Effect of berberine on thioacetamide-induced hepatic encephalopathy: Possible modulation of gut microbiota-liver-brain axis in rats
Keywords:
Hepatic Encephalopathy, Berberine, Thioacetamide, Gut-Liver-Brain Axis, Neuroinflammation, Oxidative StressAbstract
Background: Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver disease associated with hyperammonemia, gut microbiota dysbiosis, inflammation, and oxidative stress along the gut–liver–brain axis. This study investigated the protective effects of berberine (BBR) against thioacetamide (TAA)-induced HE in rats, with particular emphasis on its modulation of the gut–liver–brain axis. Methods: Forty male Wistar rats were divided into four groups: control, BBR control, TAA-induced HE, and BBR-treated HE. HE was induced with TAA for 2 weeks, while BBR was administered orally throughout the same period. Cognitive function, biochemical markers, and histopathological changes in the liver, brain, and colon were evaluated. Results: TAA significantly increased ALT, AST, ammonia, LPS, TLR-4, NF-κB, and MDA, while decreasing SCFAs, glutamic acid, GSH, and ZO-1 levels (p<0.05). BBR significantly reversed these changes, improved cognitive function, and restored histopathological architecture in liver, brain, and colon. However, all parameters in the BBR-treated HE G continued to vary significantly from the control G (p < 0.05), reflecting partial recovery. Conclusions: BBR exerts multi-targeted protective effects against TAA-induced HE via regulation of the gut-liver-brain axis, suggesting its utility as a therapeutic agent for HE. Further investigations are warranted to explore its full therapeutic potential.
Downloads
References
Abd Elrazik, N. A., & Abd El Salam, A. S. G. (2024). Diacerein ameliorates thioacetamide-induced hepatic encephalopathy in rats via modulation of TLR4/AQP4/MMP-9 axis. Metab Brain Dis, 40(1), 10-55. doi:10.1007/s11011-024-01457-x DOI: https://doi.org/10.1007/s11011-024-01457-x
Acharya, C., & Bajaj, J. S. (2018). Current management of hepatic encephalopathy. Am J Gastroenterol, 113(11), 1600-1612. doi:10.1038/s41395-018-0179-4 DOI: https://doi.org/10.1038/s41395-018-0179-4
Ali, S. A., & Datusalia, A. K. (2025). Therapeutic effects of berberine on hyperammonemia-associated neuroinflammation in thioacetamide-induced hepatic encephalopathy. Toxicol Appl Pharmacol, 505(52), 11-69. doi:10.1016/j.taap.2025.117569 DOI: https://doi.org/10.1016/j.taap.2025.117569
Cao, J., Chen, M., Xu, R., & Guo, M. (2022). Therapeutic mechanisms of berberine to improve the intestinal barrier function via modulating gut microbiota, TLR4/NF-κ B/MTORC pathway and autophagy in cats. Front Microbiol, 13(5), 961885. doi:10.3389/fmicb.2022.961885 DOI: https://doi.org/10.3389/fmicb.2022.961885
Claeys, W., Geerts, A., Van Hoecke, L., Van Steenkiste, C., & Vandenbroucke, R. E. (2024). Role of astrocytes and microglia in hepatic encephalopathy associated with advanced chronic liver disease: lessons from animal studies. Neural Regen Res, 20(2), 34-61. DOI: https://doi.org/10.4103/NRR.NRR-D-24-00600
Di Ciaula, A., Stella, A., Bonfrate, L., Wang, D. Q., & Portincasa, P. (2020). Gut microbiota between environment and genetic background in familial Mediterranean fever (FMF). Genes, 11(9), 10-41. DOI: https://doi.org/10.3390/genes11091041
Elsaid, M. I., & Rustgi, V. K. (2020). Epidemiology of Hepatic Encephalopathy. Clin Liver Dis, 24(2), 157-174. doi:10.1016/j.cld.2020.01.001 DOI: https://doi.org/10.1016/j.cld.2020.01.001
Engelmann, C., Clària, J., Szabo, G., Bosch, J., & Bernardi, M. (2021a). Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol, 75(1), 49-66. doi:10.1016/j.jhep.2021.01.002
Engelmann, C., Clària, J., Szabo, G., Bosch, J., & Bernardi, M. (2021b). Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol, 75 Suppl 1(Suppl 1), S49-s66. doi:10.1016/j.jhep.2021.01.002 DOI: https://doi.org/10.1016/j.jhep.2021.01.002
Ezhilarasan, D. (2023a). Molecular mechanisms in thioacetamide-induced acute and chronic liver injury models. Environ Toxicol Pharmacol, 99(5), 10-93. doi:10.1016/j.etap.2023.104093
Ezhilarasan, D. (2023b). Molecular mechanisms in thioacetamide-induced acute and chronic liver injury models. Environ Toxicol Pharmacol, 99, 104093. doi:10.1016/j.etap.2023.104093 DOI: https://doi.org/10.1016/j.etap.2023.104093
Fang, Y., Zhang, J., Zhu, S., He, M., Ma, S., Jia, Q., . . . Duan, L. (2021). Berberine ameliorates ovariectomy-induced anxiety-like behaviors by enrichment in equol generating gut microbiota. Pharmacol Res, 165(42), 105-125. doi:10.1016/j.phrs.2021.105439 DOI: https://doi.org/10.1016/j.phrs.2021.105439
Ferah Okkay, I., Okkay, U., Gundogdu, O. L., Bayram, C., Mendil, A. S., Ertugrul, M. S., & Hacimuftuoglu, A. (2022). Syringic acid protects against thioacetamide-induced hepatic encephalopathy: Behavioral, biochemical, and molecular evidence. Neurosci Lett, 769(45), 13-85. doi:10.1016/j.neulet.2021.136385 DOI: https://doi.org/10.1016/j.neulet.2021.136385
Gallego-Durán, R., Hadjihambi, A., Ampuero, J., Rose, C. F., Jalan, R., & Romero-Gómez, M. (2024). Ammonia-induced stress response in liver disease progression and hepatic encephalopathy. Nat Rev Gastroenterol Hepatol, 21(11), 774-791. doi:10.1038/s41575-024-00970-9 DOI: https://doi.org/10.1038/s41575-024-00970-9
Hajipour, S., Farbood, Y., Dianat, M., Nesari, A., & Sarkaki, A. (2023a). Effect of berberine against cognitive deficits in rat model of thioacetamide-induced liver cirrhosis and hepatic encephalopathy (behavioral, biochemical, molecular and histological evaluations). Brain Sci, 13(6), 17-26. doi:10.3390/brainsci13060944
Hajipour, S., Farbood, Y., Dianat, M., Nesari, A., & Sarkaki, A. (2023b). Effect of Berberine against Cognitive Deficits in Rat Model of Thioacetamide-Induced Liver Cirrhosis and Hepatic Encephalopathy (Behavioral, Biochemical, Molecular and Histological Evaluations). Brain Sci, 13(6). doi:10.3390/brainsci13060944 DOI: https://doi.org/10.3390/brainsci13060944
Izadparast, F., Riahi-Zajani, B., Yarmohammadi, F., Hayes, A. W., & Karimi, G. (2022). Protective effect of berberine against LPS-induced injury in the intestine: a review. Cell Cycle, 21(22), 2365-2378. doi:10.1080/15384101.2022.2100682 DOI: https://doi.org/10.1080/15384101.2022.2100682
Juanola, O., Ferrusquía-Acosta, J., García-Villalba, R., Zapater, P., Magaz, M., Marín, A., . . . Francés, R. (2019). Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis. Faseb j, 33(10), 11595-11605. doi:10.1096/fj.201901327R DOI: https://doi.org/10.1096/fj.201901327R
Kaboutari, M., Asle-Rousta, M., & Mahmazi, S. (2024). Protective effect of menthol against thioacetamide-induced hepatic encephalopathy by suppressing oxidative stress and inflammation, augmenting expression of BDNF and α7-nACh receptor, and improving spatial memory. Eur J Pharmacol, 981(55), 176-210. doi:10.1016/j.ejphar.2024.176916 DOI: https://doi.org/10.1016/j.ejphar.2024.176916
Kajal, K., Ganesh, V., & Sethi, S. (2023). Physiological role of liver and interpreting liver function tests. In Peri-operative anesthetic management in liver transplantation (2nd ed., pp. 15-30): Springer. DOI: https://doi.org/10.1007/978-981-19-6045-1_2
Lemberg, A., & Fernández, M. A. (2009). Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress. Ann Hepatol, 8(2), 95-102. DOI: https://doi.org/10.1016/S1665-2681(19)31785-5
Li, H. M., Wang, Y. Y., Wang, H. D., Cao, W. J., Yu, X. H., Lu, D. X., . . . Yan, Y. X. (2011). Berberine protects against lipopolysaccharide-induced intestinal injury in mice via alpha 2 adrenoceptor-independent mechanisms. Acta Pharmacol Sin, 32(11), 1364-1372. doi:10.1038/aps.2011.102 DOI: https://doi.org/10.1038/aps.2011.102
Liu, D., Meng, X., Wu, D., Qiu, Z., & Luo, H. (2019). A natural isoquinoline alkaloid with antitumor activity: studies of the biological activities of berberine. Front Pharmacol, 10(2), 9-55. DOI: https://doi.org/10.3389/fphar.2019.00009
Lu, K. (2023). Cellular pathogenesis of hepatic encephalopathy: An update. Biomolecules, 13(2), 17-26. doi:10.3390/biom13020396 DOI: https://doi.org/10.3390/biom13020396
Luo, M., Xin, R. J., Hu, F. R., Yao, L., Hu, S. J., & Bai, F. H. (2023). Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis. World J Gastroenterol, 29(1), 144-156. doi:10.3748/wjg.v29.i1.144 DOI: https://doi.org/10.3748/wjg.v29.i1.144
Mondal, P., & Trigun, S. K. (2014). Pannexin1 as a novel cerebral target in pathogenesis of hepatic encephalopathy. Metab Brain Dis, 29(4), 1007-1015. doi:10.1007/s11011-014-9556-x DOI: https://doi.org/10.1007/s11011-014-9556-x
Nassar, S. E., Abdalfattah, A. A., Hassan, S. S., & Nasif, E. M. (2021). Study of the effects of quercetin on experimentally induced hepatic toxicity in rats. Tanta Med J, 49(4), 227-233. DOI: https://doi.org/10.4103/tmj.tmj_12_20
Ohikere, K., & Wong, R. J. (2024). Hepatic encephalopathy: Clinical manifestations. Clin Liver Dis, 28(2), 253-263. doi:10.1016/j.cld.2024.01.005 DOI: https://doi.org/10.1016/j.cld.2024.01.005
Saleh, D. O., Mansour, D. F., & Fayez, A. M. (2021). Thioacetamide-induced acute hepatic encephalopathy: central vs peripheral effect of Allicin. Metab Brain Dis, 36(6), 1331-1340. doi:10.1007/s11011-021-00695-7 DOI: https://doi.org/10.1007/s11011-021-00695-7
Shurubor, Y. I., Rogozhin, A. E., Isakova, E. P., Deryabina, Y. I., & Krasnikov, B. F. (2023). Residual amino acid imbalance in rats during recovery from acute thioacetamide-induced hepatic encephalopathy indicates incomplete healing. Int J Mol Sci, 24(4), 17-25. doi:10.3390/ijms24043647 DOI: https://doi.org/10.3390/ijms24043647
Tian, E., Sharma, G., & Dai, C. (2023). Neuroprotective properties of berberine: Molecular mechanisms and clinical implications. Antioxidants (Basel), 125(10), 10-26. doi:10.3390/antiox12101883 DOI: https://doi.org/10.3390/antiox12101883
Vairappan, B., Sundhar, M., & Srinivas, B. H. (2019). Resveratrol restores neuronal tight junction proteins through correction of ammonia and inflammation in CCl(4)-induced cirrhotic mice. Mol Neurobiol, 56(7), 4718-4729. doi:10.1007/s12035-018-1389-x DOI: https://doi.org/10.1007/s12035-018-1389-x
Wang, H., Zhang, H., Gao, Z., Zhang, Q., & Gu, C. (2022). The mechanism of berberine alleviating metabolic disorder based on gut microbiome. Front Cell Infect Microbiol, 12(5), 85-175. doi:10.3389/fcimb.2022.854885 DOI: https://doi.org/10.3389/fcimb.2022.854885
Yan, M., Man, S., Sun, B., Ma, L., Guo, L., Huang, L., & Gao, W. (2023). Gut liver brain axis in diseases: the implications for therapeutic interventions. Signal Transduct Target Ther, 8(1), 443-459. DOI: https://doi.org/10.1038/s41392-023-01673-4
Yang, F., Gao, R., Luo, X., Liu, R., & Xiong, D. (2023a). Berberine influences multiple diseases by modifying gut microbiota. Front Nutr, 10(2), 118-718. doi:10.3389/fnut.2023.1187718
Yang, F., Gao, R., Luo, X., Liu, R., & Xiong, D. (2023b). Berberine influences multiple diseases by modifying gut microbiota. Front Nutr, 10, 1187718. doi:10.3389/fnut.2023.1187718 DOI: https://doi.org/10.3389/fnut.2023.1187718
Yang, L., Bian, X., Wu, W., Lv, L., Li, Y., Ye, J., . . . Li, L. (2020). Protective effect of Lactobacillus salivarius Li01 on thioacetamide-induced acute liver injury and hyperammonaemia. Microb Biotechnol, 13(6), 1860-1876. doi:10.1111/1751-7915.13629 DOI: https://doi.org/10.1111/1751-7915.13629
Yi, J., Wu, S., Tan, S., Qin, Y., Wang, X., Jiang, J., . . . Wu, B. (2021). Berberine alleviates liver fibrosis through inducing ferrous redox to activate ROS-mediated hepatic stellate cells ferroptosis. Cell Death Discov, 7(1), 374-378. doi:10.1038/s41420-021-00768-7 DOI: https://doi.org/10.1038/s41420-021-00768-7
Yuan, L., Li, W., Li, G., Jin, W., Wang, B., Li, S., & Wang, H. (2025). Effect of berberine on LPS-induced intestinal epithelial injury and m6A methylation in broilers. Poult Sci, 178(55), 105-677. DOI: https://doi.org/10.1016/j.psj.2025.105677
Zhang, Z.-W., Wang, W.-P., Hu, J.-C., Lu, J.-Y., Feng, R., Xu, S.-F., . . . Xu, H. (2025). Berberine protects cerebral vessels and alleviates diabetic encephalopathy by inhibiting the production of δ-valerobetaine in the gut microbiota. Engineering, 49(5), 290-303. DOI: https://doi.org/10.1016/j.eng.2025.04.018
Zhang, Z., Li, B., Meng, X., Yao, S., Jin, L., Yang, J., . . . Ning, G. (2016). Berberine prevents progression from hepatic steatosis to steatohepatitis and fibrosis by reducing endoplasmic reticulum stress. Sci Rep, 6(2), 20-48. doi:10.1038/srep20848 DOI: https://doi.org/10.1038/srep20848
Zhou, Z., Li, K., Guo, J., Wang, Y., Wei, Y., Duan, J., . . . Hu, W. (2023). Green tea catechin EGCG ameliorates thioacetamide-induced hepatic encephalopathy in rats via modulation of the microbiota-gut-liver axis. Mol Nutr Food Res, 67(8), 22-55. doi:10.1002/mnfr.202200821 DOI: https://doi.org/10.1002/mnfr.202200821
Zhu, Y., Geng, S.-Y., Chen, Y., Ru, Q.-J., Zheng, Y., Jiang, N., . . . Zhang, Y.-S. (2025). Machine learning algorithms reveal gut microbiota signatures associated with chronic hepatitis B-related hepatic fibrosis. World J Gastroenterol, 31(16), 105-120. DOI: https://doi.org/10.3748/wjg.v31.i16.105985
Zhu, Z., Xueying, L., Chunlin, L., Wen, X., Rongrong, Z., Jing, H., . . . Zili, W. (2020). Effect of berberine on LPS-induced expression of NF-κB/MAPK signalling pathway and related inflammatory cytokines in porcine intestinal epithelial cells. Innate Immun, 26(7), 627-634. doi:10.1177/1753425920930074 DOI: https://doi.org/10.1177/1753425920930074
Published
How to Cite
Issue
Section
Copyright (c) 2026 International journal of health sciences
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Articles published in the International Journal of Health Sciences (IJHS) are available under Creative Commons Attribution Non-Commercial No Derivatives Licence (CC BY-NC-ND 4.0). Authors retain copyright in their work and grant IJHS right of first publication under CC BY-NC-ND 4.0. Users have the right to read, download, copy, distribute, print, search, or link to the full texts of articles in this journal, and to use them for any other lawful purpose.
Articles published in IJHS can be copied, communicated and shared in their published form for non-commercial purposes provided full attribution is given to the author and the journal. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
This copyright notice applies to articles published in IJHS volumes 4 onwards. Please read about the copyright notices for previous volumes under Journal History.
