Research on the Interaction Between Autoimmune Diseases and Gut Microbiota and Regulation of Chinese Herbal Medicines
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摘要: 自身免疫性疾病是一大类以自身耐受破坏、免疫细胞异常激活、自身抗体产生和大量炎症因子释放, 进而产生多系统损伤为主要特征的疾病。肠道菌群与宿主健康息息相关, 菌群生态失调已被确认与许多自身免疫性疾病的病理生理学有关, 包括类风湿性关节炎、溃疡性结肠炎、自身免疫性甲状腺炎等。中药能改变肠道菌群的组成, 二者之间有紧密联系, 研究发现, 中药可通过重塑肠道微生态结构而发挥治疗作用。该文针对肠道菌群如何影响自身免疫疾病的发生和发展, 结合中药对肠道菌群调节作用的研究, 针对中药调节肠道菌群与其发挥疾病防治效果之间的相关性, 以期为中药的临床应用及药理学研究提供一定的参考依据。Abstract: Autoimmune diseases are characterized as the destruction of self-tolerance, abnormal activation of immune cells, production of autoantibodies and the release of large amounts of inflammatory factors, which in turn result in multisystem damage. The gut microbiota balance is closely related to the host health.Dysbiosis of gut microbiota has been identified in relation to many autoimmune diseases, including rheumatoid arthritis ulcerative colitis and autoimmune thyroiditis, etc. There has strong relationship between Chinese herbal medicine and its ability to alter the composition of the gut microbiota, and many studies has been proved that Chinese herbal medicine has therapeutic effect by reshaping the intestinal micro-ecological structure. In this review, we aim to investigate how gut microbiota affects the occurrence and development of autoimmune diseases, and to correlate the effects of Chinese herbal medicine on the regulation of gut microbiota with its effectiveness in disease prevention and treatment, with a view to providing a certain reference basis for the clinical application and pharmacological research of Chinese herbal medicine.
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图 1 肠道菌群与自身免疫性疾病关系示意图
注: Haemophilus.嗜血杆菌; Lactobacillus salivarius.唾液乳杆菌; Prevotella.普雷沃氏菌属; Bacteroides.拟杆菌属; Firmicutes.厚壁菌; Actinomycete. 放线菌; Lactobacillus.乳酸杆菌; Desulfotomacvlum.脱硫菌; Proteus.变形杆菌; Bifidobacterium.双歧杆菌; Lachnospira.毛螺菌属; Roseburia.罗氏菌属; Devosia.沃斯菌属; Enterococcus.肠球菌; Streptococcus.链球菌; klebsiella.克雷伯氏菌; Ruminococcus.瘤胃球菌; SCFAs.短链脂肪酸; TPO-Ab.甲状腺过氧化物酶抗体; Tg-Ab.甲状腺球蛋白抗体
Figure 1. Schematic representation of the association between gut microbiota and autoimmune diseases
表 1 中药活性成分调节肠道菌群治疗RA
Table 1. Modulation of gut microbiota by active ingredients in Chinese medicine for RA
中药 菌群变化 相应的指标变化 作用机制 人参皂苷Rg2[17] P. disasonis↑ ZO-1, Occludin↑, LPS↓, Th17↓, Treg↑ 促进P. disasonis的生长, 改变Th17/Treg细胞平衡, 中和致病性自身抗体和改善肠道通透性 朝鲜白术(Nakai)[22] Proteobacteria, Verrucomibia↓
调节Akkermansia、Allobaculum、Anaerovorax、Coriobacteriaceae_UCG-002、Lachnoclostridium、Ruminantium_group、Erysipelotricaceae和Muribaculaceae等菌群滑膜浸润和血管增殖减轻, TNF-α、IL-1、IL-1β、IL-2、IL-6、hs-CRP水平↓ 可能与下调炎症因子、改善肠道菌群和SCFAs平衡有关 棘球蚴总多糖和糖苷[23] Proteobacteria、Acidobacteria和Gemmatimonadetes↑, Tenericutes、Fusobacteria、Kiritimatiellaeota和Patescibacteria↓ 抑制关节炎, 血清中IL-1β和TNF-α↓ 可能是通过调节肠道菌群来调节代谢产物的产生 紫檀芪[24] Helicobacter、Desulfovibrio、Lachnospiraceae和Mucispirillium↓ MPO、IgG1、IgG2A、TNF-α、COX-2、NF-κB↓, IL-10↑ 通过降低炎症因子和介质的水平显著抑制炎症 鸡矢藤提取物[25] Desulfotomacvlum、Spirochaete、Mucilaginosa、Helicobacterpylori和Lachnospiraceae↓ TNF-α、IL-1β、IL-6、IL-7和IL-23↓ 直接抑制循环血液中促炎细胞因子和介质的产生 铁总线莲三萜皂苷[26] Firmicutes和Actinobacteria的G-细菌↓, G+细菌↑, 达到G-/G+比率平衡 总SCFAs↓ 可能通过平衡肠道微生物群和SCFAs代谢来缓解DMARDs的胃肠道损害副作用 当归四逆汤[27] g-Norank-f-Eubacterium-coprostanoligenes-group和g-Lactobacillus↓, g-Bacteroides↑ 滑膜浸润和血管增殖减轻, SCFAs↓ 通过影响肠道微生物群及其代谢物 
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表 2 中药活性成分调节肠道菌群治疗UC
Table 2. Modulation of gut microbiota by active ingredients in Chinese medicine for UC
中药成分 菌群变化 相应的指标变化 作用机制 白头翁皂苷[37] norank_F_Muribaculaceae和norank_F_norank_O_Clostridia_UCG-014↑, 有害拟杆菌↓ 结肠黏膜结构和病理炎症改善 可能与有益菌的显著增加以及有害菌的减少有关 柴胡皂苷-d[38] Lachnospiraceae、Ruminiclostridium_5、Mucispirillum、Ruminiclostridium_9、Ruminiclostridium、Oscillibacter、Blautia和Anaerotruncus↑, Ruminiclostridium-6↓ 结肠病理炎症改善, IL-10、ZO-1、Occludin、Claudin-1↑, IL-6、IL-8、IL-1β、TNF-α↓ 通过抑制NF-κB活化和调节小鼠肠道微生物群来改善葡聚糖硫酸钠诱导的结肠炎 地黄多糖[39] Firmicutes和Lactobacillus↑, Bacteroides↓ IL-10、ZO-1、Occludin、Claudin-1↑, IL-6、IL-1β、TNF-α↓, 抑制NF-κB通路 可能通过恢复紊乱的肠道微生物组和微生物群落代谢物来介导, 从而增强肠上皮屏障, 增强紧密连接蛋白的表达, 并通过NF-κB途径抑制促炎因子的过表达 雷公藤[40] Bacteroides和Lachnospiraceae↓ 结肠病理炎症减轻, IL-6、IL-17和TNF-α↓ 可能与通过改善肠道菌群结构, 恢复细菌多样性, 来调节肠道菌群有关 人参皂苷Rg1[41] Lachnospiraceae↑, Staphylococcus、Bacteroide和Ruminococcaceae_UCG_014↓ 结肠病理炎症改善, IL-4、IL-10↑, IL-6、IL-33、TNF-α、Rock1、RhoA和Nogo-B蛋白↓ 调节炎性细胞因子表达; 抑制巨噬细胞活化; 调节M1/M2巨噬细胞极化平衡并改善肠道菌群; 抑制结肠炎小Nogo-B/RhoA信号通路激活等 淫羊藿苷[42] Helicobacteraceae、Bacteroides和Tricibacter↓, Lachnospiraceae、Akkermansia和Lactobacillus↑ 结肠病理结构改善, 结肠长度延长, IL-6、TNF-α↓, 抑制NF-κB通路 通过调节p-p65/p65表达, 提高肠道菌群丰度和组成, 抑制组织损伤和炎症反应 黄芪素[43] Ruminiclostridium_9, Oscillibacter, Butyricicoccus, Ruminiclostridium, Ruminococcaceae_NK4A214_group, and Ruminococcaceae_UCG-009↑ ZO-1和Occludin↑, TNF-α、IL-1β、IL-6↓, 抑制NF-κB通路 抑制促炎细胞因子和NF-κB信号通路的活化, 改善肠道屏障功能和代谢内毒素血症, 并部分逆转UC小鼠肠道微生物群的改变 丹参酸A[44] Akkermansia、Bacillus、Blautia、Lachnoclostridium和Lactobacillus↑, Bacteroides、Roseburia和Ruminiclostridium↓ 结肠病理炎症改善, ZO-1、TGF-β↑, IL-1β、IL-6、MCP-1↓ 对炎症介质的调节, 利于肠道菌群的稳定, 通过选择性地促进益生菌的生长 雪积草苷[45] Helicobacter、Jeotgalicoccus和Staphylococcus↓ 结肠病理炎症改善, ZO-1、E-cadherin表达↑ 可能依赖于黏膜屏障和肠道微生物群稳态的恢复 苦豆子总碱[46] Desulfovibrio、Corynebacterium和Adlercreutzia↑, Mucispirillum和Butyricimonas↓ IL-1β、TGF-β1、血清TBA、T-CHO↓，IL-10↑ 减轻结肠损伤, 调节肠道微生物群的平衡和胆汁酸代谢
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表 3 中药活性成分调节肠道菌群治疗AIT
Table 3. Modulation of gut microbiota by active ingredients in Chinese medicine for AIT
中药成分 菌群变化 相应的指标变化 作用机制 芪箭消瘿方[52] Lactobacillus↑(中、低剂量)Prevotellaceae↓(中、高剂量) sIgA、ZO-1和Occludin↑ 可能与调节肠道菌群生物多样性及物种组成有关, 进而增加结肠紧密连接蛋白及sIgA表达 软坚消瘿颗粒[53] Firmicutes、Clostridium、Clostridiales、Ruminococcaceae和Prevotella↓, Proteobacteria、Moraxoniaceae、Alphaproteobacteria、Escherichia和Myroides↑ TGAb和TPoAb↓, TSH↑ 影响代谢产物和代谢通路, 调节肠道菌群有关 白芍总苷[54] Lactobacillus、Prevotellaceae和Romboutsia↑ 甲状腺病变程度减轻, TG-Ab、TPO-Ab和TNF-α↓, IL-10、sIgA、ZO-1和Occludin蛋白↑ 可能通过调节肠道菌群组成及多样性, 改善肠黏膜屏障损伤从而发挥治疗AIT的作用 益气化痰活血方[55] Firmicutes和F/B↓, Bacteroidetes和Actinobacteria↑ 血清TG-Ab↓，减轻甲状腺淋巴细胞炎症浸润程度 可能与改变肠道菌群的结构及组成有关
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