Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Effect of fermented red ginseng on gut microbiota dysbiosis- or immobilization stress-induced anxiety, depression, and colitis in mice

  • Yoon-Jung, Shin (Neurobiota Research Center, College of Pharmacy, Kyung Hee University) ;
  • Dong-Yun, Lee (Neurobiota Research Center, College of Pharmacy, Kyung Hee University) ;
  • Joo Yun, Kim (R&BD Center, hy Co.Ltd.) ;
  • Keon, Heo (R&BD Center, hy Co.Ltd.) ;
  • Jae-Jung, Shim (R&BD Center, hy Co.Ltd.) ;
  • Jung-Lyoul, Lee (R&BD Center, hy Co.Ltd.) ;
  • Dong-Hyun, Kim (Neurobiota Research Center, College of Pharmacy, Kyung Hee University)
  • Received : 2021.12.17
  • Accepted : 2022.08.16
  • Published : 2023.03.02
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Red ginseng (RG) alleviates psychiatric disorders. Fermented red ginseng (fRG) alleviates stress-induced gut inflammation. Gut dysbiosis causes psychiatric disorders with gut inflammation. To understand the gut microbiota-mediated action mechanism of RG and fRG against anxiety/depression (AD), we investigated the effects of RG, fRG, ginsenoside Rd, and 20(S)-β-D-glucopyranosyl protopanaxadiol (CK) on gut microbiota dysbiosis-induced AD and colitis in mice. Methods: Mice with AD and colitis were prepared by exposing to immobilization stress (IS) or transplanting the feces of patients with ulcerative colitis and depression (UCDF). AD-like behaviors were measured in the elevated plus maze, light/dark transition, forced swimming, and tail suspension tests. Results: Oral gavage of UCDF increased AD-like behaviors and induced neuroinflammation, gastrointestinal inflammation, and gut microbiota fluctuation in mice. Oral administration of fRG or RG treatment reduced UCDF-induced AD-like behaviors, hippocampal and hypothalamic IL-6 expression, and blood corticosterone level, whereas UCDF-suppressed hippocampal BDNF+NeuN+ cell population and dopamine and hypothalamic serotonin levels increased. Furthermore, their treatments suppressed UCDF-induced colonic inflammation and partially restored UCDF-induced gut microbiota fluctuation. Oral administration of fRG, RG, Rd, or CK also decreased IS-induced AD-like behaviors, blood IL-6 and corticosterone and colonic IL-6 and TNF-α levels, and gut dysbiosis, while IS-suppressed hypothalamic dopamine and serotonin levels increased. Conclusion: Oral gavage of UCDF caused AD, neuroinflammation, and gastrointestinal inflammation in mice. fRG mitigated AD and colitis in UCDF-exposed mice by the regulation of the microbiota-gut-brain axis and IS-exposed mice by the regulation of the hypothalamic-pituitary-adrenal axis.

Keywords

Acknowledgement

The work was assisted by the Medical Research Program through the National Research Foundation of Korea (NRF) (NRF-2017R1A5A2014768). We thank Prof Hyo-Jong Kim, a professor of Kyung Hee University Hospital, for the human stool collection assistance.

References

  1. Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull 2014;140:774-815.  https://doi.org/10.1037/a0035302
  2. Troubat R, Barone P, Leman S, Desmidt T, Cressant A, Atanasova B, Brizard B, El Hage W, Surget A, Belzung C, et al. Neuroinflammation and depression: a review. Eur J Neurosci 2021;53:151-71.  https://doi.org/10.1111/ejn.14720
  3. Sekiyama A, Ueda H, Kashiwamura S, Nishida K, Yamaguchi S, Sasaki H, Kuwano Y, Kawai K, Teshima-Kondo S, Rokutan K, et al. A role of the adrenal gland in stress-induced up-regulation of cytokines in plasma. J Neuroimmunol 2006;171:38-44.  https://doi.org/10.1016/j.jneuroim.2005.09.010
  4. Gadek-Michalska A, Tadeusz J, Rachwalska P, Bugajski J. Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems. Pharmacol Rep 2013;65:1655-62.  https://doi.org/10.1016/S1734-1140(13)71527-5
  5. Caviedes A, Lafourcade C, Soto C, Wyneken U. BDNF/NF-κB signaling in the neurobiology of depression. Curr Pharm Des 2017;23:3154-63.  https://doi.org/10.2174/1381612823666170111141915
  6. Kalkman HO, Feuerbach D. Antidepressant therapies inhibit inflammation and microglial M1-polarization. Pharmacol Ther 2016;163:82-93.  https://doi.org/10.1016/j.pharmthera.2016.04.001
  7. Leclercq S, Forsythe P, Bienenstock J. Posttraumatic stress disorder: does the gut microbiome hold the key? Can J Psychiatry 2016;61:204-13.  https://doi.org/10.1177/0706743716635535
  8. Jang SE, Lim SM, Jeong JJ, Jang HM, Lee HJ, Han MJ, Kim DH. Gastrointestinal inflammation by gut microbiota disturbance induces memory impairment in mice. Mucosal Immunol 2018;11:369-79.  https://doi.org/10.1038/mi.2017.49
  9. Jang HM, Lee HJ, Jang SE, Han MJ, Kim DH. Evidence for interplay among antibacterial-induced gut microbiota disturbance, neuro-inflammation, and anxiety in mice. Mucosal Immunol 2018;11:1386-97.  https://doi.org/10.1038/s41385-018-0042-3
  10. Zhu S, Jiang Y, Xu K, Cui M, Ye W, Zhao G, Jin L, Chen X. The progress of gut microbiome research related to brain disorders. J Neuroinflam 2020;17:25. 
  11. Jang HM, Lee KE, Lee HJ, Kim DH. Immobilization stress-induced Escherichia coli causes anxiety by inducing NF-κB activation through gut microbiota disturbance. Sci Rep 2018;8:13897. 
  12. Kim JK, Lee KE, Lee SA, Jang HM, Kim DH. Interplay between human gut bacteria Escherichia coli and Lactobacillus mucosae in the occurrence of neuropsychiatric disorders in mice. Front Immunol 2020;11:273. 
  13. Kim DH. Chemical diversity of Panax ginseng, Panax quinquifolium, and Panax notoginseng. J Ginseng Res 2012;36:1-15.  https://doi.org/10.5142/jgr.2012.36.1.1
  14. Mancuso C, Santangelo R. Panax ginseng and Panax quinquefolius: from pharmacology to toxicology. Food Chem Toxicol 2017;107(Pt A):362-72.  https://doi.org/10.1016/j.fct.2017.07.019
  15. Han MJ, Kim DH. Effects of Red and fermented ginseng and ginsenosides on allergic disorders. Biomolecules 2020;10:634. 
  16. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93.  https://doi.org/10.1016/S0006-2952(99)00212-9
  17. Shi ZY, Zeng JZ, Wong AST. Chemical structures and pharmacological profiles of ginseng saponins. Molecules 2019;24:2443. 
  18. 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
  19. 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. 
  20. Bae EA, Han MJ, Choo MK, Park SY, Kim DH. Metabolism of 20(S)- and 20(R)-ginsenoside Rg3 by human intestinal bacteria and its relation to in vitro biological activities. Biol Pharm Bull 2002;25:58-63.  https://doi.org/10.1248/bpb.25.58
  21. Joh EH, Lee IA, Jung IH, Kim DH. Ginsenoside Rb1 and its metabolite compound K inhibit IRAK-1 activation-the key step of inflammation. Biochem Pharmacol 2011;82:278-86.  https://doi.org/10.1016/j.bcp.2011.05.003
  22. Tian F, Wang X, Ni H, Feng X, Yuan X, Huang Q. The ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells by regulating the RhoA/ROCKs/YAP signaling pathway and cytoskeleton formation. J Pharmacol Sci 2021;145:88-96.  https://doi.org/10.1016/j.jphs.2020.11.005
  23. 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
  24. Kim DH. Metabolism of ginsenosides to bioactive compounds by intestinal microflora and its industrial application. J Ginseng Res 2009;33:165-76.  https://doi.org/10.5142/JGR.2009.33.3.165
  25. Yokozawa T, Kang KS, Yamabe N, Kim HY. Therapeutic potential of heat-processed Panax ginseng with respect to oxidative tissue damage. Drug Discov Ther 2007;1:30-44. 
  26. Kim JK, Kim JY, Jang SE, Choi MS, Jang HM, Yoo HH, Kim DH. Fermented red ginseng alleviates cyclophosphamide-induced immunosuppression and 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice by regulating macrophage activation and T cell differentiation. Am J Chin Med 2018;46:1879-97.  https://doi.org/10.1142/S0192415X18500945
  27. Han SK, Joo MK, Kim JK, Jeung W, Kang H, Kim DH. Bifidobacteria-fermented red ginseng and its constituents ginsenoside Rd and protopanaxatriol alleviate anxiety/depression in mice by the amelioration of gut dysbiosis. Nutrients 2020;12:901. 
  28. Jang HM, Kim JK, Joo MK, Shin YJ, Lee CK, Kim HJ, Kim DH. Transplantation of fecal microbiota from patients with inflammatory bowel disease and depression alters immune response and behavior in recipient mice. Sci Rep 2021;11:20406. 
  29. Jang HM, Lee KE, Kim DH. The Preventive and Curative effects of Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 on immobilization stress-induced anxiety/depression and colitis in mice. Nutrients 2019;11:E819. 
  30. Lee KE, Kim JK, Han SK, Lee DY, Lee HJ, Yim SV, Kim DH. The extracellular vesicle of gut microbial Paenalcaligenes hominis is a risk factor for vagus nerve-mediated cognitive impairment. Microbiome 2020;8:107. 
  31. Morais LH, Schreiber HL, Mazmanian SK. The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol 2021;19:241-55.  https://doi.org/10.1038/s41579-020-00460-0
  32. Quigley EMM. Microbiota-brain-gut axis and neurodegenerative diseases. Curr Neurol Neurosci Rep 2017;17:94. 
  33. Tode T, Kikuchi Y, Hirata J, Kita T, Nakata H, Nagata I. Effect of Korean red ginseng on psychological functions in patients with severe climacteric syndromes. Int J Gynaecol Obstet 1999;67:169-74.  https://doi.org/10.1016/S0020-7292(99)00168-X
  34. Han SK, Kim DH. Lactobacillus mucosae and Bifidobacterium longum synergistically alleviate immobilization stress-induced anxiety/depression in mice by suppressing gut dysbiosis. J Microbiol Biotechnol 2019;29:1369-74.  https://doi.org/10.4014/jmb.1907.07044
  35. Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 2011;108:3047-52.  https://doi.org/10.1073/pnas.1010529108
  36. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 2004;558:263-75.  https://doi.org/10.1113/jphysiol.2004.063388
  37. Kim KA, Yoo HH, Gu W, Yu DH, Jin MJ, Choi HL, Yuan K, Guerin-Deremaux L, Kim DH. A prebiotic fiber increases the formation and subsequent absorption of compound K following oral administration of ginseng in rats. J Ginseng Res 2015;39(2):183-7.  https://doi.org/10.1016/j.jgr.2014.11.002
  38. 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 Ginseng Res 2014;38(3):203-7.  https://doi.org/10.1016/j.jgr.2014.03.003
  39. Kim TW, Choi HJ, Kim NJ, Kim DH. Anxiolytic-like effects of ginsenosides Rg3 and Rh2 from red ginseng in the elevated plus-maze model. Planta Med 2009;75:836-9.  https://doi.org/10.1055/s-0029-1185402
  40. Kang A, Xie T, Zhu D, Shan J, Di L, Zheng X. Suppressive effect of ginsenoside Rg3 against lipopolysaccharide-induced depression-like behavior and neuroinflammation in mice. J Agric Food Chem 2017;65:6861-9.  https://doi.org/10.1021/acs.jafc.7b02386
  41. Song W, Guo Y, Jiang S, Wei L, Liu Z, Wang X, Su Y. AntidepressanteEffects of the ginsenoside metabolite compound K, assessed by behavioral despair test and chronic unpredictable mild stress model. Neurochem Res 2018;43:1371-82.  https://doi.org/10.1007/s11064-018-2552-5
  42. Kim JK, Kim JY, Jang SE, Choi MS, Jang HM, Yoo HH, Kim DH. Fermented red ginseng alleviates cyclophosphamide-induced immunosuppression and 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice by regulating macrophage activation and T cell differentiation. Am J Chin Med 2018;46:1879-97.  https://doi.org/10.1142/S0192415X18500945
  43. Kim JK, Choi MS, Jeung W, Ra J, Kim DH. Effects of gut microbiota on the pharmacokinetics of protopanaxadiol ginsenosides Rd, Rg3, F2, and compound K in healthy volunteers treated orally with red ginseng. J Ginseng Res 2020;44:611-8. https://doi.org/10.1016/j.jgr.2019.05.012