脂肪肝病[66]。
此外，中药组分及其复方可通过调节肠道微生物的结构和功能参与多种中长链脂肪酸的代谢，进而影响疾病转归(表 2)。人参提取物通过富集粪肠球菌(Enterococcus faecalis)及其衍生的代谢物肉豆蔻油酸(myristoleic acid)增加能量代谢，激活棕色脂肪组织，促进白色脂肪米色化，进而改善小鼠肥胖和脂肪肝症状[67]。肠道共生菌狄氏副拟杆菌(Parabacteroides distasonis)可将菊粉进一步代谢成十五烷酸(pentadecanoic acid)，进而减少肝脏脂肪变性、坏死性炎症和纤维化，抑制非酒精性脂肪性肝炎进展[68]。中药复方保元汤可以逆转心肌肥大大鼠关键肠道微生物群及相关代谢物的变化，如短链/中链脂肪酸、初级/次级胆汁酸和氨基酸，发挥心脏保护功能[69]。
表 2 中药及活性组分调控脂类代谢物干预疾病
Table 2 TCM and/or active ingredients regulate lipids to manage diseases
| TCM and/or active ingredients | Disease model | Changes in gut microbiota composition (vs. model group) | Changes in lipids levels (vs. model group) |
References |
| Polysaccharides of Wolfiporia cocos | Ethanol feeding-induced alcoholic hepatic steatosis mice | ↑: Blautla, Ruminoclostridum, unidentified_Clostridials, Alistipes ↓: Meyerozyma guilliermondi |
↓: Prostaglandin E2 | [66] |
| Ginseng extract | db/db mice | ↑: Enterococcus, Enterococcus faecalis | ↑: Myristoleic acid, non-adecylic acid, linoleic acid | [67] |
| Inulin | Choline-deficient high-fat diet (CDHFD) induced non-alcoholic steatohepatitis (NASH) mice; high-fat, high-cholesterol diet (HFHCD) plus high-fructose drinking water induced NASH mice | ↑: Bacteroides, Parabacteroides, Parabacteroides distasonis | ↑: Pentadecanoic acid, phosphatidylserine ↓: Sphingosine |
[68] |
氨基酸(amino acids, AAs)是一类两性有机化合物，是生物功能大分子蛋白质和肽类的基本组成单位。肠道微生物对维持宿主氨基酸稳态具有重要贡献，不仅可以广泛参与氨基酸的代谢与利用，改变其生物利用度、分布和结构，生成多种代谢产物，还可以直接参与部分氨基酸的从头合成[70-71]。中药及其组分可以通过重塑肠道菌群，改变氨基酸代谢途径，进而发挥功效(表 3)。
表 3 中药及活性组分调控氨基酸代谢物干预疾病
Table 3 TCM and/or active ingredients regulate amino acids to manage diseases
| TCM and/or active ingredients | Disease model | Changes in gut microbiota composition (vs. model group) | Changes in amino acids levels (vs. model group) | References |
| Ganoderma meroterpene derivative | HFD-fed ApoE−/− mice | ↑: Parabacteroides, Akkermansia, Roseburia | ↓: BCAAs (leucine, valine, isoleucine) |
[60] |
| Shouhuitongbian | HFD-fed mice; db/db mice |
↑: Akkermansia, Parabacteroides ↓: Desulfovibrio, Lachnoclostridium |
↓: BCAAs | [61] |
| Baoyuan decoction | Isoproterenol (ISO)-induced cardiac hypertrophy rats | ↑: Prevotella_9, Prevotellaceae ↓: Faecalibacterium |
↑: BCAAs, arginine ↓: Asymmetric dimethyl-arginine (ADMA), tryptophan and its derivatives |
[69] |
| Citrus polymethoxyflavones | HFD-induced metabolic syndrome mice | ↑: Bacteroides ↓: Paraprevotella, Streptococcus |
↓: BCAAs, phenylalanine | [74] |
| Berberine | HFD-fed mice | ↑: Akkermansia ↓: BCAA-producing bacteria (Streptococcus, Prevotella) |
↓: BCAAs | [75] |
| Berberine | DSS-induced colitis rats | ↑: rc4.4, Lactobacillus, Clostridium, Akkermansia ↓: Mycoplasma |
↑: (Serum) tryptophan, N-Acetyl-l-tryptophan, 5-hydroxy-l-tryptophan, indolepropionic (IPA), indole-3-acetic acid (IAA), indoleacrylic acid (IA) | [78] |
| Berberine | Adenine-induced chronic kidney disease rats | ↑: Lachnospiraceae_UCG-006, Alistipes, Streptococcus ↓: Clostridium_sensu_stricto_1, Adlercreutzia, Romboutsia, Jeotgalicoccus |
↑: Tryptophan, tyrosine ↓: Indoxy1 sulfate, p-cresol, p-cresol sulfate |
[79] |
支链氨基酸(branched-chain amino acid, BCAAs)包括亮氨酸、缬氨酸和异亮氨酸，属于必需氨基酸。BCAAs可在植物、细菌和真菌中合成，不能在动物体内合成[72]。BCAAs的分解代谢由支链氨基转移酶(branched-chain amino transferase, BCAT)和支链α-酮酸脱氢酶(branched- chain α-keto acid dehydrogenase, BCKDH)介导，终止于三羧酸(tricarboxylic acid, TCA)循环，并伴随多种重要的代谢中间体产生，如缬氨酸代谢产物3-羟基异丁酸酯(3-hydroxyisobutyrate, 3-HIB)和单甲基支链脂肪酸(monomethyl branched- chain fatty acids, mmBCFA)可以参与细胞内分泌和旁分泌的信号传导过程[73]。中药陈皮中的功能组分多甲氧基黄酮(polymethoxyflavone-rich extract, PMFE)通过富集肠道益生菌卵形拟杆菌(Bacteroides ovatus)，促进肠道中BCAAs分解代谢，降低循环中BCAAs水平改善代谢综合征[74]。中药黄连中的功能组分小檗碱(berberine, BBR)可调节高脂饮食诱导的胰岛素抵抗(insulin resistance, IR)小鼠肠道菌群结构，降低BCAAs产生菌链球菌科(Streptococcaceae)、梭菌科(Clostridiaceae)、普雷沃氏菌科(Prevotellaceae)、链球菌属(Streptococcus)和普雷沃氏菌属(Prevotella)的丰度；宏基因组结果显示BBR处理可下调小鼠肠道中涉及BCAAs合成的相关基因，上调BCAAs降解和转运的相关基因，进而降低血清中BCAAs水平；Western blotting结果显示BBR通过激活支链α-酮酸脱氢酶复合物(branched-chain α-ketoacid dehydrogenase complex, BCKDC)、抑制BCKDC的E1α亚基(BCKDHA)和支链α-酮酸脱氢酶激酶(branched-chain α-ketoacid dehydrogenase kinase, BCKDK)磷酸化，增强肝脏和附睾白色脂肪组织中的BCAAs分解代谢，进而改善IR[75]。灵芝杂萜衍生物(Ganoderma meroterpene derivative, GMD)可以富集肠道粪副拟杆菌(Parabacteroides merdae)，由该菌porA基因介导将肠道中的BCAAs代谢为支链短链脂肪酸(branched-short chain fatty acids, BSCFAs)，降低循环系统BCAAs水平，进而抑制动脉粥样硬化斑块巨噬细胞哺乳动物雷帕霉素靶蛋白复合物1 (mammalian target of rapamycin complex 1, mTORC1)通路激活，发挥抗动脉粥样硬化作用[60]。类似地，首荟通便胶囊(Shouhuitongbian, SHTB)是治疗便秘的传统中药方剂，由芦荟、何首乌、决明子、枸杞、白术、枳实、人参7味中药和阿胶组成，研究发现SHTB干预可以调节糖尿病小鼠肠道菌群结构和功能，富集阿克曼氏菌属(Akkermansia)和副拟杆菌属(Parabacteroides)，促进肠道中BCAAs向BSCFAs的转化，通过调控mTORC1介导的胰岛素受体底物1 (insulin receptor substrate 1, IRS1)/磷脂酰肌醇-3-激酶(phosphoinositide 3-kinase, PI3K)/蛋白激酶B (protein kinase B, AKT)信号通路改善2型糖尿病症状[61]。
色氨酸(tryptophan, Trp)是唯一一种含有吲哚结构的氨基酸，是一种人体必需氨基酸。色氨酸代谢主要涉及犬尿氨酸、5-羟色胺和吲哚途径，代谢产生的各种生物活性物质具有调节免疫、炎症、代谢、肠道稳态和神经系统等生理功能[76]。肠道微生物可以直接参与色氨酸代谢过程，产生吲哚、吲哚衍生物、色胺和粪臭素等芳香烃受体(aromatic hydrocarbon receptor, AhR)的配体，有助于维持免疫稳态和肠道屏障功能[76]。异槲皮苷(isoquercitrin, ISO)是一种广泛分布于中草药、蔬果中的小分子黄酮类化合物，可以通过调节肠道细菌的电子传递链，抑制色氨酸传输，减少微生物群介导的吲哚产生，进而减少肾脏硫酸吲哚酚的产生，改善慢性肾病[77]。小檗碱可以缓解葡聚糖硫酸钠(dextran sulfate sodium, DSS)诱导结肠炎大鼠的菌群失调，上调拟杆菌属(Bacteroides)和阿克曼氏菌属(Akkermansia)的丰度，逆转色氨酸代谢紊乱，通过激活AhR活性增强肠道屏障功能，进而改善大鼠的结肠炎症状[78]。小檗碱还通过降低梭菌属细菌Clostridium_sensu_stricto_1的丰度和抑制肠道菌群的酪氨酸-对甲酚途径来降低血浆中肠道来源的尿毒症毒素对甲酚硫酸盐的含量，进而改善慢性肾脏疾病[79]。
4 胆酸代谢物胆汁酸(bile acids, BAs)是胆汁的重要成分，在脂肪代谢中起着重要作用。人体在肝脏由至少17种不同的酶将胆固醇代谢为胆酸(cholic acid, CA)和鹅去氧胆酸(chenodeoxycholic acid, CDCA)等初级胆汁酸，经胆汁释放到肠道，由肠道微生物代谢为脱氧胆酸(deoxycholic acid, DCA)、石胆酸(lithocholic acid, LCA)等次级胆汁酸[80]。次级胆汁酸可以通过调控法尼醇X受体(farnesoid X receptor, FXR)、武田G蛋白偶联受体5 (Takeda G protein-coupled receptor 5, TGR5)、维生素D受体(vitamin D receptor, VDR)等调控宿主糖脂代谢、免疫应答、骨髓造血等多个病理生理过程[81-86]。
胆汁酸是沟通宿主与肠道微生物的关键信使分子，中药活性成分可以调控胆酸代谢，发挥药理功能(表 4)。人参皂苷Rg2可促进P. distasonis生长，P. distasonis通过胆盐水解酶(bile acid hydrolase, BSH)等多种途径产生次级胆汁酸LCA、DCA、异石胆酸(iso LCA)和3-氧代石胆酸(3-oxo LCA)，激活TGR5受体促进巨噬细胞M2极化，同时3-oxo LCA和iso LCA直接抑制Th17分化，从而恢复Th17/Treg平衡，改善肠道屏障功能，改善RA症状[87]。来源于中药雷公藤的雷公藤红素(celastrol)可以选择性促进P. distasonis生长，增强BSH活性，抑制肠道FXR信号，降低肝脏中牛磺鹅脱氧胆酸(taurochenodeoxycholic acid, TCDCA)水平，改善小鼠肝纤维化症状[88]。天然产物新橙皮苷(neohesperidin)能够促进B. ovatus生长，B. ovatus通过上调具有产猪脱氧胆酸(hyodeoxycholic acid, HDCA)能力的闪烁梭菌(Clostridium scindens)的丰度，增加肠道内HDCA的水平；HDCA通过激活肠道TGR5、抑制FXR表达促进肠道胰高糖素样肽-1 (glucagon-like peptide-1, GLP-1)的分泌，进一步激活肾脏GLP-1受体并上调肾脏TGR5，从而减轻肾脏纤维化，延缓慢性肾脏疾病的进展[89]。而中药复方生脉散可以显著改变肥胖小鼠肠道微生物组成结构，降低具有BSH活性的乳杆菌属(Lactobacillus)的丰度，从而增加了血液、回肠和腹股沟白色脂肪组织(inguinal white adipose tissue, iWAT)中结合型胆汁酸牛磺胆酸(taurocholic acid, TCA)的水平，进一步促进iWAT M2巨噬细胞分泌Slit3，Slit3通过其受体ROBO1 (roundabouts receptor 1)激活交感神经元蛋白激酶A/钙调蛋白依赖性蛋白激酶Ⅱ (protein kinase A/calmodulin-dependent protein kinase Ⅱ, PKA/CaMKII)信号通路，导致去甲肾上腺素的释放并增加了肥胖小鼠的WAT褐变，发挥对抗肥胖的作用[90]。中药方剂片仔癀(Pien Tze Huang, PTH)在治疗NAFLD和抑制结直肠癌发生发展具有重要作用，在氧化偶氮甲烷联合葡聚糖硫酸钠(azoxymethane/dextran sulfate sodium, AOM/DSS)处理小鼠和Apcmin/+结直肠癌小鼠模型中，PTH增加益生菌假丁酸弧菌(Pseudobutyrivibrio xylanivorans)和黏液真杆菌(Eubacterium limosum)丰度，降低致病菌维氏气单胞菌(Aeromonas veronii)、空肠弯曲菌(Campylobacter jejuni)、产气柯林斯菌(Collinsella aerofaciens)和兔嗜肽杆菌(Peptoniphilus harei)丰度，增加有益代谢产物牛磺酸(taurine)和亚牛磺酸(hypotaurine)、胆汁酸牛磺胆酸(taurocholic acid, TCA)和不饱和脂肪酸硬脂酸(stearidonic acid)、蓖麻油酸(ricinoleic acid)，显著恢复肠道屏障功能，抑制致癌PI3K-AKT信号通路、促炎IL-17信号通路、TNF信号通路、细胞因子-细胞因子受体相互作用和趋化因子信号通路，进而抑制结直肠癌的发生[91]。在NAFLD发病过程中，PTH治疗显著改善蛋氨酸和胆碱缺乏(methionine and choline deficient diet, MCD)饮食诱导的小鼠脂肪变性和肝损伤，富集嗜酸乳杆菌(Lactobacillus acidophilus)、植物乳植杆菌(Lactiplantibacillus plantarum)、乳酸乳球菌(Lactococcus lactis)和枯草芽孢杆菌(Bacillus subtilis)等益生菌，调节门静脉血胆汁酸代谢，改善肠道屏障功能[92]。
表 4 中药及活性组分调控胆酸代谢物干预疾病
Table 4 TCM and/or active ingredients regulate bile acids to manage diseases
| TCM and/or active ingredients | Disease model | Changes in gut microbiota composition (vs. model group) | Changes in bile acids levels (vs. model group) | References |
| α-d-1, 3-glucan from Radix Puerariae thomsonii | HFD-induced NAFLD mice | ↑: Phocea, Ruthenibacterium, Flavonifractor, Oscillibacter, Flintibacter, Butyricicoccus | ↑: Chenodeoxycholic acid, cholesterol, 3a, 7a-dihydroxy- 5b-cholestane, cholic acid | [30] |
| TCM and/or active ingredients | Disease model | Changes in gut microbiota composition (vs. model group) | Changes in bile acids levels (vs. model group) | References |
| Forsythiaside A | CCl4-induced liver fibrosis mice | ↑: Prevotellaceae_UCG-001, Ruminococcus_1, Bacteroides ↓: Mucispirillum, Lactobacillus |
↑: Taurodeoxycholate, chenodeoxycholic acid ↓: Lithocholic acid, deoxycholic acid, α-hyodeoxycholic acid, glydeoxycholic acid, β-muricholic acid, α-muricholic acid |
[31] |
| Wu-tou decoction | Adjuvant-induced arthritis rats | ↑: Lactobacillus, Oscillospira ↓: Akkermansia, Bacteroides, Prevotella, Enterococcus, Dorea, Jeotgalicoccis |
↑: Cholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid ↓: Lithocholic acid, taurochenodeoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid |
[59] |
| Ginsenoside Rg2 | Collagen-induced arthritis (CIA) mice | ↑: Parabacteroides distasonis | ↑: Deoxycholic acid, lithocholic acid, 3-oxolithocholic acid, isolithocholic acid | [87] |
| Celastrol | Thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis mice | ↑: Parabacteroides distasonis | ↓: Taurochenodeoxycholic acid | [88] |
| Neohesperidin | Unilateral ureteral obstruction or adenine-induced chronic kidney disease mice | ↑: Bacteroides ovatus | ↑: Hyodeoxycholic acid | [89] |
| Shengmai San formula | HFD-induced obesity mice | ↑: Akkermansia ↓: Lactobacillus, Blautia, Eubacterium, Lactococcus, Enterococcus |
↑: Taurocholic acid, T-α/β/ω-muricholic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, taurohyodeoxycholic acid | [90] |
| Pien Tze Huang and its components ginsenoside-F2 and ginsenoside-Re | Azoxymethane plus DSS-treated mice and in Apcmin/+ mice | ↑: Pseudobutyrivibrio xylanivorans, Eubacterium limosum ↓: Aeromonas veronii, Campylobacter jejuni, Collinsella aerofaciens, Peptoniphilus harei |
↑: Taurine, hypotaurine, stearidonic acid, ricinoleic acid | [91] |
| Pien Tze Huang | High-fat high-cholesterol (HFHC) diet, choline-deficient high-fat diet (CD-HFD), and MCD diet induced NASH mice | ↑: Lactobacillus acidophilus, Lactiplantibacillus plantarum, Lactococcus lactis, Bacillus subtilis ↓: Citrobacter, Pseudomonas |
↑: Tauroursodeoxycholic acid, taurodeoxycholic acid, taurocholic acid, glycocholic acid, chenodeoxycholic acid | [92] |
胆碱(choline)是一种人体必需营养素，是所有生物膜的组成成分和胆碱能神经元中乙酰胆碱的前体，调节细胞内的基本信号传导过程[93]。胆碱可以来源于食物，也可以由磷脂酰乙醇胺(phosphatidylethanolamine, PE)的连续甲基化过程内源性合成[94]。肠道菌群可通过胆碱三甲胺-裂解酶(choline trimethylamine-lyase, CutC)及其激活酶(CutD)将红肉、蛋和奶酪等食物中的胆碱、磷脂酰胆碱、左旋肉碱等物质代谢为三甲胺(trimethylamine, TMA)，TMA通过门静脉循环输送到肝脏，被黄素单氧化酶(flavin-containing monooxygenases, FMO)转化为氧化三甲胺(trimethylamine N-oxide, TMAO)[95-96]。胆碱及其代谢物可以影响心血管疾病、神经系统疾病和代谢性疾病等疾病进展，是防治各类疾病的潜在靶点。
目前的研究普遍认为TMA/TMAO是动脉粥样硬化、高血压、中风、炎症性疾病和慢性肾脏疾病的危险因素[97-101]。中药及活性组分可以作用于宿主肠道菌群，调节胆碱-TMA-TMAO轴，进而发挥健康促进的作用(表 5)。如普雷沃氏菌(Prevotella copri)及其产生的TMA会加剧动脉粥样硬化症状，而中药活性组分葛根素可以破坏P. copri的膜功能以抑制其丰度，进而降低TMA和TMAO的产生，缓解高脂饮食喂养ApoE−/−小鼠的动脉粥样硬化症状[102]。而小檗碱的菌群代谢物二氢小檗碱(dihydroberberine, dhBBR)可抑制菌群中胆碱-三甲胺裂解酶CutC/CutD和FMO活性，从而减少胆碱向TMA/TMAO的转化，降低血浆和粪便中TMA和TMAO含量，进而改善动脉粥样硬化[103]。鸭跖草、白藜芦醇和左归降糖益肾方可以重塑疾病小鼠/大鼠的菌群结构，抑制TMA/TMAO产生，分别调控NF-κB/NLRP3炎症信号通路、肠肝法尼醇X受体-成纤维细胞生长因子15 (farnesoid X receptor-fibroblast growth factor 15 axis, FXR-FGF15)轴和线粒体活性氧(mitochondrial reactive oxygen species, mROS)- NLRP3轴，进而改善脓毒性急性肺损伤、动脉粥样硬化和糖尿病肾病[104-106]。
表 5 中药及活性组分调控胆碱代谢物干预疾病
Table 5 TCM and/or active ingredients regulate choline metabolites to manage diseases
| TCM and/or its active ingredients | Disease model | Changes in gut microbiota composition (vs. model group) |
Changes in choline metabolites levels (vs. model group) |
References |
| Puerarin | HFD-fed ApoE−/− mice | ↓: Prevotella copri | ↓: TMA, TMAO | [102] |
| Berberine | Arteriosclerosis hamsters | ↑: Allobaculum, Akkermansia, Lachnospiraceae_NK4A136 ↓: Eubacterium coprostanoligenes, Treponema_2, Ruminococcaceae_UCG-002, Prevotellaceae_UDG-001, Flavobacterium, Candidatus Saccharimonas, Empedobacter, Corynebacterium_1, Jeotgalicoccus, Myroides, Kurthia, Acinetobacter, Ruminoccoccus_2 |
↓: Trimethylamine (TMA), trimethylamine N-oxide (TMAO) | [103] |
| Yazhicao (Commelina communis L., YZC) extract | Septic-acute lung injury mice | ↑: Akkermansia, Parabacteroides, Prevotellaceae_UCG_001 ↓: Kurthi, Cetobacterium, Methylobacterium, Alloprevotella |
↓: TMA, TMAO | [104] |
| Resveratrol | TMAO-induced atherosclerosis ApoE−/− mice | ↑: Bacteroides, Lactobacillus, Bifidobacterium, Akkermansia ↓: Prevotella, Ruminococcaceae_uncultured, Anaerotruncus, Alistipes, Helicobacter, Peptococcaceae_uncultured |
↓: TMA, TMAO | [105] |
| Zuogui- Jiangtang-Yishen decoction |
Goto-Kakizaki (GK) rats | ↑: Romboutsia, Parabacteroides, Alistipes, Lactobacillus ↓: Bacteroides, Blautia, Parabacteroides, Ruminococcus torques_group, Fusicatenibacter |
↓: TMA, TMAO | [106] |
维生素(vitamin)是人体六大营养素之一，在支持基本细胞功能的各种代谢途径中发挥着重要作用，如能量产生代谢、DNA合成、氧气运输等，是一个具有广泛生理功能的庞大家族[107]。维生素主要通过食物摄取，部分可以在体内合成或由肠道微生物产生。因此，以肠道微生物群为靶点调控维生素合成代谢，可作为疾病干预的一种思路。具体地，叶酸(folate)是一种水溶性维生素，属于B族维生素，以四氢叶酸(tetrahydrofolate, THF)的活性形式存在，是包括DNA和氨基酸合成在内的几种代谢反应的辅因子[108]。肠道细菌由三磷酸鸟苷(guanosine triphosphate, GTP)、赤藓糖-4-磷酸和磷酸烯醇丙酮酸合成THF，由质子偶联叶酸转运体(proton-coupled folate transporter, PCFT)介导吸收，并通过血液在体内分布[108]。研究表明，叶酸生物合成途径存在于几乎所有Bacteroidetes基因组以及大多数梭杆菌门(Fusobacteria)和变形菌门(Proteobacteria)基因组中[109]，即肠道菌群是宿主维持叶酸稳态的重要因素。口服灵芝杂萜衍生物(GMD)可富集参与叶酸生物合成的拟杆菌属细菌解木聚糖拟杆菌(Bacteroides xylanisolvens)、多形拟杆菌(Bacteroides thetaiotaomicron)、单形拟杆菌(Bacteroides uniformis)和多氏拟杆菌(Bacteroides dorei)，进一步增加脂肪肝动物模型肠道中叶酸的含量，改善糖脂代谢紊乱，减轻内毒素血症，改善非酒精性肝脂肪变性。烟酸(nicotinic acid, NA)是吡啶-3-甲酸，属于B族维生素。铁皮石斛多糖(Dendrobium officinale polysaccharide, DOP)可以选择性富集P. distasoni，介导烟酸(nicotinic acid, NA)产生并通过激活G蛋白偶联受体109a (G-protein-coupled receptor 109a, GPR109a)改善肠道屏障功能，缓解IR[110]。
7 结语与展望中医药是我国医药学家对自然界、人和疾病关系的实践探索和规律总结，是经长期医疗实践积累得来的宝贵财富。近年来，肠道微生物作为中医药防治疾病的靶点被逐渐揭示和阐明。肠道菌群代谢产生的SCFAs、脂类、氨基酸、胆汁酸、胆碱和维生素作为肠道微生物与宿主交流的媒介，通过“肠-心轴” “肠-肝轴” “肠- 脑轴”和“肠-肾轴”等调控宿主糖脂代谢、能量稳态、炎症和免疫稳态。中药中的多糖组分调节拟杆菌门和厚壁菌门相关细菌的丰度，代谢生成的SCFAs等通过作用于肠内分泌细胞表达的GPCRs影响宿主的胰腺、脂肪组织和大脑等靶器官GLP-1、肽YY (peptide YY, PYY)和解偶联蛋白1 (uncoupling protein 1, UCP-1)等信号的表达，进而调控宿主糖脂代谢，增强胰岛素敏感性。中药成分通过调节某些特异性的肠道菌群介导的次级胆汁酸代谢，作用于宿主肠道、肝脏、肾脏和脂肪组织的FXR或TGR5信号通路等，改善宿主健康；通过调节某些三甲胺产生菌和支链氨基酸代谢菌的丰度，改变循环中TMA/TMAO和BCAAs的水平，影响动脉粥样硬化和糖尿病等疾病的发生发展。中药活性成分作用于宿主肠道菌群，调整其结构和功能，介导宿主来源和/或菌群来源的重要信号分子的产生，进一步作用于下游信号通路，从而发挥药效，这一作用模式在多种药物和疾病研究中被证实(图 1)。未来，肠道微生物组学技术的应用将进一步揭开中医药理论体系作用机制的面纱，肠菌代谢物库的建立和挖掘也将为疾病防治提出新的靶点和思路。
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| 图 1 中药及其活性成分调节肠道菌群代谢物改善疾病机制 Fig. 1 Mechanism of TCM and its active ingredients in the treatment of diseases via regulating gut microbiota metabolites. |
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作者贡献声明
杨德仪：文献搜集和整理、初稿写作；林靖涵、王涛：文献搜集和整理、稿件润色修改；刘宏伟：监督指导、稿件润色修改。
作者利益冲突公开声明
作者声明没有任何可能会影响本文所报告工作的已知经济利益或个人关系。
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