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Microbiota transplantation reveals beneficial impact of berberine on hepatotoxicity by improving gut homeostasis

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Abstract

Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products and metabolites. In this study, we showed that berberine has beneficial effects on both hepatotoxicity and intestinal damage in a rat model of chronic or acute liver injury. Microbiota transplantation from the rats with chronic hepatotoxicity could aggravate acute hepatotoxicity in mice treated with diethylnitrosamine (DEN). In rat models with gut homeostasis disruption induced by penicillin or dextran sulfate sodium (DSS), their fecal microbiota could also cause an enhanced hepatotoxicity of recipient mice. When treated with berberine, the DSS-induced enteric dysbacteriosis could be mitigated and their fecal bacteria were able to reduce acute hepatotoxicity in recipient mice. This study indicates that berberine could improve intestinal dysbacteriosis, which reduces the hepatotoxicity caused by pathological or pharmacological intervention. Fecal microbiota transplantation might be a useful method to directly explore homeostatic alteration in gut microbiota.

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References

  • Alolga, R.N., Fan, Y., Chen, Z., Liu, L.W., Zhao, Y.J., Li, J., Chen, Y., Lai, M.D., Li, P., and Qi, L.W. (2016). Significant pharmacokinetic differences of berberine are attributable to variations in gut microbiota between Africans and Chinese. Sci Rep 6, 27671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alpini, G., Lenzi, R., Sarkozi, L., and Tavoloni, N. (1988). Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules. J Clin Investig 81, 569–578.

    CAS  PubMed  Google Scholar 

  • Bakken, J.S., Borody, T., Brandt, L.J., Brill, J.V., Demarco, D.C., Franzos, M.A., Kelly, C., Khoruts, A., Louie, T., Martinelli, L.P., Moore, T.A., Russell, G., Surawicz, C., and Surawicz, C. (2011). Treating clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 9, 1044–1049.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bernal, W., and Wendon, J. (2013). Acute liver failure. N Engl J Med 369, 2525–2534.

    Article  CAS  Google Scholar 

  • Betrapally, N.S., Gillevet, P.M., and Bajaj, J.S. (2016). Gut microbiome and liver disease. Transl Res 179, 49–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bojanova, D.P., and Bordenstein, S.R. (2016). Fecal transplants: what is being transferred? PLoS Biol 14, e1002503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borody, T.J., and Khoruts, A. (2011). Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 9, 88–96.

    Article  CAS  PubMed  Google Scholar 

  • Cao, Y., Pan, Q., Cai, W., Shen, F., Chen, G.Y., Xu, L.M., and Fan, J.G. (2016). Modulation of gut microbiota by berberine improves steatohepatitis in high-fat diet-fed BALB/C mice. Arch Iranian Med 19, 197–203.

    Google Scholar 

  • Caradonna, L., Amati, L., Magrone, T., Pellegrino, N.M., Jirillo, E., and Caccavo, D. (2000). Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance. J Endotoxin Res 6, 205–214.

    CAS  PubMed  Google Scholar 

  • Chen, C., Yu, Z., Li, Y., Fichna, J., and Storr, M. (2014). Effects of berberine in the gastrointestinal tract—A review of actions and therapeutic implications. Am J Chin Med 42, 1053–1070.

    Article  CAS  PubMed  Google Scholar 

  • Chen, X., Zhang, Y., Zhu, Z., Liu, H., Guo, H., Xiong, C., Xie, K., Zhang, X., and Su, S. (2016). Protective effect of berberine on doxorubicin-induced acute hepatorenal toxicity in rats. Mol Med Rep 13, 3953–3960.

    Article  CAS  PubMed  Google Scholar 

  • Cicero, A.F., and Baggioni, A. (2016). Berberine and its role in chronic disease. Adv Exp Med Biol 928, 27–45.

    Article  CAS  PubMed  Google Scholar 

  • Davern, T.J. (2012). Drug-induced liver disease. Clin Liver Dis 16, 231–245.

    Article  PubMed  Google Scholar 

  • De Minicis, S., Rychlicki, C., Agostinelli, L., Saccomanno, S., Candelaresi, C., Trozzi, L., Mingarelli, E., Facinelli, B., Magi, G., Palmieri, C., Marzioni, M., Benedetti, A., and Svegliati-Baroni, G. (2014). Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology 59, 1738–1749.

    Article  CAS  PubMed  Google Scholar 

  • Derosa, G., Maffioli, P., and Cicero, A.F.G. (2012). Berberine on metabolic and cardiovascular risk factors: an analysis from preclinical evidences to clinical trials. Expert Opin Biol Ther 12, 1113–1124.

    Article  CAS  PubMed  Google Scholar 

  • Dong, H., Zhao, Y., Zhao, L., and Lu, F. (2013). The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials. Planta Med 79, 437–446.

    Article  CAS  PubMed  Google Scholar 

  • Francis, H., Franchitto, A., Ueno, Y., Glaser, S., DeMorrow, S., Venter, J., Gaudio, E., Alvaro, D., Fava, G., Marzioni, M., Vaculin, B., and Alpini, G. (2007). H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway. Lab Invest 87, 473–487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frazier, T.H., DiBaise, J.K., and McClain, C.J. (2011). Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury. JPEN J Parenter Enteral Nutr 35, 14S–20S.

    Article  Google Scholar 

  • Fukui, H. (2015). Gut microbiota and host reaction in liver diseases. Microorganisms 3, 759–791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaudio, E., Taddei, G., Vetuschi, A., Sferra, R., Frieri, G., Ricciardi, G., and Caprilli, R. (1999). Dextran sulfate sodium (DSS) colitis in rats: clinical, structural, and ultrastructural aspects. Dig Dis Sci 44, 1458–1475.

    Article  CAS  PubMed  Google Scholar 

  • Gregory, J.C., Buffa, J.A., Org, E., Wang, Z., Levison, B.S., Zhu, W., Wagner, M.A., Bennett, B.J., Li, L., DiDonato, J.A., Lusis, A.J., and Hazen, S.L. (2015). Transmission of atherosclerosis susceptibility with gut microbial transplantation. J Biol Chem 290, 5647–5660.

    Article  CAS  PubMed  Google Scholar 

  • Gu, Y., Zhang, Y., Shi, X., Li, X., Hong, J., Chen, J., Gu, W., Lu, X., Xu, G., and Ning, G. (2010). Effect of traditional Chinese medicine berberine on type 2 diabetes based on comprehensive metabonomics. Talanta 81, 766–772.

    Article  CAS  PubMed  Google Scholar 

  • Gupta, S., Allen-Vercoe, E., and Petrof, E.O. (2016). Fecal microbiota transplantation: in perspective. Therapeutic Adv Gastroenterol 9, 229–239.

    Article  Google Scholar 

  • Habtemariam, S. (2016). Berberine and inflammatory bowel disease: a concise review. Pharmacol Res 113, 592–599.

    Article  CAS  PubMed  Google Scholar 

  • Han, J., Lin, H., and Huang, W. (2011). Modulating gut microbiota as an antidiabetic mechanism of berberine. Med Sci Monit 17, RA164–RA167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He, Q., Mei, D., Sha, S., Fan, S., Wang, L., and Dong, M. (2016). ERKdependent mTOR pathway is involved in berberine-induced autophagy in hepatic steatosis. J Mol Endocrinol 59, X1–X1.

    Article  Google Scholar 

  • Hwang, J.M., Wang, C.J., Chou, F.P., Tseng, T.H., Hsieh, Y.S., Lin, W.L., and Chu, C.Y. (2002). Inhibitory effect of berberine on tert-butyl hydroperoxide- induced oxidative damage in rat liver. Arch Toxicol 76, 664–670.

    Article  CAS  PubMed  Google Scholar 

  • Imenshahidi, M., and Hosseinzadeh, H. (2016). Berberis Vulgaris and Berberine: an update review. Phytother Res 30, 1745–1764.

    Article  PubMed  Google Scholar 

  • Jayashree, B., Bibin, Y.S., Prabhu, D., Shanthirani, C.S., Gokulakrishnan, K., Lakshmi, B.S., Mohan, V., and Balasubramanyam, M. (2014). Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol Cell Biochem 388, 203–210.

    Article  CAS  PubMed  Google Scholar 

  • Ji, H.F., and Shen, L. (2011). Berberine: a potential multipotent natural product to combat Alzheimer’s disease. Molecules 16, 6732–6740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khin Maung, U., Myo, K., Nyunt Nyunt, W., Aye, K., and Tin, U. (1985). Clinical trial of berberine in acute watery diarrhoea. Br Med J 291, 1601–1605.

    Article  Google Scholar 

  • Kong, W., Wei, J., Abidi, P., Lin, M., Inaba, S., Li, C., Wang, Y., Wang, Z., Si, S., Pan, H., Wang, S., Wu, J., Wang, Y., Li, Z., Liu, J., and Jiang, J.D. (2004). Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10, 1344–1351.

    Article  CAS  PubMed  Google Scholar 

  • Mekawi, M. (1966). Effect of berberine alkaloid on cholera Vibro and its endotoxin. J Egypt Med Assoc 49, 554–559.

    CAS  PubMed  Google Scholar 

  • Mo, C., Wang, L., Zhang, J., Numazawa, S., Tang, H., Tang, X., Han, X., Li, J., Yang, M., Wang, Z., Wei, D., and Xiao, H. (2014). The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin- shocked mice. Antioxid Redox Signal 20, 574–588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pang, B., Zhao, L.H., Zhou, Q., Zhao, T.Y., Wang, H., Gu, C.J., and Tong, X.L. (2015). Application of berberine on treating type 2 diabetes mellitus. Int J Endocrinol 2015, 1–12.

    Article  CAS  Google Scholar 

  • Potdar, D., Hirwani, R.R., and Dhulap, S. (2012). Phyto-chemical and pharmacological applications of Berberis aristata. Fitoterapia 83, 817–830.

    Article  CAS  PubMed  Google Scholar 

  • Qin, N., Yang, F., Li, A., Prifti, E., Chen, Y., Shao, L., Guo, J., Le Chatelier, E., Yao, J., Wu, L., Zhou, J., Ni, S., Liu, L., Pons, N., Batto, J.M., Kennedy, S.P., Leonard, P., Yuan, C., Ding, W., Chen, Y., Hu, X., Zheng, B., Qian, G., Xu, W., Ehrlich, S.D., Zheng, S., and Li, L. (2014). Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64.

    Article  CAS  PubMed  Google Scholar 

  • Quigley, E.M., Stanton, C., and Murphy, E.F. (2013). The gut microbiota and the liver. Pathophysiological and clinical implications. J Hepatol 58, 1020–1027.

    PubMed  Google Scholar 

  • Rabbani, G.H., Butler, T., Knight, J., Sanyal, S.C., and Alam, K. (1987). Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae. J Infect Dis 155, 979–984.

    Article  CAS  PubMed  Google Scholar 

  • Savage, D.C., and Dubos, R. (1968). Alterations in the mouse cecum and its flora produced by antibacterial drugs. J Exp Med 128, 97–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh, A., Bajpai, V., Srivastava, M., Arya, K.R., and Kumar, B. (2014). Rapid profiling and structural characterization of bioactive compounds and their distribution in different parts of Berberis petiolaris Wall. ex G. Don applying hyphenated mass spectrometric techniques. Rapid Commun Mass Spectrom 28, 2089–2100.

    Article  CAS  Google Scholar 

  • Sun, D., Abraham, S.N., and Beachey, E.H. (1988). Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli. Antimicrob Agents Chemother 32, 1274–1277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang, L.Q., Ni, W.J., Cai, M., Ding, H.H., Liu, S., and Zhang, S.T. (2016). Renoprotective effects of berberine and its potential effect on the expreßsion of β-arrestins and intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in streptozocin-diabetic nephropathy rats. J Diabetes 8, 693–700.

    Article  CAS  PubMed  Google Scholar 

  • Turnbaugh, P.J., Ley, R.E., Mahowald, M.A., Magrini, V., Mardis, E.R., and Gordon, J.I. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–131.

    Article  PubMed  Google Scholar 

  • Turnbaugh, P.J., Ridaura, V.K., Faith, J.J., Rey, F.E., Knight, R., and Gordon, J.I. (2009). The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1, 6ra14–6ra14.

    Article  CAS  Google Scholar 

  • Wyatt, J., Vogelsang, H., Hübl, W., Waldhoer, T., and Lochs, H. (1993). Intestinal permeability and the prediction of relapse in Crohri’s disease. Lancet 341, 1437–1439.

    Article  CAS  PubMed  Google Scholar 

  • Yao, J., Kong, W.J., and Jiang, J.D. (2015). Learning from berberine: treating chronic diseases through multiple targets. Sci China Life Sci 58, 854–859.

    Article  CAS  PubMed  Google Scholar 

  • Yu, L.X., Yan, H.X., Liu, Q., Yang, W., Wu, H.P., Dong, W., Tang, L., Lin, Y., He, Y.Q., Zou, S.S., Wang, C., Zhang, H.L., Cao, G.W., Wu, M.C., and Wang, H.Y. (2010). Endotoxin accumulation prevents carcinogen- induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322–1333.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, H.L., Yu, L.X., Yang, W., Tang, L., Lin, Y., Wu, H., Zhai, B., Tan, Y.X., Shan, L., Liu, Q., Chen, H.Y., Dai, R.Y., Qiu, B.J., He, Y.Q., Wang, C., Zheng, L.Y., Li, Y.Q., Wu, F.Q., Li, Z., Yan, H.X., and Wang, H.Y. (2012a). Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J Hepatol 57, 803–812.

    Article  PubMed  Google Scholar 

  • Zhang, P., Ma, D., Wang, Y., Zhang, M., Qiang, X., Liao, M., Liu, X., Wu, H., and Zhang, Y. (2014a). Berberine protects liver from ethanol-induced oxidative stress and steatosis in mice. Food Chem Toxicol 74, 225–232.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, X., Zhao, Y., Zhang, M., Pang, X., Xu, J., Kang, C., Li, M., Zhang, C., Zhang, Z., Zhang, Y., Li, X., Ning, G., and Zhao, L. (2012b). Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS ONE 7, e42529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, Z., Zhang, H., Li, B., Meng, X., Wang, J., Zhang, Y., Yao, S., Ma, Q., Jin, L., Yang, J., Wang, W., and Ning, G. (2014b). Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun 5, 5493.

    Article  CAS  PubMed  Google Scholar 

  • Zhao, G., Yu, L., Gao, W., Duan, W., Jiang, B., Liu, X., Zhang, B., Liu, Z., Zhai, M., Jin, Z., Yu, S., and Wang, Y. (2016). Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress. Acta Pharmacol Sin 37, 354–367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou, J.Y., Zhou, S.W., Zhang, K.B., Tang, J.L., Guang, L.X., Ying, Y., Xu, Y., Zhang, L., and Li, D.D. (2008). Chronic effects of berberine on blood, liver glucolipid metabolism and liver PPARs expression in diabetic hyperlipidemic rats. Biol Pharmaceut Bull 31, 1169–1176.

    Article  CAS  Google Scholar 

  • Zhu, W., Gregory, J.C., Org, E., Buffa, J.A., Gupta, N., Wang, Z., Li, L., Fu, X., Wu, Y., Mehrabian, M., Sartor, R.B., McIntyre, T.M., Silverstein, R.L., Tang, W.H.W., DiDonato, J.A., Brown, J.M., Lusis, A.J., and Hazen, S.L. (2016). Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the projects of the National Key Research Program of China (2016YFC1101402), the National Natural Science Foundation of China (31371440, 31571477) and Program of Shanghai Academic/Technology Research Leader (16XD1403300).

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Authors and Affiliations

  1. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, 200438, China

    Chenjie Qin, Linghao Zhao, Min Zeng, Weijian Huang, Gongbo Fu, Weiping Zhou, Hongyang Wang & Hexin Yan

  2. National Center for Liver Cancer Research, Shanghai, 201805, China

    Chenjie Qin, Linghao Zhao, Min Zeng, Weijian Huang, Gongbo Fu, Weiping Zhou, Hongyang Wang & Hexin Yan

  3. Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Huilu Zhang

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  1. Chenjie Qin
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Qin, C., Zhang, H., Zhao, L. et al. Microbiota transplantation reveals beneficial impact of berberine on hepatotoxicity by improving gut homeostasis. Sci. China Life Sci. 61, 1537–1544 (2018). https://doi.org/10.1007/s11427-017-9202-0

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