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Ketamine pp 127-141 | Cite as

The Role of Gut Microbiota in the Antidepressant Effects of Ketamine

  • Yue Wang
  • Xiaolin Xu
  • Ailin Luo
  • Chun Yang
Chapter
  • 33 Downloads

Abstract

In recent years, the prevalence, mental disability, and suicide rates of depression have been increasing without a corresponding significant change in cure rate, making depression the second largest disease burden worldwide. There is an urgent need to find more effective drugs and other therapeutic strategies. Accumulating evidence has revealed that ketamine elicits a fast-acting and sustained antidepressant effect, but the potential mechanisms underlying its antidepressant effects are not yet fully clear. Previous studies have indicated that ketamine’s mechanism of action involves the inhibition of presynaptic and postsynaptic N-methyl-d-aspartate receptors (NMDARs) in GABAergic interneurons and the activation of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and the brain-derived neurotrophic factor-tyrosine kinase receptor B (BDNF-TrkB) signaling pathway. Additionally, there is growing evidence that the gut microbiota may play a crucial role in the antidepressant effects of ketamine. In this chapter, we will discuss recent findings regarding the correlation between gut microbiota and the antidepressant effects of ketamine and their potential mechanisms of action. Further understanding of these pathways will likely lead to the development of novel and more effective treatments for depression.

Keywords

Gut microbiota Ketamine Depression Gut–brain axis Probiotics 

References

  1. Abildgaard A, Elfving B, Hokland M et al (2017a) Probiotic treatment protects against the pro-depressant-like effect of high-fat diet in Flinders Sensitive Line rats. Brain Behav Immun 65:33–42PubMedCrossRefPubMedCentralGoogle Scholar
  2. Abildgaard A, Elfving B, Hokland M et al (2017b) Probiotic treatment reduces depressive-like behaviour in rats independently of diet. Psychoneuroendocrinology 79:40–48PubMedCrossRefPubMedCentralGoogle Scholar
  3. Ago Y, Tanabe W, Higuchi M et al (2019) (R)-ketamine induces a greater increase in prefrontal 5-HT release than (S)-ketamine and ketamine metabolites via an AMPA receptor-independent mechanism. Int J Neuropsychopharmacol 22(10):665–674.  https://doi.org/10.1093/ijnp/pyz041CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ait-Belgnaoui A, Durand H, Cartier C et al (2012) Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology 37(11):1885–1895PubMedCrossRefPubMedCentralGoogle Scholar
  5. Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M et al (2016) Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. Nutrition 32(3):315–320CrossRefGoogle Scholar
  6. Barden N (2004) Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. J Psychiatry Neurosci 29(3):185–193PubMedPubMedCentralGoogle Scholar
  7. Bartoli F, Riboldi I, Crocamo C et al (2017) Ketamine as a rapid-acting agent for suicidal ideation: a meta-analysis. Neurosci Biobehav Rev 77:232–236PubMedCrossRefPubMedCentralGoogle Scholar
  8. Berman RM, Cappiello A, Anand A et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354CrossRefGoogle Scholar
  9. Borre YE, Moloney RD, Clarke G et al (2014) The impact of microbiota on brain and behavior: mechanisms and therapeutic potential. Adv Exp Med Biol 817:373–403PubMedCrossRefPubMedCentralGoogle Scholar
  10. Bortolozzi A, Celada P, Artigas F (2014) Novel therapeutic strategies in major depression: focus on RNAi and ketamine. Curr Pharm Des 20(23):3848–3860PubMedCrossRefPubMedCentralGoogle Scholar
  11. Bravo JA, Forsythe P, Chew MV et al (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 108(38):16050–16055PubMedPubMedCentralCrossRefGoogle Scholar
  12. Carabotti M, Scirocco A, Maselli MA et al (2015) The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 28(2):203–209PubMedPubMedCentralGoogle Scholar
  13. Chou D, Peng HY, Lin TB et al (2018) (2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray. Neuropharmacology 139:1–12PubMedCrossRefPubMedCentralGoogle Scholar
  14. Clark-Raymond A, Halaris A (2013) VEGF and depression: a comprehensive assessment of clinical data. J Psychiatr Res 47(8):1080–1087PubMedCrossRefPubMedCentralGoogle Scholar
  15. Desbonnet L, Garrett L, Clarke G et al (2008) The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat. J Psychiatr Res 43(2):164–174PubMedCrossRefPubMedCentralGoogle Scholar
  16. Deyama S, Bang E, Wohleb ES et al (2019) Role of neuronal VEGF signaling in the prefrontal cortex in the rapid antidepressant effects of ketamine. Am J Psychiatry 176(5):388–400PubMedCrossRefPubMedCentralGoogle Scholar
  17. Dinan TG, Cryan JF (2019) Gut microbes and depression: still waiting for godot. Brain Behav Immun 79:1–2PubMedCrossRefPubMedCentralGoogle Scholar
  18. Fukumoto K, Toki H, Iijima M et al (2017) Antidepressant potential of (R)-ketamine in rodent models: comparison with (S)-ketamine. J Pharmacol Exp Ther 361(1):9–16PubMedPubMedCentralCrossRefGoogle Scholar
  19. Getachew B, Aubee JI, Schottenfeld RS et al (2018) Ketamine interactions with gut-microbiota in rats: relevance to its antidepressant and anti-inflammatory properties. BMC Microbiol 18(1):222PubMedPubMedCentralCrossRefGoogle Scholar
  20. Goitsuka R, Hirota Y, Hasegawa A et al (1987) Release of interleukin 1 from peritoneal exudate cells of cats with feline infectious peritonitis. Nihon Juigaku Zasshi 49(5):811–818PubMedCrossRefPubMedCentralGoogle Scholar
  21. Grunebaum MF, Galfalvy HC, Choo TH et al (2018) Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry 175(4):327–335PubMedCrossRefPubMedCentralGoogle Scholar
  22. Hashimoto K (2019) Rapid-acting antidepressant ketamine, its metabolites and other candidates: a historical overview and future perspective. Psychiatry Clin Neurosci 73(10):613–627.  https://doi.org/10.1111/pcn.12902CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hoban AE, Moloney RD, Golubeva AV et al (2016) Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat. Neuroscience 339:463–477CrossRefGoogle Scholar
  24. Hold GL, Hansen R (2019) impact of the gastrointestinal microbiome in health and disease: co-evolution with the host immune system. Curr Top Microbiol Immunol 421:303–318PubMedPubMedCentralGoogle Scholar
  25. Huang N, Hua D, Zhan G et al (2019) Role of actinobacteria and coriobacteriia in the antidepressant effects of ketamine in an inflammation model of depression. Pharmacol Biochem Behav 176:93–100PubMedCrossRefPubMedCentralGoogle Scholar
  26. Jiang H, Ling Z, Zhang Y et al (2015) Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun 48:186–194PubMedCrossRefPubMedCentralGoogle Scholar
  27. Jin Y, Sun LH, Yang W et al (2019) The role of BDNF in the neuroimmune axis regulation of mood disorders. Front Neurol 10:515PubMedPubMedCentralCrossRefGoogle Scholar
  28. Kim KA, Gu W, Lee IA et al (2012) High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 7(10):e47713PubMedPubMedCentralCrossRefGoogle Scholar
  29. Lavelle A, Hill C (2019) Gut microbiome in health and disease: emerging diagnostic opportunities. Gastroenterol Clin North Am 48(2):221–235PubMedCrossRefPubMedCentralGoogle Scholar
  30. Lee EE, Della Selva MP, Liu A et al (2015a) Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis. Gen Hosp Psychiatry 37(2):178–184PubMedCrossRefPubMedCentralGoogle Scholar
  31. Lee SP, Sung IK, Kim JH et al (2015b) The effect of emotional stress and depression on the prevalence of digestive diseases. J Neurogastroenterol Motil 21(2):273–282PubMedPubMedCentralCrossRefGoogle Scholar
  32. Liang S, Wang T, Hu X et al (2015) Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience 310:561–577PubMedCrossRefPubMedCentralGoogle Scholar
  33. Liu RT, Walsh RFL, Sheehan AE (2019) Prebiotics and probiotics for depression and anxiety: a systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev 102:13–23PubMedCrossRefPubMedCentralGoogle Scholar
  34. Lyte M (2013) Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behavior. PLoS Pathog 9(11):e1003726PubMedPubMedCentralCrossRefGoogle Scholar
  35. Lyte M (2014) Microbial endocrinology and the microbiota-gut-brain axis. Adv Exp Med Biol 817:3–24PubMedCrossRefPubMedCentralGoogle Scholar
  36. Malhi GS, Mann JJ (2018) Depression. Lancet 392(10161):2299–2312PubMedCrossRefGoogle Scholar
  37. Maqsood R, Stone TW (2016) The gut-brain axis, BDNF, NMDA and CNS disorders. Neurochem Res 41(11):2819–2835PubMedCrossRefPubMedCentralGoogle Scholar
  38. Mastrodonato A, Martinez R, Pavlova IP et al (2018) Ventral CA3 activation mediates prophylactic ketamine efficacy against stress-induced depressive-like behavior. Biol Psychiatry 84(11):846–856PubMedPubMedCentralCrossRefGoogle Scholar
  39. Mayer EA, Padua D, Tillisch K (2014) Altered brain-gut axis in autism: comorbidity or causative mechanisms? Bioessays 36(10):933–939PubMedCrossRefPubMedCentralGoogle Scholar
  40. McGirr A, Berlim MT, Bond DJ et al (2015) A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med 45(4):693–704PubMedCrossRefPubMedCentralGoogle Scholar
  41. McLean PG, Borman RA, Lee K (2007) 5-HT in the enteric nervous system: gut function and neuropharmacology. Trends Neurosci 30(1):9–13PubMedCrossRefPubMedCentralGoogle Scholar
  42. Messaoudi M, Lalonde R, Violle N et al (2011) Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr 105(5):755–764PubMedCrossRefPubMedCentralGoogle Scholar
  43. Mohammadi AA, Jazayeri S, Khosravi-Darani K et al (2016) The effects of probiotics on mental health and hypothalamic-pituitary-adrenal axis: a randomized, double-blind, placebo-controlled trial in petrochemical workers. Nutr Neurosci 19(9):387–395PubMedCrossRefPubMedCentralGoogle Scholar
  44. Murrough JW, Iosifescu DV, Chang LC et al (2013) Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 170(10):1134–1142PubMedPubMedCentralCrossRefGoogle Scholar
  45. Murrough JW, Soleimani L, DeWilde KE et al (2015) Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med 45(16):3571–3580CrossRefGoogle Scholar
  46. Pennisi E (2019) Gut bacteria linked to mental well-being and depression. Science 363(6427):569PubMedCrossRefPubMedCentralGoogle Scholar
  47. Peyrovian B, Rosenblat JD, Pan Z et al (2019) The glycine site of NMDA receptors: A target for cognitive enhancement in psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 92:387–404PubMedCrossRefPubMedCentralGoogle Scholar
  48. Price RB, Nock MK, Charney DS et al (2009) Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 66(5):522–526PubMedPubMedCentralCrossRefGoogle Scholar
  49. Qin J, Li R, Raes J et al (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464(7285):59–65PubMedPubMedCentralCrossRefGoogle Scholar
  50. Qu Y, Yang C, Ren Q et al (2017) Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model. Sci Rep 7(1):15725PubMedPubMedCentralCrossRefGoogle Scholar
  51. Reardon S (2019) Antidepressant based on party drug gets backing from FDA advisory group. https://www.nature.com/articles/d41586-019-00559-2. Accessed 13 Feb 2019
  52. Shi H, Kokoeva MV, Inouye K et al (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116(11):3015–3025PubMedPubMedCentralCrossRefGoogle Scholar
  53. Skolnick P, Layer RT, Popik P et al (1996) Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 29(1):23–26PubMedCrossRefPubMedCentralGoogle Scholar
  54. Smith K (2014) Mental health: a world of depression. Nature 515(7526):181PubMedCrossRefPubMedCentralGoogle Scholar
  55. Stower H (2019) Depression linked to the microbiome. Nat Med 25(3):358PubMedPubMedCentralGoogle Scholar
  56. Sudo N, Chida Y, Aiba Y et al (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558(Pt 1):263–275PubMedPubMedCentralCrossRefGoogle Scholar
  57. Sun HL, Zhou ZQ, Zhang GF et al (2016) Role of hippocampal p11 in the sustained antidepressant effect of ketamine in the chronic unpredictable mild stress model. Transl Psychiatry 6:e741PubMedPubMedCentralCrossRefGoogle Scholar
  58. Tannock GW, Savage DC (1974) Influences of dietary and environmental stress on microbial populations in the murine gastrointestinal tract. Infect Immun 9(3):591–598PubMedPubMedCentralCrossRefGoogle Scholar
  59. Trivedi MH, Rush AJ, Wisniewski SR et al (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR∗D: implications for clinical practice. Am J Psychiatry 163(1):28–40PubMedCrossRefPubMedCentralGoogle Scholar
  60. U.S. Food and Drug Administration (2019) FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Accessed 6 Mar 2019
  61. Vlainic JV, Suran J, Vlainic T et al (2016) Probiotics as an adjuvant therapy in major depressive disorder. Curr Neuropharmacol 14(8):952–958PubMedPubMedCentralCrossRefGoogle Scholar
  62. Warden D, Rush AJ, Trivedi MH et al (2007) The STAR∗D Project results: a comprehensive review of findings. Curr Psychiatry Rep 9(6):449–459PubMedCrossRefPubMedCentralGoogle Scholar
  63. Weilburg JB (2004) An overview of SSRI and SNRI therapies for depression. Manag Care 13(6 Suppl Depression):25–33PubMedPubMedCentralGoogle Scholar
  64. Williams NR, Heifets BD, Blasey C et al (2018) Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry 175(12):1205–1215PubMedPubMedCentralCrossRefGoogle Scholar
  65. World Health Organization (2017) Depression: let’s talk. https://www.who.int/mental_health/management/depression/en/. Accessed 7 Apr 2017
  66. Wren AM, Bloom SR (2007) Gut hormones and appetite control. Gastroenterology 132(6):2116–2130PubMedCrossRefPubMedCentralGoogle Scholar
  67. Xu Y, Hackett M, Carter G et al (2016) Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol 19(4):pyv124PubMedCrossRefPubMedCentralGoogle Scholar
  68. Yang J, Yu J (2018) The association of diet, gut microbiota and colorectal cancer: what we eat may imply what we get. Protein Cell 9(5):474–487PubMedPubMedCentralCrossRefGoogle Scholar
  69. Yang C, Shirayama Y, Zhang JC et al (2015) R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry e632:5Google Scholar
  70. Yang C, Fujita Y, Ren Q et al (2017a) Bifidobacterium in the gut microbiota confer resilience to chronic social defeat stress in mice. Sci Rep 7:45942PubMedPubMedCentralCrossRefGoogle Scholar
  71. Yang C, Qu Y, Fujita Y et al (2017b) Possible role of the gut microbiota-brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model. Transl Psychiatry 7(12):1294PubMedPubMedCentralCrossRefGoogle Scholar
  72. Yang C, Kobayashi S, Nakao K et al (2018a) AMPA receptor activation-independent antidepressant actions of ketamine metabolite (S)-norketamine. Biol Psychiatry 84(8):591–600PubMedCrossRefPubMedCentralGoogle Scholar
  73. Yang C, Ren Q, Qu Y et al (2018b) Mechanistic target of rapamycin-independent antidepressant effects of (R)-ketamine in a social defeat stress model. Biol Psychiatry 83(1):18–28PubMedCrossRefPubMedCentralGoogle Scholar
  74. Zarate CA Jr, Singh JB, Carlson PJ et al (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864PubMedCrossRefPubMedCentralGoogle Scholar
  75. Zarate CA Jr, Brutsche NE, Ibrahim L et al (2012) Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 71(11):939–946PubMedPubMedCentralCrossRefGoogle Scholar
  76. Zhang K, Hashimoto K (2019) Lack of opioid system in the antidepressant actions of ketamine. Biol Psychiatry 85(6):e25–e27PubMedCrossRefPubMedCentralGoogle Scholar
  77. Zhang JC, Li SX, Hashimoto K (2014) R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol Biochem Behav 116:137–141PubMedPubMedCentralCrossRefGoogle Scholar
  78. Zhang K, Xu T, Yuan Z et al (2016) Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine. Sci Signal 9(458):ra123PubMedPubMedCentralCrossRefGoogle Scholar
  79. Zhang JC, Yao W, Dong C et al (2017) Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut-microbiota-brain axis. Transl Psychiatry 7(5):e1138PubMedPubMedCentralCrossRefGoogle Scholar
  80. Zheng P, Zeng B, Zhou C et al (2016) Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry 21(6):786–796PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Yue Wang
    • 1
  • Xiaolin Xu
    • 1
  • Ailin Luo
    • 1
  • Chun Yang
    • 2
  1. 1.Department of AnesthesiologyTongji Medical College, Huazhong University of Science and Technology, Tongji HospitalWuhanChina
  2. 2.Department of Anesthesiology and Perioperative MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina

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