利福昔明调节肠道菌群治疗非酒精性脂肪性肝病的研究进展
Research Progress on Rifaximin in Modulating Gut Microbiota for the Treatment of Nonalcoholic Fatty Liver Disease
DOI: 10.12677/acm.2025.151161, PDF,   
作者: 范裕梅, 杨朝霞*：重庆医科大学附属第二医院消化内科，重庆
关键词: 非酒精性脂肪肝病；肠道菌群；利福昔明；Non-Alcoholic Fatty Liver Disease； Intestinal Flora； Rifaximin
摘要: 非酒精性脂肪肝病(NAFLD)是一种与代谢相关的常见肝脏疾病，患病率逐年上升。其发生与肠道菌群失衡密切相关，肠–肝轴紊乱、肠屏障受损、内毒素血症等机制在其病理中起关键作用。近年来，调节肠道菌群成为治疗NAFLD的热点，尤其是利福昔明作为一种口服不可吸收抗生素，能够改善肠道微生态，减少内毒素和炎症因子，展现出治疗潜力。尽管短期应用已有积极效果，长期使用的安全性和对益生菌的影响仍需进一步研究。未来的研究应探索优化利福昔明的治疗策略，为NAFLD提供更有效的治疗方案。
Abstract: Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder associated with metabolic abnormalities, and its prevalence is increasing annually. Its development is closely related to gut microbiota imbalance, with mechanisms such as disruption of the gut-liver axis, damage to the intestinal barrier, and endotoxemia playing key roles in its pathogenesis. In recent years, modulation of the gut microbiota has become a hot topic in the treatment of NAFLD. Rifaximin, an orally administered non-absorbable antibiotic, has shown potential in improving gut microbiota, reducing endotoxins, and decreasing inflammatory factors. While short-term use has shown positive effects, the safety of long-term use and its impact on beneficial bacteria still require further investigation. Future research should focus on optimizing rifaximin treatment strategies to provide more effective therapeutic options for NAFLD.
文章引用：范裕梅, 杨朝霞. 利福昔明调节肠道菌群治疗非酒精性脂肪性肝病的研究进展[J]. 临床医学进展, 2025, 15(1): 1218-1225. https://doi.org/10.12677/acm.2025.151161

参考文献

[1] Rinella, M.E., Neuschwander-Tetri, B.A., Siddiqui, M.S., Abdelmalek, M.F., Caldwell, S., Barb, D., et al. (2023) AASLD Practice Guidance on the Clinical Assessment and Management of Nonalcoholic Fatty Liver Disease. Hepatology, 77, 1797-1835. [Google Scholar] [CrossRef] [PubMed]
[2] Li, W., Liu, J., Cai, J., Zhang, X., Zhang, P., She, Z., et al. (2022) NAFLD as a Continuous Driver in the Whole Spectrum of Vascular Disease. Journal of Molecular and Cellular Cardiology, 163, 118-132. [Google Scholar] [CrossRef] [PubMed]
[3] Buzzetti, E., Pinzani, M. and Tsochatzis, E.A. (2016) The Multiple-Hit Pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD). Metabolism, 65, 1038-1048. [Google Scholar] [CrossRef] [PubMed]
[4] Machado, M.V. and Diehl, A.M. (2016) Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology, 150, 1769-1777. [Google Scholar] [CrossRef] [PubMed]
[5] Karkucinska-Wieckowska, A., Simoes, I.C.M., Kalinowski, P., Lebiedzinska-Arciszewska, M., Zieniewicz, K., Milkiewicz, P., et al. (2021) Mitochondria, Oxidative Stress and Nonalcoholic Fatty Liver Disease: A Complex Relationship. European Journal of Clinical Investigation, 52, e13622. [Google Scholar] [CrossRef] [PubMed]
[6] Chang, E., Chang, J.S., Kong, I.D., Baik, S.K., Kim, M.Y. and Park, K. (2022) Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease. Gut and Liver, 16, 171-189. [Google Scholar] [CrossRef] [PubMed]
[7] DuPont, H.L. (2015) Introduction: Understanding Mechanisms of the Actions of Rifaximin in Selected Gastrointestinal Diseases. Alimentary Pharmacology & Therapeutics, 43, 1-2. [Google Scholar] [CrossRef] [PubMed]
[8] Bajaj, J.S., Barbara, G., DuPont, H.L., Mearin, F., Gasbarrini, A. and Tack, J. (2018) New Concepts on Intestinal Microbiota and the Role of the Non-Absorbable Antibiotics with Special Reference to Rifaximin in Digestive Diseases. Digestive and Liver Disease, 50, 741-749. [Google Scholar] [CrossRef] [PubMed]
[9] Luo, M., Xie, P., Deng, X., Fan, J. and Xiong, L. (2023) Rifaximin Ameliorates Loperamide-Induced Constipation in Rats through the Regulation of Gut Microbiota and Serum Metabolites. Nutrients, 15, Article 4502. [Google Scholar] [CrossRef] [PubMed]
[10] Abdel-Razik, A., Mousa, N., Shabana, W., Refaey, M., Elzehery, R., Elhelaly, R., et al. (2018) Rifaximin in Nonalcoholic Fatty Liver Disease: Hit Multiple Targets with a Single Shot. European Journal of Gastroenterology & Hepatology, 30, 1237-1246. [Google Scholar] [CrossRef] [PubMed]
[11] Gangarapu, V., Ince, A.T., Baysal, B., Kayar, Y., Klç, U., Gök, Ö., et al. (2015) Efficacy of Rifaximin on Circulating Endotoxins and Cytokines in Patients with Nonalcoholic Fatty Liver Disease. European Journal of Gastroenterology & Hepatology, 27, 840-845. [Google Scholar] [CrossRef] [PubMed]
[12] Li, S., Han, W., He, Q., Zhang, W. and Zhang, Y. (2022) Relationship between Intestinal Microflora and Hepatocellular Cancer Based on Gut-Liver Axis Theory. Contrast Media & Molecular Imaging, 2022, Article 6533628. [Google Scholar] [CrossRef] [PubMed]
[13] Ponziani, F.R., Zocco, M.A., Cerrito, L., Gasbarrini, A. and Pompili, M. (2018) Bacterial Translocation in Patients with Liver Cirrhosis: Physiology, Clinical Consequences, and Practical Implications. Expert Review of Gastroenterology & Hepatology, 12, 641-656. [Google Scholar] [CrossRef] [PubMed]
[14] Fang, J., Yu, C., Li, X., Yao, J., Fang, Z., Yoon, S., et al. (2022) Gut Dysbiosis in Nonalcoholic Fatty Liver Disease: Pathogenesis, Diagnosis, and Therapeutic Implications. Frontiers in Cellular and Infection Microbiology, 12, Article 997018. [Google Scholar] [CrossRef] [PubMed]
[15] Rebelos, E., Iozzo, P., Guzzardi, M.A., Brunetto, M.R. and Bonino, F. (2021) Brain-Gut-Liver Interactions across the Spectrum of Insulin Resistance in Metabolic Fatty Liver Disease. World Journal of Gastroenterology, 27, 4999-5018. [Google Scholar] [CrossRef] [PubMed]
[16] Wang, X.X., Zhang, B., Xia, R. and Jia, Q.Y. (2020) Inflammation, Apoptosis and Autophagy as Critical Players in Vascular Dementia. European Review for Medical and Pharmacological Sciences, 24, 9601-9614. [Google Scholar] [CrossRef] [PubMed]
[17] Oh, T.G., Kim, S.M., Caussy, C., Fu, T., Guo, J., Bassirian, S., et al. (2020) A Universal Gut-Microbiome-Derived Signature Predicts Cirrhosis. Cell Metabolism, 32, 878-888.e6. [Google Scholar] [CrossRef] [PubMed]
[18] Loomba, R., Seguritan, V., Li, W., Long, T., Klitgord, N., Bhatt, A., et al. (2019) Gut Microbiome-Based Metagenomic Signature for Non-Invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metabolism, 30, Article 607. [Google Scholar] [CrossRef] [PubMed]
[19] Jadhav, K. and Cohen, T.S. (2020) Can You Trust Your Gut? Implicating a Disrupted Intestinal Microbiome in the Progression of NAFLD/NASH. Frontiers in Endocrinology, 11, Article 592157. [Google Scholar] [CrossRef] [PubMed]
[20] Pettinelli, P., Arendt, B.M., Schwenger, K.J.P., Sivaraj, S., Bhat, M., Comelli, E.M., et al. (2022) Relationship between Hepatic Gene Expression, Intestinal Microbiota and Inferred Functional Metagenomic Analysis in NAFLD. Clinical and Translational Gastroenterology, 13, e00466. [Google Scholar] [CrossRef] [PubMed]
[21] Caussy, C., Hsu, C., Lo, M., Liu, A., Bettencourt, R., Ajmera, V.H., et al. (2018) Link between Gut-Microbiome Derived Metabolite and Shared Gene-Effects with Hepatic Steatosis and Fibrosis in NAFLD. Hepatology, 68, 918-932. [Google Scholar] [CrossRef] [PubMed]
[22] 张丹琴, 杨帆, 李胜保. 非酒精性脂肪性肝病患者血清TLR4、IL-10、IL-22与肠道菌群的相关性[J]. 肝脏, 2019, 24(12): 1432-1434.
[23] 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. [Google Scholar] [CrossRef] [PubMed]
[24] Paolella, G. (2014) Gut-Liver Axis and Probiotics: Their Role in Non-Alcoholic Fatty Liver Disease. World Journal of Gastroenterology, 20, Article 15518. [Google Scholar] [CrossRef] [PubMed]
[25] Gassler, N. (2017) Paneth Cells in Intestinal Physiology and Pathophysiology. World Journal of Gastrointestinal Pathophysiology, 8, 150-160. [Google Scholar] [CrossRef] [PubMed]
[26] Jia, W., Rajani, C., Xu, H. and Zheng, X. (2020) Gut Microbiota Alterations Are Distinct for Primary Colorectal Cancer and Hepatocellular Carcinoma. Protein & Cell, 12, 374-393. [Google Scholar] [CrossRef] [PubMed]
[27] Verdam, F.J., Rensen, S.S., Driessen, A., Greve, J.W. and Buurman, W.A. (2011) Novel Evidence for Chronic Exposure to Endotoxin in Human Nonalcoholic Steatohepatitis. Journal of Clinical Gastroenterology, 45, 149-152. [Google Scholar] [CrossRef] [PubMed]
[28] Chávez-Carbajal, A., Nirmalkar, K., Pérez-Lizaur, A., Hernández-Quiroz, F., Ramírez-del-Alto, S., García-Mena, J., et al. (2019) Gut Microbiota and Predicted Metabolic Pathways in a Sample of Mexican Women Affected by Obesity and Obesity Plus Metabolic Syndrome. International Journal of Molecular Sciences, 20, Article 438. [Google Scholar] [CrossRef] [PubMed]
[29] Rowland, I., Gibson, G., Heinken, A., Scott, K., Swann, J., Thiele, I., et al. (2017) Gut Microbiota Functions: Metabolism of Nutrients and Other Food Components. European Journal of Nutrition, 57, 1-24. [Google Scholar] [CrossRef] [PubMed]
[30] Krishnan, S., Ding, Y., Saedi, N., Choi, M., Sridharan, G.V., Sherr, D.H., et al. (2018) Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. Cell Reports, 23, 1099-1111. [Google Scholar] [CrossRef] [PubMed]
[31] Chi, Y., Lin, Y., Lu, Y., Huang, Q., Ye, G. and Dong, S. (2019) Gut Microbiota Dysbiosis Correlates with a Low-Dose Pcb126-Induced Dyslipidemia and Non-Alcoholic Fatty Liver Disease. Science of the Total Environment, 653, 274-282. [Google Scholar] [CrossRef] [PubMed]
[32] Miura, K. (2014) Role of Gut Microbiota and Toll-Like Receptors in Nonalcoholic Fatty Liver Disease. World Journal of Gastroenterology, 20, 7381-7391. [Google Scholar] [CrossRef] [PubMed]
[33] Tsukamoto, H., Takeuchi, S., Kubota, K., Kobayashi, Y., Kozakai, S., Ukai, I., et al. (2018) Lipopolysaccharide (LPS)-Binding Protein Stimulates CD14-Dependent Toll-Like Receptor 4 Internalization and LPS-Induced TBK1-IKKϵ-IRF3 Axis Activation. Journal of Biological Chemistry, 293, 10186-10201. [Google Scholar] [CrossRef] [PubMed]
[34] Li, Y., Zhou, Y., Wang, L., Lin, X., Mao, M., Yin, S., et al. (2022) Emerging Trends and Hotspots in the Links between the Gut Microbiota and MAFLD from 2002 to 2021: A Bibliometric Analysis. Frontiers in Endocrinology, 13, Article 990953. [Google Scholar] [CrossRef] [PubMed]
[35] Molinaro, A., Wahlström, A. and Marschall, H. (2018) Role of Bile Acids in Metabolic Control. Trends in Endocrinology & Metabolism, 29, 31-41. [Google Scholar] [CrossRef] [PubMed]
[36] Duboc, H., Taché, Y. and Hofmann, A.F. (2014) The Bile Acid TGR5 Membrane Receptor: From Basic Research to Clinical Application. Digestive and Liver Disease, 46, 302-312. [Google Scholar] [CrossRef] [PubMed]
[37] Sayin, S.I., Wahlström, A., Felin, J., Jäntti, S., Marschall, H., Bamberg, K., et al. (2013) Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-Beta-Muricholic Acid, a Naturally Occurring FXR Antagonist. Cell Metabolism, 17, 225-235. [Google Scholar] [CrossRef] [PubMed]
[38] Schaap, F.G., Trauner, M. and Jansen, P.L.M. (2013) Bile Acid Receptors as Targets for Drug Development. Nature Reviews Gastroenterology & Hepatology, 11, 55-67. [Google Scholar] [CrossRef] [PubMed]
[39] Pathak, P., Xie, C., Nichols, R.G., Ferrell, J.M., Boehme, S., Krausz, K.W., et al. (2018) Intestine Farnesoid X Receptor Agonist and the Gut Microbiota Activate G-Protein Bile Acid Receptor-1 Signaling to Improve Metabolism. Hepatology, 68, 1574-1588. [Google Scholar] [CrossRef] [PubMed]
[40] Pineda Torra, I., Claudel, T., Duval, C., Kosykh, V., Fruchart, J. and Staels, B. (2003) Bile Acids Induce the Expression of the Human Peroxisome Proliferator-Activated Receptor Α Gene via Activation of the Farnesoid X Receptor. Molecular Endocrinology, 17, 259-272. [Google Scholar] [CrossRef] [PubMed]
[41] Wiest, R., Albillos, A., Trauner, M., Bajaj, J.S. and Jalan, R. (2017) Targeting the Gut-Liver Axis in Liver Disease. Journal of Hepatology, 67, 1084-1103. [Google Scholar] [CrossRef] [PubMed]
[42] Maccaferri, S., Vitali, B., Klinder, A., Kolida, S., Ndagijimana, M., Laghi, L., et al. (2010) Rifaximin Modulates the Colonic Microbiota of Patients with Crohn's Disease: An in Vitro Approach Using a Continuous Culture Colonic Model System. Journal of Antimicrobial Chemotherapy, 65, 2556-2565. [Google Scholar] [CrossRef] [PubMed]
[43] Kamal, F., Khan, M.A., Khan, Z., Cholankeril, G., Hammad, T.A., Lee, W.M., et al. (2017) Rifaximin for the Prevention of Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome in Cirrhosis: A Systematic Review and Meta-Analysis. European Journal of Gastroenterology & Hepatology, 29, 1109-1117. [Google Scholar] [CrossRef] [PubMed]
[44] Graziano, T., Amoruso, A., Nicola, S., Deidda, F., Allesina, S., Pane, M., et al. (2016) The Possible Innovative Use of Bifidobacterium Longum W11 in Association with Rifaximin. Journal of Clinical Gastroenterology, 50, S153-S156. [Google Scholar] [CrossRef] [PubMed]
[45] Terc, J., Hansen, A., Alston, L. and Hirota, S.A. (2014) Pregnane X Receptor Agonists Enhance Intestinal Epithelial Wound Healing and Repair of the Intestinal Barrier Following the Induction of Experimental Colitis. European Journal of Pharmaceutical Sciences, 55, 12-19. [Google Scholar] [CrossRef] [PubMed]
[46] Hirota, S.A. (2015) Understanding the Molecular Mechanisms of Rifaximin in the Treatment of Gastrointestinal Disorders—A Focus on the Modulation of Host Tissue Function. Mini-Reviews in Medicinal Chemistry, 16, 206-217. [Google Scholar] [CrossRef] [PubMed]
[47] Wan, Y.C., Li, T., Han, Y.D., Zhang, H.Y., Lin, H. and Zhang, B. (2015) Effect of Pregnane Xenobiotic Receptor Activation on Inflammatory Bowel Disease Treated with Rifaximin. Journal of Biological Regulators and Homeostatic Agents, 29, 401-410.
[48] Dogan, B., Fu, J., Zhang, S., Scherl, E.J. and Simpson, K.W. (2018) Rifaximin Decreases Virulence of Crohn’s Disease-Associated Escherichia coli and Epithelial Inflammatory Responses. The Journal of Antibiotics, 71, 485-494. [Google Scholar] [CrossRef] [PubMed]
[49] Gao, J., Gillilland, M. and Owyang, C. (2014) Rifaximin, Gut Microbes and Mucosal Inflammation: Unraveling a Complex Relationship. Gut Microbes, 5, 571-575. [Google Scholar] [CrossRef] [PubMed]
[50] Thomas, C.M., Hong, T., van Pijkeren, J.P., Hemarajata, P., Trinh, D.V., Hu, W., et al. (2012) Histamine Derived from Probiotic Lactobacillus Reuteri Suppresses TNF via Modulation of PKA and ERK Signaling. PLOS ONE, 7, e31951. [Google Scholar] [CrossRef] [PubMed]
[51] Pimentel, M. (2015) Review Article: Potential Mechanisms of Action of Rifaximin in the Management of Irritable Bowel Syndrome with Diarrhoea. Alimentary Pharmacology & Therapeutics, 43, 37-49. [Google Scholar] [CrossRef] [PubMed]
[52] Xu, D., Gao, J., Gillilland, M., Wu, X., Song, I., Kao, J.Y., et al. (2014) Rifaximin Alters Intestinal Bacteria and Prevents Stress-Induced Gut Inflammation and Visceral Hyperalgesia in Rats. Gastroenterology, 146, 484-496.e4. [Google Scholar] [CrossRef] [PubMed]
[53] Ponziani, F.R., Scaldaferri, F., Petito, V., Paroni Sterbini, F., Pecere, S., Lopetuso, L.R., et al. (2016) The Role of Antibiotics in Gut Microbiota Modulation: The Eubiotic Effects of Rifaximin. Digestive Diseases, 34, 269-278. [Google Scholar] [CrossRef] [PubMed]
[54] Ponziani, F.R., Pecere, S., Lopetuso, L., Scaldaferri, F., Cammarota, G. and Gasbarrini, A. (2016) Rifaximin for the Treatment of Irritable Bowel Syndrome—A Drug Safety Evaluation. Expert Opinion on Drug Safety, 15, 983-991. [Google Scholar] [CrossRef] [PubMed]
[55] Brown, E.L., Xue, Q., Jiang, Z., Xu, Y. and DuPont, H.L. (2010) Pretreatment of Epithelial Cells with Rifaximin Alters Bacterial Attachment and Internalization Profiles. Antimicrobial Agents and Chemotherapy, 54, 388-396. [Google Scholar] [CrossRef] [PubMed]
[56] Du Plessis, J., Vanheel, H., Janssen, C.E.I., Roos, L., Slavik, T., Stivaktas, P.I., et al. (2013) Activated Intestinal Macrophages in Patients with Cirrhosis Release NO and IL-6 That May Disrupt Intestinal Barrier Function. Journal of Hepatology, 58, 1125-1132. [Google Scholar] [CrossRef] [PubMed]

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