中医药干预类风湿关节炎的“肠–关节轴” 机制：聚焦肠道微生物及其代谢物
The “Gut-Joint Axis” Mechanism of Traditional Chinese Medicine in the Treatment of Rheumatoid Arthritis: Focusing on Intestinal Microorganisms and Their Metabolites
摘要: 类风湿关节炎(rheumatoid arthritis, RA)是一类以慢性滑膜炎、进行性骨破坏和多系统受累为特征的免疫介导性疾病，现有NSAIDs、糖皮质激素、抗风湿药(disease-modifying antirheumatic drugs, DMARDs)及生物制剂/靶向小分子虽可控制炎症，但长期用药仍面临感染风险、器官毒性与经济负担等问题。近年来，“肠–关节轴”理论推动RA发病机制由“关节局部炎症”拓展至“黏膜免疫–微生态–代谢物–系统性免疫重塑”的整体网络，RA患者肠道菌群结构及功能异常与Th17/Treg失衡、屏障破坏、分子模拟及促炎代谢物谱改变密切相关；而疾病控制后菌群可出现部分回归，提示微生态具有可干预性。中医药在“多成分–多靶点–多通路”方面具备优势，既可直接调控炎症因子网络与免疫细胞谱，也可通过重塑肠道微生物组成、影响短链脂肪酸(Short-chain fatty acid, SCFAs)、胆汁酸与吲哚类代谢物等关键介质，进而改善黏膜屏障与系统免疫稳态。该文综述了RA相关肠道微生态异常的病理意义，并系统归纳中药单体、复方及中成药通过微生态介导发挥作用的关键药理机制。
Abstract: Rheumatoid arthritis (RA) is an immune-mediated disease characterized by chronic synovitis, progressive bone destruction, and multi-system involvement. Currently, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, anti-rheumatic drugs (disease-modifying antirheumatic drugs, DMARDs), and biological agents/targeted small molecules can control inflammation, but long-term use still faces issues such as infection risks, organ toxicity, and economic burden. In recent years, the “gut-joint axis” theory has promoted the expansion of the pathogenesis of RA from “local joint inflammation” to “mucosal immunity, microecology, metabolites, systemic immune remodeling” as an integrated network. The abnormal structure and function of the intestinal microbiota in RA patients are closely related to Th17/Treg imbalance, barrier disruption, molecular mimicry, and changes in pro-inflammatory metabolite spectra; and the microbiota can partially return after disease control, suggesting that the microecology is controllable. Traditional Chinese medicine has advantages in “multi-component, multi-target, multi-pathway”, which can directly regulate the inflammatory factor network and immune cell spectrum, and also affect the composition of intestinal microorganisms, influence short-chain fatty acids (SCFAs), bile acids, and indole metabolites, thereby improving the mucosal barrier and systemic immune homeostasis. This article reviews the pathological significance of intestinal microecological abnormalities in RA and systematically summarizes the key pharmacological mechanisms by which traditional Chinese medicine monomers, combinations, and patent medicines exert effects through microecology mediation.
文章引用：叶静利, 杜晓明, 段学庆, 陈福, 李荣光, 王海亮. 中医药干预类风湿关节炎的“肠–关节轴” 机制：聚焦肠道微生物及其代谢物[J]. 临床医学进展, 2026, 16(2): 3252-3262. https://doi.org/10.12677/acm.2026.162738

参考文献

[1] Figus, F.A., Piga, M., Azzolin, I., McConnell, R. and Iagnocco, A. (2021) Rheumatoid Arthritis: Extra-Articular Manifestations and Comorbidities. Autoimmunity Reviews, 20, Article ID: 102776. [Google Scholar] [CrossRef] [PubMed]
[2] Di Matteo, A., Bathon, J.M. and Emery, P. (2023) Rheumatoid Arthritis. The Lancet, 402, 2019-2033. [Google Scholar] [CrossRef] [PubMed]
[3] Zhang, X., Zhang, D., Jia, H., Feng, Q., Wang, D., Liang, D., et al. (2015) The Oral and Gut Microbiomes Are Perturbed in Rheumatoid Arthritis and Partly Normalized after Treatment. Nature Medicine, 21, 895-905. [Google Scholar] [CrossRef] [PubMed]
[4] Xu, X., Wang, M., Wang, Z., Chen, Q., Chen, X., Xu, Y., et al. (2022) The Bridge of the Gut-Joint Axis: Gut Microbial Metabolites in Rheumatoid Arthritis. Frontiers in Immunology, 13, Article ID: 1007610. [Google Scholar] [CrossRef] [PubMed]
[5] Winthrop, K.L. (2017) Erratum: The Emerging Safety Profile of JAK Inhibitors in Rheumatic Disease. Nature Reviews Rheumatology, 13, Article No. 320. [Google Scholar] [CrossRef] [PubMed]
[6] Hsieh, P., Wu, O., Geue, C., McIntosh, E., McInnes, I.B. and Siebert, S. (2020) Economic Burden of Rheumatoid Arthritis: A Systematic Review of Literature in Biologic Era. Annals of the Rheumatic Diseases, 79, 771-777. [Google Scholar] [CrossRef] [PubMed]
[7] Wang, Y., Chen, S., Du, K., Liang, C., Wang, S., Owusu Boadi, E., et al. (2021) Traditional Herbal Medicine: Therapeutic Potential in Rheumatoid Arthritis. Journal of Ethnopharmacology, 279, Article ID: 114368. [Google Scholar] [CrossRef] [PubMed]
[8] Wang, Q., Zhang, S., Chang, M., Qiao, J., Wang, C., Li, X., et al. (2022) Characteristics of the Gut Microbiome and Its Relationship with Peripheral CD4+ T Cell Subpopulations and Cytokines in Rheumatoid Arthritis. Frontiers in Microbiology, 13, Article ID: 799602. [Google Scholar] [CrossRef] [PubMed]
[9] Abdollahi-Roodsaz, S., Joosten, L.A.B., Koenders, M.I., Devesa, I., Roelofs, M.F., Radstake, T.R.D.J., et al. (2008) Stimulation of TLR2 and TLR4 Differentially Skews the Balance of T Cells in a Mouse Model of Arthritis. Journal of Clinical Investigation, 118, 205-216. [Google Scholar] [CrossRef] [PubMed]
[10] Maeda, Y., Kurakawa, T., Umemoto, E., Motooka, D., Ito, Y., Gotoh, K., et al. (2016) Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine. Arthritis & Rheumatology, 68, 2646-2661. [Google Scholar] [CrossRef] [PubMed]
[11] Zhao, T., Wei, Y., Zhu, Y., Xie, Z., Hai, Q., Li, Z., et al. (2022) Gut Microbiota and Rheumatoid Arthritis: From Pathogenesis to Novel Therapeutic Opportunities. Frontiers in Immunology, 13, Article ID: 1007165. [Google Scholar] [CrossRef] [PubMed]
[12] Majumdar, A., Siva Venkatesh, I.P. and Basu, A. (2023) Short-Chain Fatty Acids in the Microbiota-gut-brain Axis: Role in Neurodegenerative Disorders and Viral Infections. ACS Chemical Neuroscience, 14, 1045-1062. [Google Scholar] [CrossRef] [PubMed]
[13] Park, J., Kim, M., Kang, S.G., Jannasch, A.H., Cooper, B., Patterson, J., et al. (2015) Short-Chain Fatty Acids Induce Both Effector and Regulatory T Cells by Suppression of Histone Deacetylases and Regulation of the mTOR-S6K Pathway. Mucosal Immunology, 8, 80-93. [Google Scholar] [CrossRef] [PubMed]
[14] Lin, Y., Anzaghe, M. and Schülke, S. (2020) Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis. Cells, 9, Article No. 880. [Google Scholar] [CrossRef] [PubMed]
[15] Xu, Q., Bauer, R., Hendry, B.M., Fan, T., Zhao, Z., Duez, P., et al. (2013) The Quest for Modernisation of Traditional Chinese Medicine. BMC Complementary and Alternative Medicine, 13, Article No. 132. [Google Scholar] [CrossRef] [PubMed]
[16] Liu, W., Zhang, Y., Zhu, W., Ma, C., Ruan, J., Long, H., et al. (2018) Sinomenine Inhibits the Progression of Rheumatoid Arthritis by Regulating the Secretion of Inflammatory Cytokines and Monocyte/Macrophage Subsets. Frontiers in Immunology, 9, Article No. 2228. [Google Scholar] [CrossRef] [PubMed]
[17] Shan, J., Peng, L., Qian, W., Xie, T., Kang, A., Gao, B., et al. (2018) Integrated Serum and Fecal Metabolomics Study of Collagen-Induced Arthritis Rats and the Therapeutic Effects of the Zushima Tablet. Frontiers in Pharmacology, 9, Article No. 891. [Google Scholar] [CrossRef] [PubMed]
[18] Mei, L., Yang, Z., Zhang, X., Liu, Z., Wang, M., Wu, X., et al. (2021) Sustained Drug Treatment Alters the Gut Microbiota in Rheumatoid Arthritis. Frontiers in Immunology, 12, Article ID: 704089. [Google Scholar] [CrossRef] [PubMed]
[19] Lv, Q., Zhang, W., Shi, Q., Zheng, W., Li, X., Chen, H., et al. (2015) Comparison of Tripterygium wilfordii Hook F with Methotrexate in the Treatment of Active Rheumatoid Arthritis (TRIFRA): A Randomised, Controlled Clinical Trial. Annals of the Rheumatic Diseases, 74, 1078-1086. [Google Scholar] [CrossRef] [PubMed]
[20] Feng, W., Liu, J., Cheng, H. and Peng, C. (2021) Integration of Gut Microbiota and Metabolomics for Chinese Medicine Research: Opportunities and Challenges. Chinese Journal of Integrative Medicine, 28, 1032-1039. [Google Scholar] [CrossRef] [PubMed]
[21] Zhang, M., Peng, C. and Li, X. (2015) In Vivo and in Vitro Metabolites from the Main Diester and Monoester Diterpenoid Alkaloids in a Traditional Chinese Herb, the Aconitum Species. Evidence-Based Complementary and Alternative Medicine, 2015, Article ID: 252434. [Google Scholar] [CrossRef] [PubMed]
[22] Che, Q., Luo, T., Shi, J., He, Y. and Xu, D. (2022) Mechanisms by Which Traditional Chinese Medicines Influence the Intestinal Flora and Intestinal Barrier. Frontiers in Cellular and Infection Microbiology, 12, Article ID: 863779. [Google Scholar] [CrossRef] [PubMed]
[23] Yue, M., Tao, Y., Fang, Y., Lian, X., Zhang, Q., Xia, Y., et al. (2019) The Gut Microbiota Modulator Berberine Ameliorates Collagen‐Induced Arthritis in Rats by Facilitating the Generation of Butyrate and Adjusting the Intestinal Hypoxia and Nitrate Supply. The FASEB Journal, 33, 12311-12323. [Google Scholar] [CrossRef] [PubMed]
[24] Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., et al. (2013) Metabolites Produced by Commensal Bacteria Promote Peripheral Regulatory T-Cell Generation. Nature, 504, 451-455. [Google Scholar] [CrossRef] [PubMed]
[25] Jiang, Z., Zeng, S., Huang, T., Lin, Y., Wang, F., Gao, X., et al. (2023) Sinomenine Ameliorates Rheumatoid Arthritis by Modulating Tryptophan Metabolism and Activating Aryl Hydrocarbon Receptor via Gut Microbiota Regulation. Science Bulletin, 68, 1540-1555. [Google Scholar] [CrossRef] [PubMed]
[26] Liu, Y., Liu, L., Luo, J. and Peng, X. (2023) Metabolites from Specific Intestinal Bacteria in Vivo Fermenting Lycium barbarum Polysaccharide Improve Collagenous Arthritis in Rats. International Journal of Biological Macromolecules, 226, 1455-1467. [Google Scholar] [CrossRef] [PubMed]
[27] Chan, T.Y.K. (2009) Aconite Poisoning. Clinical Toxicology, 47, 279-285. [Google Scholar] [CrossRef] [PubMed]
[28] Peng, A.H., Chen, Y.J., Gu, J.X., et al. (2025) Research Advance on the Role of Gut Microbiota and Its Metabolites in Juvenile Idiopathic Arthritis. Acta Physiologica Sinica, 77, 587-601.
[29] Furusawa, Y., Obata, Y., Fukuda, S., Endo, T.A., Nakato, G., Takahashi, D., et al. (2013) Commensal Microbe-Derived Butyrate Induces the Differentiation of Colonic Regulatory T Cells. Nature, 504, 446-450. [Google Scholar] [CrossRef] [PubMed]
[30] Zelante, T., Iannitti, R.G., Cunha, C., De Luca, A., Giovannini, G., Pieraccini, G., et al. (2013) Tryptophan Catabolites from Microbiota Engage Aryl Hydrocarbon Receptor and Balance Mucosal Reactivity via Interleukin-22. Immunity, 39, 372-385. [Google Scholar] [CrossRef] [PubMed]
[31] Pang, J., Ma, S., Xu, X., Zhang, B. and Cai, Q. (2021) Effects of Rhizome of Atractylodes koreana (Nakai) Kitam on Intestinal Flora and Metabolites in Rats with Rheumatoid Arthritis. Journal of Ethnopharmacology, 281, Article ID: 114026. [Google Scholar] [CrossRef] [PubMed]
[32] Peng, J., Lu, X., Xie, K., Xu, Y., He, R., Guo, L., et al. (2019) Dynamic Alterations in the Gut Microbiota of Collagen-Induced Arthritis Rats Following the Prolonged Administration of Total Glucosides of Paeony. Frontiers in Cellular and Infection Microbiology, 9, Article No. 204. [Google Scholar] [CrossRef] [PubMed]
[33] Hu, Q., Wu, C., Yu, J., Luo, J. and Peng, X. (2022) Angelica sinensis Polysaccharide Improves Rheumatoid Arthritis by Modifying the Expression of Intestinal Cldn5, Slit3 and Rgs18 through Gut Microbiota. International Journal of Biological Macromolecules, 209, 153-161. [Google Scholar] [CrossRef] [PubMed]
[34] Zhou, Y., Zhao, L., Chen, H., Zhang, Y., Wang, D., Huang, L., et al. (2018) Comparison of the Impact of Tripterygium wilfordii Hook F and Methotrexate Treatment on Radiological Progression in Active Rheumatoid Arthritis: 2-Year Follow up of a Randomized, Non-Blinded, Controlled Study. Arthritis Research & Therapy, 20, Article No. 70. [Google Scholar] [CrossRef] [PubMed]
[35] Lai, W., Wang, C., Lai, R., Peng, X. and Luo, J. (2022) Lycium barbarum Polysaccharide Modulates Gut Microbiota to Alleviate Rheumatoid Arthritis in a Rat Model. NPJ Science of Food, 6, Article No. 34. [Google Scholar] [CrossRef] [PubMed]
[36] Cheng, X., Pi, Z., Zheng, Z., Liu, S., Song, F. and Liu, Z. (2022) Combined 16S rRNA Gene Sequencing and Metabolomics to Investigate the Protective Effects of Wu-Tou Decoction on Rheumatoid Arthritis in Rats. Journal of Chromatography B, 1199, Article ID: 123249. [Google Scholar] [CrossRef] [PubMed]
[37] Carmody, R.N., Gerber, G.K., Luevano, J.M., Gatti, D.M., Somes, L., Svenson, K.L., et al. (2015) Diet Dominates Host Genotype in Shaping the Murine Gut Microbiota. Cell Host & Microbe, 17, 72-84. [Google Scholar] [CrossRef] [PubMed]
[38] Shaffer, J.P., Carpenter, C.S., Martino, C., Salido, R.A., Minich, J.J., Bryant, M., et al. (2022) A Comparison of Six DNA Extraction Protocols for 16S, ITS and Shotgun Metagenomic Sequencing of Microbial Communities. BioTechniques, 73, 34-46. [Google Scholar] [CrossRef] [PubMed]
[39] McLaren, M.R., Willis, A.D. and Callahan, B.J. (2019) Consistent and Correctable Bias in Metagenomic Sequencing Experiments. eLife, 8, e46923. [Google Scholar] [CrossRef] [PubMed]
[40] Knight, R., Vrbanac, A., Taylor, B.C., Aksenov, A., Callewaert, C., Debelius, J., et al. (2018) Best Practices for Analysing Microbiomes. Nature Reviews Microbiology, 16, 410-422. [Google Scholar] [CrossRef] [PubMed]
[41] Quince, C., Walker, A.W., Simpson, J.T., Loman, N.J. and Segata, N. (2017) Shotgun Metagenomics, from Sampling to Analysis. Nature Biotechnology, 35, 833-844. [Google Scholar] [CrossRef] [PubMed]
[42] Scher, J.U., Sczesnak, A., Longman, R.S., Segata, N., Ubeda, C., Bielski, C., et al. (2013) Expansion of Intestinal Prevotella copri Correlates with Enhanced Susceptibility to Arthritis. eLife, 2, e01202. [Google Scholar] [CrossRef] [PubMed]

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