Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Prebiotics enhance the biotransformation and bioavailability of ginsenosides in rats by modulating gut microbiota

  • Zhang, Xiaoyan (Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences) ;
  • Chen, Sha (Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences) ;
  • Duan, Feipeng (Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences) ;
  • Liu, An (Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences) ;
  • Li, Shaojing (Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences) ;
  • Zhong, Wen (Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences) ;
  • Sheng, Wei (College of Life Science, Huaibei Normal University) ;
  • Chen, Jun (Big Data and Engineering Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health) ;
  • Xu, Jiang (Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences) ;
  • Xiao, Shuiming (Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences)
  • Received : 2020.01.03
  • Accepted : 2020.08.02
  • Published : 2021.03.01
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Abstract

Background: Gut microbiota mainly function in the biotransformation of primary ginsenosides into bioactive metabolites. Herein, we investigated the effects of three prebiotic fibers by targeting gut microbiota on the metabolism of ginsenoside Rb1 in vivo. Methods: Sprague Dawley rats were administered with ginsenoside Rb1 after a two-week prebiotic intervention of fructooligosaccharide, galactooligosaccharide, and fibersol-2, respectively. Pharmacokinetic analysis of ginsenoside Rb1 and its metabolites was performed, whilst the microbial composition and metabolic function of gut microbiota were examined by 16S rRNA gene amplicon and metagenomic shotgun sequencing. Results: The results showed that peak plasma concentration and area under concentration time curve of ginsenoside Rb1 and its intermediate metabolites, ginsenoside Rd, F2, and compound K (CK), in the prebiotic intervention groups were increased at various degrees compared with those in the control group. Gut microbiota dramatically responded to the prebiotic treatment at both taxonomical and functional levels. The abundance of Prevotella, which possesses potential function to hydrolyze ginsenoside Rb1 into CK, was significantly elevated in the three prebiotic groups (P < 0.05). The gut metagenomic analysis also revealed the functional gene enrichment for terpenoid/polyketide metabolism, glycolysis, gluconeogenesis, propanoate metabolism, etc. Conclusion: These findings imply that prebiotics may selectively promote the proliferation of certain bacterial stains with glycoside hydrolysis capacity, thereby, subsequently improving the biotransformation and bioavailability of primary ginsenosides in vivo.

Keywords

Acknowledgement

This research was funded by the National Science and Technology Major Project (No. 2017ZX09301060-012; 2018ZX09201-011), the Youth Program of National Natural Science Foundation of China (No. 81503469) and the Emergency Management Project of National Natural Science Foundation of China (No. 81741060). We would like to thank Zhiying Huang, Xiuting Zhang, Pengpeng Tian and Junqiu Liu for assistance in generating data.

References

  1. Hemmerly TE. A ginseng farm in Lawrence County, Tennessee. Econ Bot 1977;31:160-2. https://doi.org/10.1007/BF02866586
  2. Leung KW, Wong ST. Pharmacology of ginsenosides: a literature review. Chin Med 2010;5:20. https://doi.org/10.1186/1749-8546-5-20
  3. Akao T, Kanaoka M, Kobashi K. Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration-measurement of compound K by enzyme immunoassay. Biol Pharm Bull 1998;21:245-9. https://doi.org/10.1248/bpb.21.245
  4. Akao T, Kida H, Kanaoka M, Hattori M, Kobashi K. Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of ginsenoside Rb1 from Panax ginseng. J Pharm Pharmacol 1998;50:1155-60. https://doi.org/10.1111/j.2042-7158.1998.tb03327.x
  5. Hasegawa H. Proof of the mysterious efficacy of ginseng: basic and clinical trials: metabolic activation of ginsenoside: deglycosylation by intestinal bacteria and esterification with fatty acid. J Pharmacol Sci 2004;95:153-7. https://doi.org/10.1254/jphs.FMJ04001X4
  6. Wang CZ, Du GJ, Zhang Z, Wen XD, Calway T, Zhen Z, Musch MW, Bissonnette M, Chang EB, Yuan CS. Ginsenoside compound K, not Rb1, possesses potential chemopreventive activities in human colorectal cancer. Int J Oncol 2012;40:1970-6. https://doi.org/10.3892/ijo.2012.1399
  7. Kim DH. Chemical diversity of Panax ginseng, Panax quinquifolium, and Panax notoginseng. J Gins Res 2012;36:1-15. https://doi.org/10.5142/jgr.2012.36.1.1
  8. Yan X, Fan Y, Wei W, Wang P, Liu Q, Wei Y, Zhang L, Zhao G, Yue J, Zhou Z. Production of bioactive ginsenoside compound K in metabolically engineered yeast. Cell Res 2014;24:770-3. https://doi.org/10.1038/cr.2014.28
  9. Lee J, Lee E, Kim D, Lee J, Yoo J, Koh B. Studies on absorption, distribution and metabolism of ginseng in humans after oral administration. J Ethnopharmacol 2009;122:143-8. https://doi.org/10.1016/j.jep.2008.12.012
  10. Marteau P, Pochart P, Flourie B, Pellier P, Santos L, Desjeux JF, Rambaud JC. Effect of chronic ingestion of a fermented dairy product containing Lactobacillus acidophilus and Bifidobacterium bifidum on metabolic activities of the colonic flora in humans. Am J Clin Nutr 1990;52:685-8. https://doi.org/10.1093/ajcn/52.4.685
  11. Kim KA, Yoo HH, Gu W, Yu DH, Jin MJ, Choi HL, Yuan K, Guerin-Deremaux L, Kim DH. Effect of a soluble prebiotic fiber, NUTRIOSE, on the absorption of ginsenoside Rd in rats orally administered ginseng. J Gins Res 2014;38:203-7. https://doi.org/10.1016/j.jgr.2014.03.003
  12. Goossens D, Jonkers D, Russel M, Stobberingh E, Bogaard AVD, Stockbrugger R. The effect of Lactobacillus plantarum 299v on the bacterial composition and metabolic activity in faeces of healthy volunteers: a placebo-controlled study on the onset and duration of effects. Aliment Pharmacol Ther 2003;18:495-505. https://doi.org/10.1046/j.1365-2036.2003.01708.x
  13. Kim KA, Jung IH, Park SH, Ahn YT, Huh CS, Kim DH. Comparative analysis of the gut microbiota in people with different levels of ginsenoside Rb1 degradation to compound K. PLoS One 2013;8:e62409. https://doi.org/10.1371/journal.pone.0062409
  14. Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J 2012;6:1621-4. https://doi.org/10.1038/ismej.2012.8
  15. Chen Y, Xiao S, Gong Z, Zhu X, Yang Q, Li Y, Gao S, Dong Y, Shi Z, Wang Y, et al. Wuji Wan formula ameliorates diarrhea and disordered colonic motility in post-inflammation irritable bowel syndrome rats by modulating the gut microbiota. Front Microbiol 2017;8:2307. https://doi.org/10.3389/fmicb.2017.02307
  16. Liu Z, Sun Y, Zhang Y, Feng W, Lai Z, Fa K, Qin S. Metagenomic and 13C tracing evidence for autotrophic atmospheric carbon absorption in a semiarid desert. Soil Biol Biochem 2018;125:156-66. https://doi.org/10.1016/j.soilbio.2018.07.012
  17. Luo R, Liu B, Xie Y, Li Z, Huang W, Yuan J, He G, Chen Y, Pan Q, Liu Y, et al. SOAPdenovo2: an empirically improved memory-efficient short-read de novo assembler. GigaScience 2012;1:18. https://doi.org/10.1186/2047-217X-1-18
  18. Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, Arumugam M, Kultima JR, Prifti E, Nielsen T, et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol 2014;32:834-41. https://doi.org/10.1038/nbt.2942
  19. Fu L, Niu B, Zhu Z, Wu S, Li W. Cd-Hit: Accelerated for clustering the next-generation sequencing data. Bioinformatics 2012;28:3150-2. https://doi.org/10.1093/bioinformatics/bts565
  20. Li R, Yu C, Li Y, Lam TW, Yiu SM, Kristiansen K, Wang J. SOAP2: an improved ultrafast tool for short read alignment. Bioinformatics 2009;25:1966-7. https://doi.org/10.1093/bioinformatics/btp336
  21. Huson DH, Mitra S, Ruscheweyh HJ, Weber N, Schuster SC. Integrative analysis of environmental sequences using MEGAN4. Genome Res 2011;21:1552-60. https://doi.org/10.1101/gr.120618.111
  22. Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M. The KEGG resource for deciphering the genome. Nucleic Acids Res 2004;32:D277. https://doi.org/10.1093/nar/gkh063
  23. Park BH, Karpinets TV, Syed MH, Leuze MR, Uberbacher EC. CAZymes Analysis Toolkit (CAT): web service for searching and analyzing carbohydrate-active enzymes in a newly sequenced organism using CAZy database. Glycobiology 2010;20:1574. https://doi.org/10.1093/glycob/cwq106
  24. Wilson ID, Nicholson JK. The role of gut microbiota in drug response. Curr Pharm Des 2009;15:1519-23. https://doi.org/10.2174/138161209788168173
  25. Saad R, Rizkallah MR, Aziz RK. Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog 2012;4:16. https://doi.org/10.1186/1757-4749-4-16
  26. Doestzada M, Vila AV, Zhernakova A, Koonen DPY, Weersma RK, Touw DJ, Kuipers F, Wijmenga C, Fu J. Pharmacomicrobiomics: a novel route towards personalized medicine? Protein Cell 2018;9:432-45. https://doi.org/10.1007/s13238-018-0547-2
  27. Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP. Adverse drug events in hospitalized patients: excess length of stay, extra costs, and attributable mortality. J Am Med Assoc 1997;277:301-6. https://doi.org/10.1001/jama.1997.03540280039031
  28. Haiser HJ, Turnbaugh PJ. Is it time for a metagenomic basis of therapeutics? Science 2012;336:1253-5. https://doi.org/10.1126/science.1224396
  29. Lhoste EF, Ouriet V, Bruel S, Flinois JP, Brezillon C, Magdalou J, Caroline C, Lionelle NB. The human colonic microflora influences the alterations of xenobiotic-metabolizing enzymes by catechins in male F344 rats. Food Chem Toxicol 2003;41:695-702. https://doi.org/10.1016/S0278-6915(03)00010-3
  30. Niu T, Smith DL, Yang Z, Gao S, Yin T, Jiang ZH, You M, Gibbs RA, Petrosino JF, Hu M. Bioactivity and bioavailability of ginsenosides are dependent on the glycosidase activities of the A/J mouse intestinal microbiome defined by pyrosequencing. Pharm Res 2013;30:836-46. https://doi.org/10.1007/s11095-012-0925-z
  31. Rossi M, Amaretti A, Leonardi A, Raimondi S, Simone M, Quartieri A. Potential impact of probiotic consumption on the bioactivity of dietary phytochemicals. J Agric Food Chem 2013;61:9551-8. https://doi.org/10.1021/jf402722m
  32. Kekkonen RA, Holma R, Hatakka K, Suomalainen T, Poussa T, Adlercreutz H, Korpela R. A probiotic mixture including galactooligosaccharides decreases fecal β-glucosidase activity but does not affect serum enterolactone concentration in men during a two-week intervention. J Nutr 2011;141:870-6. https://doi.org/10.3945/jn.110.137703
  33. Larkin TA, Price WE, Astheimer LB. Increased probiotic yogurt or resistant starch intake does not affect isoflavone bioavailability in subjects consuming a high soy diet. Nutrition 2007;23:709-18. https://doi.org/10.1016/j.nut.2007.06.010
  34. Nettleton JA, Greany KA, Thomas W, Wangen KE, Adlercreutz H, Kurzer MS. The effect of soy consumption on the urinary 2:16-hydroxyestrone ratio in postmenopausal women depends on equol production status but is not influenced by probiotic consumption. J Nutr 2005;135:603-8. https://doi.org/10.1093/jn/135.3.603
  35. Cohen LA, Crespin JS, Wolper C, Zang EA, Pittman B, Zhao Z, Holt PR. Soy isoflavone intake and estrogen excretion patterns in young women: effect of probiotic administration. In Vivo 2007;21:507-12.
  36. Avgustin G, Ramsak A, Peterka M. Systematics and evolution of ruminal species of the genus Prevotella. Folia Microbiol 2001;46:40-4. https://doi.org/10.1007/BF02825882
  37. Hasegawa H, Sung JH, Benno Y. Role of human intestinal Prevotella oris in hydrolyzing ginseng saponins. Planta Med 1997;63:436-40. https://doi.org/10.1055/s-2006-957729
  38. Gibson GR, Probert HM, Loo JV, Rastall RA, Roberfroid MB. Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev 2004;17:259-75. https://doi.org/10.1079/NRR200479
  39. Xu J, Chen HB, Li SL. Understanding the molecular mechanisms of the interplay between herbal medicines and gut microbiota. Med Res Rev 2017;37: 1140-85. https://doi.org/10.1002/med.21431
  40. Yang L, Akao T, Kobashi K. Purification and characterization of a geniposide-hydrolyzing β-glucosidase from Euhacterium sp. A-44, a strict anaerobe from human feces. Biol Pharm Bull 1995;18:1175-8. https://doi.org/10.1248/bpb.18.1175
  41. Nicholson JK, Holmes E, Wilson ID. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol 2005;3:431-8. https://doi.org/10.1038/nrmicro1152
  42. Zhou SS, Xu J, Zhu H, Wu J, Xu JD, Yan R, Li XY, Liu HH, Duan SM, Wang Z. Gut microbiota-involved mechanisms in enhancing systemic exposure of ginsenosides by coexisting polysaccharides in ginseng decoction. Sci Rep 2016;6:22474. https://doi.org/10.1038/srep22474
  43. Hasebe T, Ueno N, Musch MW, Nadimpalli A, Kaneko A, Kaifuchi N, Watanabe J, Yamamoto M, Kono T, Inaba Y. Daikenchuto (TU-100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K. Pharma Res Per 2016;4:e00215. https://doi.org/10.1002/prp2.215
  44. Henrissat B, Bairoch A. New families in the classification of glycosyl hydrolases based on amino acid sequence similarities. Biochem J 1993;293:781-8. https://doi.org/10.1042/bj2930781
  45. Park CS, Yoo MH, Noh KH, Oh DK. Biotransformation of ginsenosides by hydrolyzing the sugar moieties of ginsenosides using microbial glycosidases. Appl Microbiol Biotechnol 2010;87:9-19. https://doi.org/10.1007/s00253-010-2567-6
  46. Kim KA, Yoo HH, Gu W, Yu DH, Jin MJ, Choi HL, Kim DH, Yuan K, Guerin-Deremaux L. A prebiotic fiber increases the formation and subsequent absorption of compound K following oral administration of ginseng in rats. J Gins Res 2015;39:183-7. https://doi.org/10.1016/j.jgr.2014.11.002
  47. Roberfroid MB, Loo JA, Van, Gibson GR. The bifidogenic nature of chicory inulin and its hydrolysis products. J Nutr 1998;128:11-9. https://doi.org/10.1093/jn/128.1.11
  48. Lefranc-Millot C, Guerin-Deremaux L, Wils D, Neut C, Miller L, Saniez-Degrave M. Impact of a resistant dextrin on intestinal ecology: how altering the digestive ecosystem with NUTRIOSE®, a soluble fibre with prebiotic properties, may be beneficial for health. J Int Med Res 2012;40:211-24. https://doi.org/10.1177/147323001204000122

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