中药大黄通过调节肠道菌群–代谢物–炎症轴改善胰岛素抵抗相关慢性病的研究进展
Research Progress on the Improvement of Insulin Resistance-Related Chronic Diseases by Rhubarb (Rheum palmatum L.) through Regulation of the Gut Microbiota-Metabolite-Inflammation Axis
摘要: 背景：胰岛素抵抗(IR)是2型糖尿病(T2DM)、非酒精性脂肪肝(NAFLD)等慢性病的核心病理机制，与肠道菌群失调和系统性炎症密切相关。中药大黄及其活性成分(如大黄素、大黄酸)展现出通过调控肠道菌群结构、抑制炎症信号通路(如JNK/NF-κB)和改善代谢紊乱的多重作用。方法：本文系统综述了大黄有效成分对IR相关信号通路(MAPK, PI3K/Akt, AMPK, PPAR)、氧化应激、内质网应激及铁死亡的调控机制，并探讨其通过重塑肠道菌群(如增加阿克曼氏菌、拟杆菌门)和代谢产物(短链脂肪酸)改善IR的潜在路径。结果：大黄中的蒽醌类成分通过以下途径发挥作用：(1) 抑制JNK/IKK介导的IRS-1丝氨酸磷酸化，恢复胰岛素信号传导；(2) 激活AMPK/Nrf2通路缓解氧化应激；(3) 调节PPARγ/NF-κB轴减轻炎症；(4) 通过增加Akkermansia muciniphila丰度增强肠道屏障功能，减少内毒素入血。结论：大黄通过“肠道菌群–代谢物–器官轴”多靶点干预IR相关慢性病，其纳米化改造(如碳量子点修饰)可进一步提高生物利用度和靶向性，为开发新型抗IR药物提供理论依据。
Abstract: Background: Insulin resistance (IR) is a core pathological mechanism of chronic diseases such as type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), closely associated with gut microbiota dysbiosis and systemic inflammation. The traditional Chinese herb Rheum palmatum (rhubarb) and its active components (e.g., emodin, rhein) exhibit multi-target effects by modulating gut microbiota composition, inhibiting inflammatory signaling pathways (e.g., JNK/NF-κB), and improving metabolic disorders. Methods: This review systematically summarizes the regulatory mechanisms of rhubarb’s active components on IR-related pathways (MAPK, PI3K/Akt, AMPK, PPAR), oxidative stress, endoplasmic reticulum stress, and ferroptosis, while exploring their potential to ameliorate IR by reshaping gut microbiota (e.g., increasing Akkermansia muciniphila and Bacteroidetes) and metabolites (e.g., short-chain fatty acids). Results: Anthraquinones in rhubarb exert therapeutic effects via: (1) inhibiting JNK/IKK-mediated serine phosphorylation of IRS-1 to restore insulin signaling; (2) activating AMPK/Nrf2 pathway to alleviate oxidative stress; (3) modulating PPARγ/NF-κB axis to reduce inflammation; and (4) enhancing gut barrier function by enriching Akkermansia muciniphila, thereby decreasing endotoxin translocation. Conclusion: Rhubarb intervenes in IR-related diseases through the “gut microbiota-metabolite-organ axis.” Nanomodification (e.g., carbon quantum dots) may further improve its bioavailability and targeting efficacy, providing a theoretical basis for developing novel anti-IR therapeutics.
文章引用：陆昕扬, 吴亮. 中药大黄通过调节肠道菌群–代谢物–炎症轴改善胰岛素抵抗相关慢性病的研究进展[J]. 临床医学进展, 2025, 15(10): 99-108. https://doi.org/10.12677/acm.2025.15102732

参考文献

[1] Jarmakiewicz-Czaja, S., Sokal, A. and Filip, R. (2020) What Was First, Obesity or Inflammatory Bowel Disease? What Does the Gut Microbiota Have to Do with It? Nutrients, 12, Article 3073. [Google Scholar] [CrossRef] [PubMed]
[2] Liu, S., Yin, R., Yang, Z., Wei, F. and Hu, J. (2022) The Effects of Rhein on D-GalN/LPS-Induced Acute Liver Injury in Mice: Results from Gut Microbiome-Metabolomics and Host Transcriptome Analysis. Frontiers in Immunology, 13, Article 971409. [Google Scholar] [CrossRef] [PubMed]
[3] Wang, L., Yu, X., Li, H., He, D., Zeng, S. and Xiang, Z. (2023) Cell and Rat Serum, Urine and Tissue Metabolomics Analysis Elucidates the Key Pathway Changes Associated with Chronic Nephropathy and Reveals the Mechanism of Action of Rhein. Chinese Medicine, 18, Article No. 158. [Google Scholar] [CrossRef] [PubMed]
[4] Zhou, Y., Gao, C., Vong, C.T., Tao, H., Li, H., Wang, S., et al. (2022) Rhein Regulates Redox-Mediated Activation of NLRP3 Inflammasomes in Intestinal Inflammation through Macrophage-Activated Crosstalk. British Journal of Pharmacology, 179, 1978-1997. [Google Scholar] [CrossRef] [PubMed]
[5] Wen, Q., Miao, J., Lau, N., Zhang, C., Ye, P., Du, S., et al. (2020) Rhein Attenuates Lipopolysaccharide-Primed Inflammation through NF-κB Inhibition in RAW264.7 Cells: Targeting the PPAR-γ Signal Pathway. Canadian Journal of Physiology and Pharmacology, 98, 357-365. [Google Scholar] [CrossRef] [PubMed]
[6] Sheng, X., Zhu, X., Zhang, Y., Cui, G., Peng, L., Lu, X., et al. (2012) Rhein Protects against Obesity and Related Metabolic Disorders through Liver X Receptor-Mediated Uncoupling Protein 1 Upregulation in Brown Adipose Tissue. International Journal of Biological Sciences, 8, 1375-1384. [Google Scholar] [CrossRef] [PubMed]
[7] Fang, J.Y., Huang, T.H., Chen, W.J., et al. (2022) Rhubarb Hydroxyanthraquinones Act as Antiobesity Agents to Inhibit Adipogenesis and Enhance Lipolysis. Biomedicine & Pharmacotherapy, 146, Article 112497. [Google Scholar] [CrossRef] [PubMed]
[8] Ji, L. and Gu, H. (2021) The Anti-Obesity Effects of Rhein on Improving Insulin Resistance (IR) and Blood Lipid Levels Are Involved in Endoplasmic Reticulum Stress (ERs), Inflammation, and Oxidative Stress in Vivo and Vitro. Bioengineered, 12, 5797-5813. [Google Scholar] [CrossRef] [PubMed]
[9] Mabwi, H.A., Lee, H.J., Hitayezu, E., Mauliasari, I.R., Pan, C., Mwaikono, K.S., et al. (2023) Emodin Modulates Gut Microbial Community and Triggers Intestinal Immunity. Journal of the Science of Food and Agriculture, 103, 1273-1282. [Google Scholar] [CrossRef] [PubMed]
[10] Otoo, A., Czika, A., Lamptey, J., et al. (2023) Emodin Improves Glucose Metabolism and Ovarian Function in PCOS Mice via the HMGB1/TLR4/NF-κB Molecular Pathway. Reproduction, 166, 323-336. [Google Scholar] [CrossRef] [PubMed]
[11] Li, J., Ding, L., Song, B., Xiao, X., Qi, M., Yang, Q., et al. (2016) Emodin Improves Lipid and Glucose Metabolism in High Fat Diet-Induced Obese Mice through Regulating SREBP Pathway. European Journal of Pharmacology, 770, 99-109. [Google Scholar] [CrossRef] [PubMed]
[12] Shen, C., Pan, Z., Wu, S., Zheng, M., Zhong, C., Xin, X., et al. (2021) Emodin Palliates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice via Activating the Farnesoid X Receptor Pathway. Journal of Ethnopharmacology, 279, Article 114340. [Google Scholar] [CrossRef] [PubMed]
[13] Lee, M.S. and Sohn, C.B. (2008) Anti-Diabetic Properties of Chrysophanol and Its Glucoside from Rhubarb Rhizome. Biological and Pharmaceutical Bulletin, 31, 2154-2157. [Google Scholar] [CrossRef] [PubMed]
[14] Kim, S.J., Kim, M.C., Lee, B.J., et al. (2010) Anti-Inflammatory Activity of Chrysophanol through the Suppression of NF-KappaB/Caspase-1 Activation in Vitro and in Vivo. Molecules, 15, 6436-6451. [Google Scholar] [CrossRef] [PubMed]
[15] Gu, M., Zhou, Y., Liao, N., Wei, Q., Bai, Z., Bao, N., et al. (2022) Chrysophanol, a Main Anthraquinone from Rheum palmatum L. (rhubarb), Protects against Renal Fibrosis by Suppressing NKD2/NF-κB Pathway. Phytomedicine, 105, Article 154381. [Google Scholar] [CrossRef] [PubMed]
[16] Chu, X., Zhou, S., Sun, R., Wang, L., Xing, C., Liang, R., et al. (2018) Chrysophanol Relieves Cognition Deficits and Neuronal Loss through Inhibition of Inflammation in Diabetic Mice. Neurochemical Research, 43, 972-983. [Google Scholar] [CrossRef] [PubMed]
[17] Wang, Y.H., Liu, Y.P., Zhu, J.Q., et al. (2023) Physcion Prevents High-Fat Diet-Induced Endothelial Dysfunction by Inhibiting Oxidative Stress and Endoplasmic Reticulum Stress Pathways. European Journal of Pharmacology, 943, Article 175554. [Google Scholar] [CrossRef] [PubMed]
[18] Li, J., Zhu, Y., Xu, M., et al. (2023) Physcion Prevents Induction of Optic Nerve Injury in Rats via Inhibition of the JAK2/STAT3 Pathway. Experimental and Therapeutic Medicine, 26, Article 381.
[19] Ahmad, S., Choe, K., Badshah, H., Ahmad, R., Ali, W., Rehman, I.U., et al. (2024) Physcion Mitigates LPS-Induced Neuroinflammation, Oxidative Stress, and Memory Impairments via TLR-4/NF-κB Signaling in Adult Mice. Pharmaceuticals, 17, Article 1199. [Google Scholar] [CrossRef] [PubMed]
[20] Khuda, F., Zahir, I., Khalil, A.A.K., Ali, S., Ullah, N., Albariqi, A.H., et al. (2023) Preparation, Characterization, and Evaluation of Physcion Nanoparticles for Enhanced Oral Bioavailability: An Attempt to Improve Its Antioxidant and Anticancer Potential. ACS Omega, 8, 33955-33965. [Google Scholar] [CrossRef] [PubMed]
[21] Zhang, L., Dong, R., Wang, Y., Wang, L., Zhou, T., Jia, D., et al. (2021) The Anti-Breast Cancer Property of Physcion via Oxidative Stress-Mediated Mitochondrial Apoptosis and Immune Response. Pharmaceutical Biology, 59, 301-308. [Google Scholar] [CrossRef] [PubMed]
[22] Liu, J., Yang, Y., Zeng, Y., Qin, X., Guo, L. and Liu, W. (2023) Exploring the Mechanism of Physcion-1-O-β-D-Monoglucoside against Acute Lymphoblastic Leukaemia Based on Network Pharmacology and Experimental Validation. Heliyon, 9, e14009. [Google Scholar] [CrossRef] [PubMed]
[23] Chen, C., Gu, J., Wang, J., Wu, Y., Yang, A., Chen, T., et al. (2021) Physcion 8-O-β-Glucopyranoside Ameliorates Liver Fibrosis through Inflammation Inhibition by Regulating SIRT3-Mediated NF-κB P65 Nuclear Expression. International Immunopharmacology, 90, Article 107206. [Google Scholar] [CrossRef] [PubMed]
[24] He, Y., Xi, J., Fang, J., Zhang, B. and Cai, W. (2023) Aloe-Emodin Alleviates Doxorubicin-Induced Cardiotoxicity via Inhibition of Ferroptosis. Free Radical Biology and Medicine, 206, 13-21. [Google Scholar] [CrossRef] [PubMed]
[25] Alshatwi, A.A. and Subash-Babu, P. (2016) Aloe-Emodin Protects RIN-5F (Pancreatic β-Cell) Cell from Glucotoxicity via Regulation of Pro-Inflammatory Cytokine and Downregulation of Bax and Caspase 3. Biomolecules & Therapeutics, 24, 49-56. [Google Scholar] [CrossRef] [PubMed]
[26] Xian, M., Cai, J., Zheng, K., et al. (2021) Aloe-Emodin Prevents Nerve Injury and Neuroinflammation Caused by Ischemic Stroke via the PI3K/AKT/mTOR and NF-κB Pathway. Food & Function, 12, 8056-8067. [Google Scholar] [CrossRef] [PubMed]
[27] Li, X., Yao, M., Li, L., Ma, H., Sun, Y., Lu, X., et al. (2024) Aloe-Emodin Alleviates Cerebral Ischemia-Reperfusion Injury by Regulating Microglial Polarization and Pyroptosis through Inhibition of NLRP3 Inflammasome Activation. Phytomedicine, 129, Article 155578. [Google Scholar] [CrossRef] [PubMed]
[28] Martin-Gallausiaux, C., Marinelli, L., Blottière, H.M., Larraufie, P. and Lapaque, N. (2020) SCFA: Mechanisms and Functional Importance in the Gut. Proceedings of the Nutrition Society, 80, 37-49. [Google Scholar] [CrossRef] [PubMed]
[29] Ji, C., Lu, F., Wu, Y., Lu, Z., Mo, Y., Han, L., et al. (2022) Rhubarb Enema Increasing Short-Chain Fatty Acids That Improves the Intestinal Barrier Disruption in CKD May Be Related to the Regulation of Gut Dysbiosis. BioMed Research International, 2022, Article 1896781. [Google Scholar] [CrossRef] [PubMed]
[30] Zhou, J., Yang, Q., Wei, W., Huo, J. and Wang, W. (2025) Codonopsis pilosula Polysaccharide Alleviates Ulcerative Colitis by Modulating Gut Microbiota and SCFA/GPR/NLRP3 Pathway. Journal of Ethnopharmacology, 337, Article 118928. [Google Scholar] [CrossRef] [PubMed]
[31] Ji, C., Deng, Y., Yang, A., Lu, Z., Chen, Y., Liu, X., et al. (2020) Rhubarb Enema Improved Colon Mucosal Barrier Injury in 5/6 Nephrectomy Rats May Associate with Gut Microbiota Modification. Frontiers in Pharmacology, 11, Article 1092. [Google Scholar] [CrossRef] [PubMed]
[32] Pham, N.H.T., Joglekar, M.V., Wong, W.K.M., Nassif, N.T., Simpson, A.M. and Hardikar, A.A. (2024) Short-Chain Fatty Acids and Insulin Sensitivity: A Systematic Review and Meta-Analysis. Nutrition Reviews, 82, 193-209. [Google Scholar] [CrossRef] [PubMed]
[33] Yang, W., Yu, T., Huang, X., Bilotta, A.J., Xu, L., Lu, Y., et al. (2020) Intestinal Microbiota-Derived Short-Chain Fatty Acids Regulation of Immune Cell IL-22 Production and Gut Immunity. Nature Communications, 11, Article No. 4457. [Google Scholar] [CrossRef] [PubMed]
[34] Singh, N., Gurav, A., Sivaprakasam, S., Brady, E., Padia, R., Shi, H., et al. (2014) Activation of Gpr109a, Receptor for Niacin and the Commensal Metabolite Butyrate, Suppresses Colonic Inflammation and Carcinogenesis. Immunity, 40, 128-139. [Google Scholar] [CrossRef] [PubMed]
[35] Kim, M.H., Kang, S.G., Park, J.H., Yanagisawa, M. and Kim, C.H. (2013) Short-Chain Fatty Acids Activate GPR41 and GPR43 on Intestinal Epithelial Cells to Promote Inflammatory Responses in Mice. Gastroenterology, 145, 396-406.e10. [Google Scholar] [CrossRef] [PubMed]
[36] Tan, J., Ribeiro, R.V., Barker, C., Daien, C., De Abreu Silveira, E., Holmes, A., et al. (2023) Functional Profiling of Gut Microbial and Immune Responses toward Different Types of Dietary Fiber: A Step toward Personalized Dietary Interventions. Gut Microbes, 15, Article 2274127. [Google Scholar] [CrossRef] [PubMed]
[37] Ji, C., Li, Y., Mo, Y., Lu, Z., Lu, F., Lin, Q., et al. (2021) Rhubarb Enema Decreases Circulating Trimethylamine N-Oxide Level and Improves Renal Fibrosis Accompanied with Gut Microbiota Change in Chronic Kidney Disease Rats. Frontiers in Pharmacology, 12, Article 780924. [Google Scholar] [CrossRef] [PubMed]
[38] Chen, S., Henderson, A., Petriello, M.C., Romano, K.A., Gearing, M., Miao, J., et al. (2019) Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell Metabolism, 30, 1141-1151.e5. [Google Scholar] [CrossRef] [PubMed]
[39] Miao, J., Ling, A.V., Manthena, P.V., Gearing, M.E., Graham, M.J., Crooke, R.M., et al. (2015) Flavin-Containing Monooxygenase 3 as a Potential Player in Diabetes-Associated Atherosclerosis. Nature Communications, 6, Article No. 6498. [Google Scholar] [CrossRef] [PubMed]
[40] Benson, T.W., Conrad, K.A., Li, X.S., Wang, Z., Helsley, R.N., Schugar, R.C., et al. (2023) Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm through Inflammatory and Apoptotic Mechanisms. Circulation, 147, 1079-1096. [Google Scholar] [CrossRef] [PubMed]
[41] Hai, S., Li, X., Xie, E., Wu, W., Gao, Q., Yu, B., et al. (2025) Intestinal IL-33 Promotes Microbiota-Derived Trimethylamine N-Oxide Synthesis and Drives Metabolic Dysfunction-Associated Steatotic Liver Disease Progression by Exerting Dual Regulation on Hif-1α. Hepatology, 82, 184-198. [Google Scholar] [CrossRef] [PubMed]
[42] Nian, F., Chen, Y., Xia, Q., Zhu, C., Wu, L. and Lu, X. (2024) Gut Microbiota Metabolite Trimethylamine N-Oxide Promoted NAFLD Progression by Exacerbating Intestinal Barrier Disruption and Intrahepatic Cellular Imbalance. International Immunopharmacology, 142, Article 113173. [Google Scholar] [CrossRef] [PubMed]
[43] Lu, Z., Zeng, Y., Lu, F., Liu, X. and Zou, C. (2015) Rhubarb Enema Attenuates Renal Tubulointerstitial Fibrosis in 5/6 Nephrectomized Rats by Alleviating Indoxyl Sulfate Overload. PLOS ONE, 10, e0144726. [Google Scholar] [CrossRef] [PubMed]
[44] Adeva, M.M., Calviño, J., Souto, G. and Donapetry, C. (2012) Insulin Resistance and the Metabolism of Branched-Chain Amino Acids in Humans. Amino Acids, 43, 171-181. [Google Scholar] [CrossRef] [PubMed]
[45] Zhu, T., Zhang, W., Feng, S. and Yu, H. (2016) Emodin Suppresses LPS-Induced Inflammation in RAW264.7 Cells through a PPARγ-Dependent Pathway. International Immunopharmacology, 34, 16-24. [Google Scholar] [CrossRef] [PubMed]
[46] Du, W., Jiang, S., Yin, S., et al. (2024) The Microbiota-Dependent Tryptophan Metabolite Alleviates High-Fat Diet-Induced Insulin Resistance through the Hepatic AhR/TSC2/mTORC1 Axis. Proceedings of the National Academy of Sciences, 121, e2400385121. [Google Scholar] [CrossRef] [PubMed]
[47] Shan, X.M., Lu, C., Chen, C.W., et al. (2025) Tangshenning Formula Alleviates Tubular Injury in Diabetic Kidney Disease via the Sestrin2/AMPK/PGC-1α Axis: Restoration of Mitochondrial Function and Inhibition of Ferroptosis. Journal of Ethnopharmacology, 345, Article 119579. [Google Scholar] [CrossRef] [PubMed]
[48] Du, X.H., Chen, Q.J., Song, J.B., et al. (2020) Rhubarb‐Aconite Decoction (RAD) Drug‐Containing Serum Alleviated Endotoxin‐Induced Oxidative Stress Injury and Inflammatory Response in Caco‐2 Cells in Vitro. Evidence-Based Complementary and Alternative Medicine, 2020, Article 5834502. [Google Scholar] [CrossRef] [PubMed]
[49] Wang, Y., Zhong, S., Yang, K., Luo, R., Dai, L., Zhong, W., et al. (2024) β-1,3-d-Glucan Particles-Based “Nest” Protected Co-Loaded Rhein and Emodin Regulates Microbiota and Intestinal Immunity for Ulcerative Colitis Treatment. International Journal of Biological Macromolecules, 260, Article 128818. [Google Scholar] [CrossRef] [PubMed]
[50] Ramdas Nayak, V.K., Satheesh, P., Shenoy, M.T., et al. (2022) Triglyceride Glucose (TyG) Index: A Surrogate Biomarker of Insulin Resistance. Journal of the Pakistan Medical Association, 72, 986-988. [Google Scholar] [CrossRef] [PubMed]

为你推荐