DOI QR코드

DOI QR Code

Korean Red Ginseng extract treatment prevents post-antibiotic dysbiosis-induced bone loss in mice

  • Ho Jun, Kang (Department of Physiology, Michigan State University) ;
  • Nicholas, Chargo (Department of Physiology, Michigan State University) ;
  • Soumya, Chennupati (Department of Physiology, Michigan State University) ;
  • Kerri, Neugebauer (Department of Biochemistry and Molecular Biology, Michigan State University) ;
  • Jae Youl, Cho (Department of Integrative Biotechnology, Sungkyunkwan University) ;
  • Robert, Quinn (Department of Biochemistry and Molecular Biology, Michigan State University) ;
  • Laura R., McCabe (Department of Physiology, Michigan State University) ;
  • Narayanan, Parameswaran (Department of Physiology, Michigan State University)
  • Received : 2022.06.07
  • Accepted : 2022.08.25
  • Published : 2023.03.02

Abstract

Background: The intestinal microbiota is an important regulator of bone health. In previous studies we have shown that intestinal microbiota dysbiosis, induced by treatment with broad spectrum antibiotics (ABX) followed by natural repopulation, results in gut barrier dysfunction and bone loss. We have also shown that treatment with probiotics or a gut barrier enhancer can inhibit dysbiosis-induced bone loss. The overall goal of this project was to test the effect of Korean Red Ginseng (KRG) extract on bone and gut health using antibiotics (ABX) dysbiosis-induced bone loss model in mice. Methods: Adult male mice (Balb/C, 12-week old) were administered broad spectrum antibiotics (ampicillin and neomycin) for 2 weeks followed by 4 weeks of natural repopulation. During this 4-week period, mice were treated with vehicle (water) or KRG extract. Other controls included mice that did not receive either antibiotics or KRG extract and mice that received only KRG extract. At the end of the experiments, we assessed various parameters to assess bone, microbiota and in vivo intestinal permeability. Results: Consistent with our previous results, post-ABX- dysbiosis led to significant bone loss. Importantly, this was associated with a decrease in gut microbiota alpha diversity and an increase in intestinal permeability. All these effects including bone loss were prevented by KRG extract treatment. Furthermore, our studies identified multiple genera including Lactobacillus and rc4-4 as well as Alistipes finegoldii to be potentially linked to the effect of KRG extract on gut-bone axis. Conclusion: Together, our results demonstrate that KRG extract regulates the gut-bone axis and is effective at preventing dysbiosis-induced bone loss in mice.

Keywords

Acknowledgement

The authors thank the staff of Campus Animal Resources for the excellent care of our animals. We also thank Dr. Sandra O'Reilly for helping with some mouse experiments. The work presented in this study was funded by the Korean Ginseng Society.

References

  1. Clynes MA, Harvey NC, Curtis EM, Fuggle NR, Dennison EM, Cooper C. The epidemiology of osteoporosis. Brit Med Bull 2020;133:105-17. https://doi.org/10.1093/bmb/ldaa005.
  2. McCabe LR, Parameswaran N. Advances in probiotic regulation of bone and mineral metabolism. Calcified Tissue International 2018;1:1-9. https://doi.org/10.1007/s00223-018-0403-7.
  3. Collins FL, Rios-Arce ND, Schepper JD, Parameswaran N, McCabe LR. The potential of probiotics as a therapy for osteoporosis. Microbiol Spectr 2017;5. https://doi.org/10.1128/microbiolspec.bad-0015-2016.
  4. McCabe L, Britton RA, Parameswaran N. Prebiotic and probiotic regulation of bone health: role of the intestine and its microbiome. Current Osteoporosis Reports 2015;13:363-71. https://doi.org/10.1007/s11914-015-0292-x.
  5. Gilbert JA, Quinn RA, Debelius J, Xu ZZ, Morton J, Garg N, et al. Microbiomewide association studies link dynamic microbial consortia to disease. Nature 2016;535:94-103. https://doi.org/10.1038/nature18850.
  6. Irwin R, Lee T, Young VB, Parameswaran N, McCabe LR. Colitis-induced bone loss is gender dependent and associated with increased inflammation. Inflammatory Bowel Diseases 2013;19:1586-97. https://doi.org/10.1097/mib.0b013-318289e17b.
  7. Schepper JD, Collins FL, Rios-Arce ND, Raehtz S, Schaefer L, Gardinier JD, et al. Probiotic Lactobacillus reuteri prevents postantibiotic bone loss by reducing intestinal dysbiosis and preventing barrier disruption. Journal of Bone and Mineral Research 2019;34:681-98. https://doi.org/10.1002/jbmr.3635.
  8. Rios-Arce ND, Schepper JD, Dageanis A, Schaefer L, Daly-Seiler CS, Gardinier JD, et al. Post-antibiotic gut dysbiosis-induced trabecular bone loss is dependent on lymphocytes. Bone 2020;134:115269. https://doi.org/10.1016/j.bone.2020.115269.
  9. Yang N, Liu D, Zhang X, Li J, Wang M, Xu T, et al. Effects of ginsenosides on bone remodelling for novel drug applications: a review. Chin Med-Uk 2020;15:42. https://doi.org/10.1186/s13020-020-00323-z.
  10. Yun TK. Brief introduction of Panax ginseng C. A. Meyer. J Korean Med Sci 2001;16:S3-5. https://doi.org/10.3346/jkms.2001.16.s.s3.
  11. Kim H-R, Cui Y, Hong S-J, Shin S-J, Kim D-S, Kim N-M, et al. Effect of ginseng mixture on osteoporosis in ovariectomized rats. Immunopharm Immunot 2008;30:333-45. https://doi.org/10.1080/08923970801949125.
  12. Lee J-H, Lee H-J, Yang M, Moon C, Kim J-C, Bae C-S, et al. Effect of Korean Red Ginseng on radiation-induced bone loss in C3H/HeN mice. Journal of Ginseng Research 2013;37:435-41. https://doi.org/10.5142/jgr.2013.37.435.
  13. Kim J, Lee H, Kang KS, Chun K-H, Hwang GS. Protective effect of Korean Red Ginseng against glucocorticoid-induced osteoporosis in vitro and in vivo. J Ginseng Res 2015;39:46-53. https://doi.org/10.1016/j.jgr.2014.06.001.
  14. Zhang X, Huang F, Chen X, Wu X, Zhu J. Ginsenoside Rg3 attenuates ovariectomy-induced osteoporosis via AMPK/mTOR signaling pathway. Drug Develop Res 2020;81:875-84. https://doi.org/10.1002/ddr.21705.
  15. Jung S-J, Oh M-R, Lee DY, Lee Y-S, Kim G-S, Park S-H, et al. Effect of ginseng extracts on the improvement of osteopathic and arthritis symptoms in women with osteopenia: a randomized, double-blind, placebo-controlled clinical trial. Nutrients 2021;13:3352. https://doi.org/10.3390/nu13103352.
  16. Kim JK, Shin KK, Kim H, Hong YH, Choi W, Kwak Y-S, et al. Korean Red Ginseng exerts anti-inflammatory and autophagy-promoting activities in aged mice. J Ginseng Res 2021;45:717-25. https://doi.org/10.1016/j.jgr.2021.03.009.
  17. Schepper JD, Collins F, Rios-Arce ND, Kang HJ, Schaefer L, Gardinier JD, et al. Involvement of the gut microbiota and barrier function in glucocorticoidinduced osteoporosis. J Bone Miner Res 2020;35. https://doi.org/10.1002/jbmr.3947.
  18. Gonzalez A, Navas-Molina JA, Kosciolek T, McDonald D, Vazquez-Baeza Y, Ackermann G, et al. Qiita: rapid, web-enabled microbiome meta-analysis. Nat Methods 2018;15:796-8. https://doi.org/10.1038/s41592-018-0141-9.
  19. Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol 2019;37:852-7. https://doi.org/10.1038/s41587-019-0209-9.
  20. Amir A, McDonald D, Navas-Molina JA, Kopylova E, Morton JT, Xu ZZ, et al. Deblur rapidly resolves single-nucleotide community sequence patterns. Msystems 2017;2. https://doi.org/10.1128/msystems.00191-16. e00191-16.
  21. Kang IS, Agidigbi TS, Kwon YM, Kim D-G, Kim RI, In G, et al. Effect of coadministration of Panax ginseng and Brassica oleracea on postmenopausal osteoporosis in ovariectomized mice. Nutrients 2020;12:2415. https://doi.org/10.3390/nu12082415.
  22. Kim J, Lee H, Kang KS, Chun K-H, Hwang GS. Protective effect of Korean Red Ginseng against glucocorticoid-induced osteoporosis in vitro and in vivo. Journal of Ginseng Research 2015;39:46-53. https://doi.org/10.1016/j.jgr.2014.06.001.
  23. Siddiqi MH, Siddiqi MZ, Ahn S, Kang S, Kim Y-J, Sathishkumar N, et al. Ginseng saponins and the treatment of osteoporosis: mini literature review. J Ginseng Res 2013;37:261-8. https://doi.org/10.5142/jgr.2013.37.261.
  24. Chen Z, Zhang Z, Liu J, Qi H, Li J, Chen J, et al. Gut microbiota: therapeutic targets of ginseng against multiple disorders and ginsenoside transformation. Front Cell Infect Mi 2022;12:853981. https://doi.org/10.3389/fcimb.2022.853981.
  25. Han K-S, Balan P, Hong H-D, Choi W-I, Cho C-W, Lee Y-C, et al. Korean ginseng modulates the ileal microbiota and mucin gene expression in the growing rat. Food Funct 2014;5:1506-12. https://doi.org/10.1039/c4fo00087k.
  26. Song M-Y, Kim B-S, Kim H. Influence of Panax ginseng on obesity and gut microbiota in obese middle-aged Korean women. Journal of Ginseng Research 2014;38:106-15. https://doi.org/10.1016/j.jgr.2013.12.004.
  27. Seong E, Bose S, Han S-Y, Song E-J, Lee M, Nam Y-D, et al. Positive influence of gut microbiota on the effects of Korean red ginseng in metabolic syndrome: a randomized, double-blind, placebo-controlled clinical trial. Epma J 2021;12: 177-97. https://doi.org/10.1007/s13167-021-00243-4.
  28. Ren D, Li S, Lin H, Xia Y, Li Z, Bo P, et al. Panax quinquefolius polysaccharides ameliorate antibiotic-associated diarrhoea induced by lincomycin hydrochloride in rats via the MAPK signaling pathways. J Immunol Res 2022;2022: 4126273. https://doi.org/10.1155/2022/4126273.
  29. Bai X, Fu R, Duan Z, Wang P, Zhu C, Fan D. Ginsenoside Rk3 alleviates gut microbiota dysbiosis and colonic inflammation in antibiotic-treated mice. Food Res Int 2021;146:110465. https://doi.org/10.1016/j.foodres.2021.110465.
  30. Quach D, Parameswaran N, McCabe L, Britton RA. Characterizing how probiotic Lactobacillus reuteri 6475 and lactobacillic acid mediate suppression of osteoclast differentiation. Bone Reports 2019:100227. https://doi.org/10.1016/j.bonr.2019.100227.
  31. Collins FL, Irwin R, Bierhalter H, Schepper J, Britton RA, Parameswaran N, et al. Lactobacillus reuteri 6475 increases bone density in intact females only under an inflammatory setting. PloS One 2016;11:e0153180. https://doi.org/10.1371/journal.pone.0153180.
  32. Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, et al. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. Journal of Cellular Physiology 2014;229:1822-30. https://doi.org/ 10.1002/jcp.24636.
  33. Parker BJ, Wearsch PA, Veloo ACM, Rodriguez-Palacios A. The genus Alistipes: gut bacteria with emerging implications to inflammation, cancer, and mental health. Front Immunol 2020;11:906. https://doi.org/10.3389/fimmu.2020.00906.
  34. Yang Y, Jobin C. Novel insights into microbiome in colitis and colorectal cancer. Curr Opin Gastroen 2017;33:422-7. https://doi.org/10.1097/mog.0000000000000399.
  35. Moschen AR, Gerner RR, Wang J, Klepsch V, Adolph TE, Reider SJ, et al. Lipocalin 2 protects from inflammation and tumorigenesis associated with gut microbiota alterations. Cell Host Microbe 2016;19:455-69. https://doi.org/10.1016/j.chom.2016.03.007.