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肠道菌群对肝硬化相关并发症的发病机制及治疗策略的影响研究
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Abstract:
肝硬化是一种由各种病因引起的慢性、进行性、弥漫性终末期肝脏病变，常伴随多种并发症的发生，例如腹水、肝性脑病、食管胃底静脉曲张、自发性腹膜炎等。这些并发症不仅影响患者的生活质量，还显著增加了死亡风险。近年来，随着对消化系统疾病的深入认识，越来越多的研究表明，肠道菌群在肝硬化的发生发展及其相关并发症的发生中起着关键作用。然而，目前关于肠道菌群如何影响肝硬化及其并发症的具体机制仍不完全清晰，且临床治疗策略尚未得到有效落实。本综述旨在深入探讨肠道菌群在肝硬化相关并发症中的发病机制，包括其通过免疫调节、代谢产物及肝肠轴等多种途径的影响。同时，我们还将回顾当前的治疗策略，为未来的研究和治疗方法提供参考和启示。
Cirrhosis is a chronic, progressive and diffuse end-stage liver disease caused by various causes, often accompanied by a variety of complications, such as ascites, hepatic encephalopathy, esophageal and gastric varices, spontaneous peritonitis and so on. These complications not only affect the quality of life of patients, but also significantly increase the risk of death. In recent years, with the in-depth understanding of digestive system diseases, more and more studies show that intestinal flora plays a key role in the occurrence and development of liver cirrhosis and related complications. However, the specific mechanism of how intestinal flora affects cirrhosis and its complications is still not completely clear, and the clinical treatment strategy has not been effectively implemented. This review aims to explore the pathogenesis of intestinal flora in related complications of liver cirrhosis, including its influence through immunomodulation, metabolites and hepatointestinal axis. At the same time, we will also review the current treatment strategies to provide reference and enlightenment for future research and treatment methods.
| [1] | Woodhouse, C., Singanayagam, A. and Patel, V.C. (2020) Modulating the Gut-Liver Axis and the Pivotal Role of the Faecal Microbiome in Cirrhosis. Clinical Medicine, 20, 493-500. https://doi.org/10.7861/clinmed.2020-0676 |
| [2] | Park, Y.R., Lee, H.L., Hyun, J.Y., Choi, J., Moon, J.H., Kim, B.Y., et al. (2023) Systemic Multiomics Evaluation of the Therapeutic Effect of Bacteroides Species on Liver Cirrhosis in Male Mice. Microbiology Spectrum, 11, e05349-22. https://doi.org/10.1128/spectrum.05349-22 |
| [3] | Effenberger, M., Grander, C., Grabherr, F. and Tilg, H. (2023) Nonalcoholic Fatty Liver Disease and the Intestinal Microbiome: An Inseparable Link. Journal of Clinical and Translational Hepatology, 11, 1498-1507. https://doi.org/10.14218/jcth.2023.00069 |
| [4] | Jiang, L., Xu, J., Cheng, S., Wang, Y. and Cai, W. (2023) The Gut Microbiome and Intestinal Failure-Associated Liver Disease. Hepatobiliary & Pancreatic Diseases International, 22, 452-457. https://doi.org/10.1016/j.hbpd.2023.07.002 |
| [5] | Luo, M., Xin, R., Hu, F., Yao, L., Hu, S. and Bai, F. (2023) Role of Gut Microbiota in the Pathogenesis and Therapeutics of Minimal Hepatic Encephalopathy via the Gut-Liver-Brain Axis. World Journal of Gastroenterology, 29, 144-156. https://doi.org/10.3748/wjg.v29.i1.144 |
| [6] | 陈钢, 廖江涛, 李清清. 双岐三联活菌对肝硬化患者肠道菌群、血浆内毒素及肝功能的影响[J]. 中国当代医药, 2012, 19(6): 26-27+29. |
| [7] | Philips, C.A. and Augustine, P. (2022) Gut Barrier and Microbiota in Cirrhosis. Journal of Clinical and Experimental Hepatology, 12, 625-638. https://doi.org/10.1016/j.jceh.2021.08.027 |
| [8] | 肖菲, 康焰. 肠道细菌移位的研究现状[J]. 中国普外基础与临床杂志, 2006, 13(2): 240-243. |
| [9] | Wu, Z., Zhou, H., Liu, D. and Deng, F. (2023) Alterations in the Gut Microbiota and the Efficacy of Adjuvant Probiotic Therapy in Liver Cirrhosis. Frontiers in Cellular and Infection Microbiology, 13, Article 1218552. https://doi.org/10.3389/fcimb.2023.1218552 |
| [10] | Yuan, M., Hu, X., Yao, L., et al. (2024) Causal Relationship Between Gut Microbiota and Liver Cirrhosis: 16S rRNA Sequencing and Mendelian Randomization Analyses. Journal of Clinical and Translational Hepatology, 12, 123-133. |
| [11] | Shu, W., Shanjian, C., Jinpiao, L. and Qishui, O. (2022) Gut Microbiota Dysbiosis in Patients with Hepatitis B Virus-Related Cirrhosis. Annals of Hepatology, 27, Article 100676. https://doi.org/10.1016/j.aohep.2022.100676 |
| [12] | 张璐, 袁浩, 郭庆红. 肝硬化并发症肠道微生态的研究现状[J]. 现代消化及介入诊疗, 2023, 28(11): 1448-1451. |
| [13] | Albillos, A., de Gottardi, A. and Rescigno, M. (2020) The Gut-Liver Axis in Liver Disease: Pathophysiological Basis for Therapy. Journal of Hepatology, 72, 558-577. https://doi.org/10.1016/j.jhep.2019.10.003 |
| [14] | Farré, R. and Vicario, M. (2016) Abnormal Barrier Function in Gastrointestinal Disorders. In: Greenwood-Van Meerveld, B., Ed., Handbook of Experimental Pharmacology, Springer International Publishing, 193-217. https://doi.org/10.1007/164_2016_107 |
| [15] | Nishimura, N., Kaji, K., Kitagawa, K., Sawada, Y., Furukawa, M., Ozutsumi, T., et al. (2021) Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis. International Journal of Molecular Sciences, 22, Article 6921. https://doi.org/10.3390/ijms22136921 |
| [16] | Seki, E. and Brenner, D.A. (2008) Toll-Like Receptors and Adaptor Molecules in Liver Disease. Hepatology, 48, 322-335. https://doi.org/10.1002/hep.22306 |
| [17] | Bertocchi, A., Carloni, S., Ravenda, P.S., Bertalot, G., Spadoni, I., Lo Cascio, A., et al. (2021) Gut Vascular Barrier Impairment Leads to Intestinal Bacteria Dissemination and Colorectal Cancer Metastasis to Liver. Cancer Cell, 39, 708-724.E11. https://doi.org/10.1016/j.ccell.2021.03.004 |
| [18] | Gao, Y., Liu, X., Gao, Y., Duan, M., Hou, B. and Chen, Y. (2024) Pharmacological Interventions for Cirrhotic Ascites: From Challenges to Emerging Therapeutic Horizons. Gut and Liver, 18, 934-948. https://doi.org/10.5009/gnl240038 |
| [19] | Sharma, S.P., Gupta, H., Kwon, G., Lee, S.Y., Song, S.H., Kim, J.S., et al. (2024) Gut Microbiome and Metabolome Signatures in Liver Cirrhosis-Related Complications. Clinical and Molecular Hepatology, 30, 845-862. https://doi.org/10.3350/cmh.2024.0349 |
| [20] | 徐小元, 丁惠国, 李文刚, 等. 肝硬化肝性脑病诊疗指南(2018年, 北京) [J]. 中华胃肠内镜电子杂志, 2018, 5(3): 97-113. |
| [21] | 高婵婵, 李京涛, 魏海梁, 等. 基于TLR4/NF-κB/NLRP3信号通路探讨M1型巨噬细胞极化在肝硬化-肝性脑病发病中的研究进展[J]. 现代消化及介入诊疗, 2020, 25(10): 1321-1323+1328. |
| [22] | 高婵婵, 张海博, 魏海梁, 等. 基于肠-肝-脑轴探讨益木脑液灌肠对肝性脑病大鼠TLR4/NF-κB/NLRP3通路的影响[J]. 中华中医药杂志, 2023, 38(6): 2599-2604. |
| [23] | Said, V.J. and Garcia-Trujillo, E. (2019) Beyond Lactulose. Treatment Options for Hepatic Encephalopathy. Gastroenterology Nursing, 42, 277-285. https://doi.org/10.1097/sga.0000000000000376 |
| [24] | 陈悦. 肠道菌群调节胆汁酸代谢介导TIPS术后肝性脑病发生的作用及机制研究[D]: [硕士学位论文]. 西安: 西北大学, 2022. |
| [25] | Xie, G., Wang, X., Liu, P., Wei, R., Chen, W., Rajani, C., et al. (2016) Distinctly Altered Gut Microbiota in the Progression of Liver Disease. Oncotarget, 7, 19355-19366. https://doi.org/10.18632/oncotarget.8466 |
| [26] | Kim, Y. and Song, J. (2021) Therapeutic Applications of Resveratrol in Hepatic Encephalopathy through Its Regulation of the Microbiota, Brain Edema, and Inflammation. Journal of Clinical Medicine, 10, Article 3819. https://doi.org/10.3390/jcm10173819 |
| [27] | Lu, H., Zhang, H., Wu, Z. and Li, L. (2024) Microbiota-Gut-Liver-Brain Axis and Hepatic Encephalopathy. Microbiome Research Reports, 3, Article 17. https://doi.org/10.20517/mrr.2023.44 |
| [28] | Schnelle, A.N.W., Richardson, L.T., Pettit, M.E., DeMorrow, S. and Solouki, T. (2021) Trihydroxycholanoyl-Taurine in Brains of Rodents with Hepatic Encephalopathy. Journal of Mass Spectrometry, 56, e4729. https://doi.org/10.1002/jms.4729 |
| [29] | Esfahani, D.E. and Zarrindast, M.R. (2021) Cholestasis and Behavioral Disorders. Gastroenterology and Hepatology from Bed to Bench, 14, 95-107. |
| [30] | Ackerman, H.D. and Gerhard, G.S. (2023) Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile. Pharmaceuticals, 16, Article 174. https://doi.org/10.3390/ph16020174 |
| [31] | Yeo, X.Y., Tan, L.Y., Chae, W.R., Lee, D., Lee, Y., Wuestefeld, T., et al. (2023) Liver’s Influence on the Brain through the Action of Bile Acids. Frontiers in Neuroscience, 17, Article 1123967. https://doi.org/10.3389/fnins.2023.1123967 |
| [32] | Wu, S., Li, L., Xi, H., Wu, X., He, Y., Sun, X., et al. (2024) Bibliometrics and Knowledge Mapping of the Pathogenesis of Hepatic Encephalopathy in Patients with Liver Cirrhosis. Heliyon, 10, e34330. https://doi.org/10.1016/j.heliyon.2024.e34330 |
| [33] | 周永健. 肠道微生态与肝硬化[J]. 实用肝脏病杂志, 2016, 19(2): 139-142. |
| [34] | 任海霞, 平付敏, 牛淑利, 等. 肝硬化食管胃底静脉曲张患者口腔和肠道菌群变化[J]. 河北医药, 2023, 45(9): 1335-1339. |
| [35] | Arab, J.P., Martin-Mateos, R.M. and Shah, V.H. (2018) Gut-Liver Axis, Cirrhosis and Portal Hypertension: The Chicken and the Egg. Hepatology International, 12, 24-33. https://doi.org/10.1007/s12072-017-9798-x |
| [36] | Tazi, K.A., Moreau, R., Hervé, P., Dauvergne, A., Cazals-Hatem, D., Bert, F., et al. (2005) Norfloxacin Reduces Aortic NO Synthases and Proinflammatory Cytokine Up-Regulation in Cirrhotic Rats: Role of Akt Signaling. Gastroenterology, 129, 303-314. https://doi.org/10.1053/j.gastro.2005.04.016 |
| [37] | Wiest, R., Das, S., Cadelina, G., Garcia-Tsao, G., Milstien, S. and Groszmann, R.J. (1999) Bacterial Translocation in Cirrhotic Rats Stimulates Enos-Derived NO Production and Impairs Mesenteric Vascular Contractility. Journal of Clinical Investigation, 104, 1223-1233. https://doi.org/10.1172/jci7458 |
| [38] | Parséus, A., Sommer, N., Sommer, F., Caesar, R., Molinaro, A., Ståhlman, M., et al. (2016) Microbiota-Induced Obesity Requires Farnesoid X Receptor. Gut, 66, 429-437. https://doi.org/10.1136/gutjnl-2015-310283 |
| [39] | Cariou, B. and Staels, B. (2006) The Expanding Role of the Bile Acid Receptor FXR in the Small Intestine. Journal of Hepatology, 44, 1213-1215. https://doi.org/10.1016/j.jhep.2006.03.006 |
| [40] | 马维娟, 许建明, 胡静, 等. 肝硬化患者肠道粘膜通透性及其与Child-Pugh分级相关性的研究[J]. 中华疾病控制杂志, 2015, 19(4): 411-414. |
| [41] | 王磊熙, 刘晨. 乳果糖联合微生态制剂对肝硬化合并自发性腹膜炎患者肠道菌群、肠黏膜屏障功能和肝功能的影响分析[J]. 中国医学前沿杂志(电子版), 2020, 12(1): 145-148. |
| [42] | Kim, B.I., Kim, H.J., Park, J.H., Park, D.I., Cho, Y.K., Sohn, C.I., et al. (2010) Increased Intestinal Permeability as a Predictor of Bacterial Infections in Patients with Decompensated Liver Cirrhosis and Hemorrhage. Journal of Gastroenterology and Hepatology, 26, 550-557. https://doi.org/10.1111/j.1440-1746.2010.06490.x |
| [43] | Agraz-Cibrián, J.M., Delgado-Rizo, V., Segura‐Ortega, J.E., Maldonado-Gómez, H.A., Zambrano-Zaragoza, J.F., Durán-Avelar, M.D.J., et al. (2018) Impaired Neutrophil Extracellular Traps and Inflammatory Responses in the Peritoneal Fluid of Patients with Liver Cirrhosis. Scandinavian Journal of Immunology, 88, e12714. https://doi.org/10.1111/sji.12714 |
| [44] | Nieto, J.C., Perea, L., Soriano, G., Zamora, C., Cantó, E., Medina, A., et al. (2018) Ascitic Fluid Regulates the Local Innate Immune Response of Patients with Cirrhosis. Journal of Leukocyte Biology, 104, 833-841. https://doi.org/10.1002/jlb.3a0218-072r |
| [45] | Li, O., Xu, H., Kim, D., Yang, F. and Bao, Z. (2024) Roles of Human Gut Microbiota in Liver Cirrhosis Risk: A Two-Sample Mendelian Randomization Study. The Journal of Nutrition, 154, 143-151. https://doi.org/10.1016/j.tjnut.2023.11.011 |
| [46] | Du, Q., Li, Q., Liu, C., Liao, G., Li, J., Yang, J., et al. (2024) Probiotics/Prebiotics/Synbiotics and Human Neuropsychiatric Outcomes: An Umbrella Review. Beneficial Microbes, 15, 589-608. |
| [47] | Xiao, Q., Yang, Y., Chen, L., Xie, Y., Li, H., Fu, Z., et al. (2023) The Causality between Gut Microbiome and Liver Cirrhosis: A Bi-Directional Two-Sample Mendelian Randomization Analysis. Frontiers in Microbiology, 14, Article 1256874. https://doi.org/10.3389/fmicb.2023.1256874 |
| [48] | Shakhpazyan, N.K., Mikhaleva, L.M., Bedzhanyan, A.L., Gioeva, Z.V., Mikhalev, A.I., Midiber, K.Y., et al. (2024) Exploring the Role of the Gut Microbiota in Modulating Colorectal Cancer Immunity. Cells, 13, Article 1437. https://doi.org/10.3390/cells13171437 |
