Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2016

Open Access 01-12-2016 | Research article

Dose-response effect of berberine on bile acid profile and gut microbiota in mice

Authors: Ying Guo, YouCai Zhang, WeiHua Huang, Felcy Pavithra Selwyn, Curtis D. Klaassen

Published in: BMC Complementary Medicine and Therapies | Issue 1/2016

Login to get access

Abstract

Background

Berberine (BBR) is a traditional antimicrobial herbal medicine. Recently, BBR has gained popularity as a supplement to lower blood lipids, cholesterol and glucose. Bile acids (BAs) are known to regulate blood levels of triglycerides, cholesterol, glucose and energy homeostasis, and gut flora play an important role in BA metabolism. However, whether BBR alters BAs metabolism or dose-response effect of BBR on gut flora is unknown.

Methods

In this study, the effects of various doses of BBR on the concentrations of BAs in liver and serum of male C57BL/6 mice were determined by UPLC-MS/MS, and the expression of BA-related genes, as well as the amount of 32 of the most abundant gut bacterial species in the terminal ileum and large intestine of male C57BL/6 mice were quantified by RT-PCR and Quantigene 2.0 Reagent System, respectively.

Results

Unconjugated BAs and total BAs were significantly altered by BBR in serum but not in liver. Increased primary BAs (βMCA, TβMCA and TUDCA) and decreased secondary BAs (DCA, LCA and the T-conjugates) were observed in livers and serum of mice fed BBR. The expression of BA-synthetic enzymes (Cyp7a1 and 8b1) and uptake transporter (Ntcp) increased 39-400 % in liver of mice fed the higher doses of BBR, whereas nuclear receptors and efflux transporters were not markedly altered. In addition, Bacteroides were enriched in the terminal ileum and large bowel of mice treated with BBR.

Conclusion

The present study indicated that various doses of BBR have effects on BA metabolism and related genes as well as intestinal flora, which provides insight into many pathways of BBR effects.
Appendix
Available only for authorised users
Literature
1.
go back to reference Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. 1999;159(22):2647–58.CrossRefPubMed Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. 1999;159(22):2647–58.CrossRefPubMed
2.
go back to reference Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484–9. doi:10.1038/nature04330.CrossRefPubMed Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484–9. doi:10.​1038/​nature04330.CrossRefPubMed
3.
go back to reference Fiorucci S, Cipriani S, Mencarelli A, Renga B, Distrutti E, Baldelli F. Counter-regulatory role of bile acid activated receptors in immunity and inflammation. Curr Mol Med. 2010;10(6):579–95.PubMed Fiorucci S, Cipriani S, Mencarelli A, Renga B, Distrutti E, Baldelli F. Counter-regulatory role of bile acid activated receptors in immunity and inflammation. Curr Mol Med. 2010;10(6):579–95.PubMed
5.
go back to reference Powolny A, Xu J, Loo G. Deoxycholate induces DNA damage and apoptosis in human colon epithelial cells expressing either mutant or wild-type p53. Int J Biochem Cell Biol. 2001;33(2):193–203.CrossRefPubMed Powolny A, Xu J, Loo G. Deoxycholate induces DNA damage and apoptosis in human colon epithelial cells expressing either mutant or wild-type p53. Int J Biochem Cell Biol. 2001;33(2):193–203.CrossRefPubMed
7.
go back to reference McGarr SE, Ridlon JM, Hylemon PB. Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature. J Clin Gastroenterol. 2005;39(2):98–109.PubMed McGarr SE, Ridlon JM, Hylemon PB. Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature. J Clin Gastroenterol. 2005;39(2):98–109.PubMed
13.
go back to reference Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell. 2000;6(3):507–15.CrossRefPubMed Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell. 2000;6(3):507–15.CrossRefPubMed
14.
go back to reference Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17(2):225–35. doi:10.1016/j.cmet.2013.01.003.CrossRefPubMed Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17(2):225–35. doi:10.​1016/​j.​cmet.​2013.​01.​003.CrossRefPubMed
16.
go back to reference Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3(5):543–53.CrossRefPubMed Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3(5):543–53.CrossRefPubMed
17.
go back to reference Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284(5418):1362–5.CrossRefPubMed Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284(5418):1362–5.CrossRefPubMed
18.
20.
go back to reference Csanaky IL, Lu H, Zhang Y, Ogura K, Choudhuri S, Klaassen CD. Organic anion-transporting polypeptide 1b2 (Oatp1b2) is important for the hepatic uptake of unconjugated bile acids: Studies in Oatp1b2-null mice. Hepatology. 2011;53(1):272–81. doi:10.1002/hep.23984.CrossRefPubMed Csanaky IL, Lu H, Zhang Y, Ogura K, Choudhuri S, Klaassen CD. Organic anion-transporting polypeptide 1b2 (Oatp1b2) is important for the hepatic uptake of unconjugated bile acids: Studies in Oatp1b2-null mice. Hepatology. 2011;53(1):272–81. doi:10.​1002/​hep.​23984.CrossRefPubMed
23.
go back to reference Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;10(12):1–23. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;10(12):1–23.
24.
go back to reference Homma N, Kono M, Kadohira H, Yoshihara S, Masuda S. The effect of berberine chloride on the intestinal flora of infants. Arzneimittelforschung. 1961;11:450–4.PubMed Homma N, Kono M, Kadohira H, Yoshihara S, Masuda S. The effect of berberine chloride on the intestinal flora of infants. Arzneimittelforschung. 1961;11:450–4.PubMed
25.
go back to reference Chae SH, Jeong IH, Choi DH, Oh JW, Ahn YJ. Growth-inhibiting effects of Coptis japonica root-derived isoquinoline alkaloids on human intestinal bacteria. J Agric Food Chem. 1999;47(3):934–8.CrossRefPubMed Chae SH, Jeong IH, Choi DH, Oh JW, Ahn YJ. Growth-inhibiting effects of Coptis japonica root-derived isoquinoline alkaloids on human intestinal bacteria. J Agric Food Chem. 1999;47(3):934–8.CrossRefPubMed
28.
go back to reference Zhang Q, Xiao X, Feng K, Wang T, Li W, Yuan T et al. Berberine moderates glucose and lipid metabolism through multipathway mechanism. Evid Based Complement Altern Med. 2011;2011. doi:10.1155/2011/924851 Zhang Q, Xiao X, Feng K, Wang T, Li W, Yuan T et al. Berberine moderates glucose and lipid metabolism through multipathway mechanism. Evid Based Complement Altern Med. 2011;2011. doi:10.​1155/​2011/​924851
31.
go back to reference Chan MY. The effect of berberine on bilirubin excretion in the rat. Comp Med East West. 1977;5(2):161–8.PubMed Chan MY. The effect of berberine on bilirubin excretion in the rat. Comp Med East West. 1977;5(2):161–8.PubMed
35.
go back to reference Masuda N. Deconjugation of bile salts by Bacteroids and Clostridium. Microbiol Immunol. 1981;25(1):1–11.CrossRefPubMed Masuda N. Deconjugation of bile salts by Bacteroids and Clostridium. Microbiol Immunol. 1981;25(1):1–11.CrossRefPubMed
36.
go back to reference Ohiwa T, Katagiri K, Hoshino M, Hayakawa T, Nakai T. Tauroursodeoxycholate and tauro-beta-muricholate exert cytoprotection by reducing intrahepatocyte taurochenodeoxycholate content. Hepatology. 1993;17(3):470–6.PubMed Ohiwa T, Katagiri K, Hoshino M, Hayakawa T, Nakai T. Tauroursodeoxycholate and tauro-beta-muricholate exert cytoprotection by reducing intrahepatocyte taurochenodeoxycholate content. Hepatology. 1993;17(3):470–6.PubMed
37.
go back to reference Takikawa H, Sano N, Aiso M, Takamori Y, Yamanaka M. Effect of tauro-alpha-muricholate and tauro-beta-muricholate on oestradiol-17 beta-glucuronide-induced cholestasis in rats. J Gastroenterol Hepatol. 1997;12(1):84–6.CrossRefPubMed Takikawa H, Sano N, Aiso M, Takamori Y, Yamanaka M. Effect of tauro-alpha-muricholate and tauro-beta-muricholate on oestradiol-17 beta-glucuronide-induced cholestasis in rats. J Gastroenterol Hepatol. 1997;12(1):84–6.CrossRefPubMed
38.
go back to reference Milkiewicz P, Roma MG, Elias E, Coleman R. Hepatoprotection with tauroursodeoxycholate and beta muricholate against taurolithocholate induced cholestasis: involvement of signal transduction pathways. Gut. 2002;51(1):113–9.CrossRefPubMedPubMedCentral Milkiewicz P, Roma MG, Elias E, Coleman R. Hepatoprotection with tauroursodeoxycholate and beta muricholate against taurolithocholate induced cholestasis: involvement of signal transduction pathways. Gut. 2002;51(1):113–9.CrossRefPubMedPubMedCentral
39.
go back to reference Jiang Q, Liu P, Wu X, Liu W, Shen X, Lan T, et al. Berberine attenuates lipopolysaccharide-induced extracelluar matrix accumulation and inflammation in rat mesangial cells: involvement of NF-kappaB signaling pathway. Mol Cell Endocrinol. 2011;331(1):34–40. doi:10.1016/j.mce.2010.07.023.CrossRefPubMed Jiang Q, Liu P, Wu X, Liu W, Shen X, Lan T, et al. Berberine attenuates lipopolysaccharide-induced extracelluar matrix accumulation and inflammation in rat mesangial cells: involvement of NF-kappaB signaling pathway. Mol Cell Endocrinol. 2011;331(1):34–40. doi:10.​1016/​j.​mce.​2010.​07.​023.CrossRefPubMed
40.
go back to reference Kim S, Choi JH, Kim JB, Nam SJ, Yang JH, Kim JH, et al. Berberine suppresses TNF-alpha-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast cancer cells. Molecules. 2008;13(12):2975–85. doi:10.3390/molecules13122975.CrossRefPubMed Kim S, Choi JH, Kim JB, Nam SJ, Yang JH, Kim JH, et al. Berberine suppresses TNF-alpha-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast cancer cells. Molecules. 2008;13(12):2975–85. doi:10.​3390/​molecules1312297​5.CrossRefPubMed
43.
go back to reference Fisher MM, Magnusson R, Miyai K. Bile acid metabolism in mammals. I. Bile acid-induced intrahepatic cholestasis. Lab Invest. 1971;25(1):88–91.PubMed Fisher MM, Magnusson R, Miyai K. Bile acid metabolism in mammals. I. Bile acid-induced intrahepatic cholestasis. Lab Invest. 1971;25(1):88–91.PubMed
44.
45.
go back to reference Bayerdorffer E, Mannes GA, Ochsenkuhn T, Dirschedl P, Paumgartner G. Variation of serum bile acids in patients with colorectal adenomas during a one-year follow-up. Digestion. 1994;55(2):121–9.CrossRefPubMed Bayerdorffer E, Mannes GA, Ochsenkuhn T, Dirschedl P, Paumgartner G. Variation of serum bile acids in patients with colorectal adenomas during a one-year follow-up. Digestion. 1994;55(2):121–9.CrossRefPubMed
46.
go back to reference Bayerdorffer E, Mannes GA, Richter WO, Ochsenkuhn T, Wiebecke B, Kopcke W, et al. Increased serum deoxycholic acid levels in men with colorectal adenomas. Gastroenterology. 1993;104(1):145–51.CrossRefPubMed Bayerdorffer E, Mannes GA, Richter WO, Ochsenkuhn T, Wiebecke B, Kopcke W, et al. Increased serum deoxycholic acid levels in men with colorectal adenomas. Gastroenterology. 1993;104(1):145–51.CrossRefPubMed
47.
go back to reference Chadwick VS, Gaginella TS, Carlson GL, Debongnie JC, Phillips SF, Hofmann AF. Effect of molecular structure on bile acid-induced alterations in absorptive function, permeability, and morphology in the perfused rabbit colon. J Lab Clin Med. 1979;94(5):661–74.PubMed Chadwick VS, Gaginella TS, Carlson GL, Debongnie JC, Phillips SF, Hofmann AF. Effect of molecular structure on bile acid-induced alterations in absorptive function, permeability, and morphology in the perfused rabbit colon. J Lab Clin Med. 1979;94(5):661–74.PubMed
48.
go back to reference Wang Y, Huang Y, Lam KS, Li Y, Wong WT, Ye H, et al. Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc Res. 2009;82(3):484–92. doi:10.1093/cvr/cvp078.CrossRefPubMed Wang Y, Huang Y, Lam KS, Li Y, Wong WT, Ye H, et al. Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc Res. 2009;82(3):484–92. doi:10.​1093/​cvr/​cvp078.CrossRefPubMed
49.
go back to reference Keitel V, Reinehr R, Gatsios P, Rupprecht C, Gorg B, Selbach O, et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007;45(3):695–704. doi:10.1002/hep.21458.CrossRefPubMed Keitel V, Reinehr R, Gatsios P, Rupprecht C, Gorg B, Selbach O, et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007;45(3):695–704. doi:10.​1002/​hep.​21458.CrossRefPubMed
Metadata
Title
Dose-response effect of berberine on bile acid profile and gut microbiota in mice
Authors
Ying Guo
YouCai Zhang
WeiHua Huang
Felcy Pavithra Selwyn
Curtis D. Klaassen
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2016
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-016-1367-7

Other articles of this Issue 1/2016

BMC Complementary Medicine and Therapies 1/2016 Go to the issue