Ukr.Biochem.J. 2025; Volume 97, Issue 2, Mar-Apr, pp. 13-30

doi: https://doi.org/10.15407/ubj97.02.013

Major depressive disorder and the microbiome-gut-brain axis

05.05.2025   Uncategorized   No comments

F. H. Ouriaghli, I. A. Elhaty*

Department of Nutrition and Dietetics, Faculty of Health Sciences,
Istanbul Gelisim University, Istanbul, Türkiye;
*e-mail: iaeismail@gelisim.edu.tr

Received: 02 January 2025; Revised: 24 April 2025;
Accepted: 25 April 2025; Available on-line: 12 May 2025

The central nervous system and the gastrointestinal tract are connected bidirectionally via the gut-brain axis (GBA). According to the gut microbiota hypothesis, changes in the composition and activity of the gut microbiota can affect the GBA, contributing to the onset of mental illnesses such as depression and anxiety­. This review aims to analyze how microbiota imbalances can affect the functioning of the gut-brain axis, causing changes in metabolism, immune system and neurotransmitters that are associated with depression. The potential of dietary modifications, probiotics, prebiotics and symbiotics to restore microbiota balance as well as the importance of microbiota profiling integration into personalized clinical practice are discussed.

Keywords: , , , ,

References:

  1. Ohland CL, Jobin C. Microbial activities and intestinal homeostasis: A delicate balance between health and disease. Cell Mol Gastroenterol Hepatol. 2015;1(1):28-40. PubMed, PubMed, CrossRef
  2. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701-712. PubMed, CrossRef
  3. Liang S, Wu X, Hu X, Wang T, Jin F. Recognizing Depression from the Microbiota–Gut–Brain Axis. Int J Mol Sci. 2018;19(6):1592. PubMed, PubMed, CrossRef
  4. Luesma MJ, Cantarero I, Álvarez-Dotu JM, Santander S, Junquera C. New insights into c-Ret signalling pathway in the enteric nervous system and its relationship with ALS. Biomed Res Int. 2014;2014:328348. PubMed, PubMed, CrossRef
  5. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203-209. PubMed, PubMed
  6. Diagnostic and statistical manual of mental disorders: DSM-5™, 5th ed. Arlington, VA, US: American Psychiatric Publishing, Inc.; 2013. CrossRef
  7. Dawson-Squibb JJ, Davids EL, Viljoen M, Rice K, Stein DJ. The WHO International Classification of Diseases 11th revision (ICD-11). In: Matson JL. (eds) Handbook of Clinical Child Psychology. Autism and Child Psychopathology Series. Springer, Cham. 2023. pp. 53-78. CrossRef
  8. Zhang N, Zhang Y, Li M, Wang W, Liu Z, Xi C, Huang X, Liu J, Huang J, Tian D, Mu J, Liao X, Zhai S. Efficacy of probiotics on stress in healthy volunteers: A systematic review and meta-analysis based on randomized controlled trials. Brain Behav. 2020;10(9):e01699. PubMed, PubMed, CrossRef
  9. Góralczyk-Bińkowska A, Szmajda-Krygier D, Kozłowska E. The microbiota-gut-brain axis in psychiatric disorders. Int J Mol Sci. 2022;23(19):11245. PubMed, PubMed, CrossRef
  10. Rathour D, Shah S, Khan S, Singh PK, Srivastava S, Singh SB, Khatri DK. Role of gut microbiota in depression: Understanding molecular pathways, recent research, and future direction. Behav Brain Res. 2023;436:114081. PubMed, CrossRef
  11. Tiller JW. Depression and anxiety. Med J Aust. 2013;199(S6):S28-:S31. PubMed, CrossRef
  12. WHO. Depressive disorder (depression). 2023. Regime of access : https://www.who.int/news-room/fact-sheets/detail/depression
  13. Kazemi A, Noorbala AA, Azam K, Eskandari MH, Djafarian K. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial. Clin Nutr. 2019;38(2):522-528. PubMed, CrossRef
  14. Okubo R, Matsuoka YJ, Sawada N, Mimura M, Kurotani K, Nozaki S, Shikimoto R, Tsugane S. Diet quality and depression risk in a Japanese population: the Japan Public Health Center (JPHC)-based Prospective Study. Sci Rep. 2019;9(1):7150. PubMed, PubMed, CrossRef
  15. Jacka FN, O’Neil A, Opie R, Itsiopoulos C, Cotton S, Mohebbi M, Castle D, Dash S, Mihalopoulos C, Chatterton ML, Brazionis L, Dean OM, Hodge AM, Berk M. A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial). BMC Med. 2017;15(1):23. PubMed, PubMed, CrossRef
  16. Cladder-Micus MB, Speckens AEM, Vrijsen JN, T Donders AR, Becker ES, Spijker J. Mindfulness-based cognitive therapy for patients with chronic, treatment-resistant depression: A pragmatic randomized controlled trial. Depress Anxiety. 2018;35(10):914-924. PubMed, PubMed, CrossRef
  17. Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015;48:258-264. PubMed, CrossRef
  18. Cheng S, Han B, Ding M, Wen Y, Ma M, Zhang L, Qi X, Cheng B, Li P, Kafle OP, Liang X, Liu L, Du Y, Zhao Y, Zhang F. Identifying psychiatric disorder-associated gut microbiota using microbiota-related gene set enrichment analysis. Brief Bioinform. 2020;21(3):1016-1022. PubMed, CrossRef
  19. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA. 2011;108(38):16050-16055. PubMed, PubMed, CrossRef
  20. Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008;29(1):117-124. PubMed
  21. 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(Pt 1):263-275. PubMed, PubMed, CrossRef
  22. Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020;11:25. PubMed, PubMed, CrossRef
  23. Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi A, Bisson JF, Rougeot C, Pichelin M, Cazaubiel M, Cazaubiel JM. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011;105(5):755-764. PubMed, CrossRef
  24. Schmidt K, Cowen PJ, Harmer CJ, Tzortzis G, Errington S, Burnet PW. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology (Berl). 2015;232(10):1793-1801. PubMed, PubMed, CrossRef
  25. Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014;34(46):15490-15496. PubMed, PubMed, CrossRef
  26. Gao M, Tu H, Liu P, Zhang Y, Zhang R, Jing L, Zhang K. Association analysis of gut microbiota and efficacy of SSRIs antidepressants in patients with major depressive disorder. J Affect Disord. 2023;330:40-47. PubMed, CrossRef
  27. Tian P, O’Riordan KJ, Lee YK, Wang G, Zhao J, Zhang H, Cryan JF, Chen W. Towards a psychobiotic therapy for depression: Bifidobacterium breve CCFM1025 reverses chronic stress-induced depressive symptoms and gut microbial abnormalities in mice. Neurobiol Stress. 2020;12:100216. PubMed, PubMed, CrossRef
  28. Jacobsen JPR, Oh A, Bangle R, Roberts WL, Royer EL, Modesto N, Windermere SA, Yi Z, Vernon R, Cajina M, Urs NM, Snyder JC, Nicholls PJ, Sachs BD, Caron MG. Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept. Neuropsychopharmacology. 2019;44(12):2082-2090. PubMed, PubMed, CrossRef
  29. Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20(2):145-155. PubMed, PubMed, CrossRef
  30. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305-312. PubMed, CrossRef
  31. Lach G, Schellekens H, Dinan TG, Cryan JF. Anxiety, depression, and the microbiome: a role for gut peptides. Neurotherapeutics. 2018;15(1):36-59. PubMed, PubMed, CrossRef
  32. Savin Z, Kivity S, Yonath H, Yehuda S. Smoking and the intestinal microbiome. Arch Microbiol. 2018;200(5):677-684. PubMed, CrossRef
  33. Kiecolt-Glaser JK, Wilson SJ, Bailey ML, Andridge R, Peng J, Jaremka LM, Fagundes CP, Malarkey WB, Laskowski B, Belury MA. Marital distress, depression, and a leaky gut: Translocation of bacterial endotoxin as a pathway to inflammation. Psychoneuroendocrinology. 2018;98:52-60. PubMed, PubMed, CrossRef
  34. Mittal R, Debs LH, Patel AP, Nguyen D, Patel K, O’Connor G, Grati M, Mittal J, Yan D, Eshraghi AA, Deo SK, Daunert S, Liu XZ. Neurotransmitters: the critical modulators regulating gut-brain axis. J Cell Physiol. 2017;232(9):2359-2372. PubMed, PubMed, CrossRef
  35. Cussotto S, Strain CR, Fouhy F, Strain RG, Peterson VL, Clarke G, Stanton C, Dinan TG, Cryan JF. Differential effects of psychotropic drugs on microbiome composition and gastrointestinal function. Psychopharmacology (Berl). 2019;236(5):1671-1685. PubMed, CrossRef
  36. Cussotto S, Clarke G, Dinan TG, Cryan JF. Psychotropics and the microbiome: a chamber of secrets… Psychopharmacology (Berl). 2019;236(5):1411-1432. PubMed, PubMed, CrossRef
  37. Dethloff F, Vargas F, Elijah E, Quinn R, Park DI, Herzog DP, Müller MB, Gentry EC, Knight R, Gonzalez A, Dorrestein PC, Turck CW. Paroxetine administration affects microbiota and bile acid levels in mice. Front Psychiatry. 2020;11:518. PubMed, PubMed, CrossRef
  38. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823-1836. PubMed, PubMed, CrossRef
  39. Munoz-Bellido JL, Munoz-Criado S, Garcìa-Rodrìguez JA. Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors. Int J Antimicrob Agents. 2000;14(3):177-180. PubMed, CrossRef
  40. Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, Zeng L, Chen J, Fan S, Du X, Zhang X, Yang D, Yang Y, Meng H, Li W, Melgiri ND, Licinio J, Wei H, Xie P. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016;21(6):786-796. PubMed, cr id=”https://doi.org/10.1038/mp.2016.44″]
  41. Jiang H, Ling Z, Zhang Y, Mao H, Ma Z, Yin Y, Wang W, Tang W, Tan Z, Shi J, Li L, Ruan B. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun. 2015;48:186-194. PubMed, CrossRef
  42. Bharwani A, Mian MF, Surette MG, Bienenstock J, Forsythe P. Oral treatment with Lactobacillus rhamnosus attenuates behavioural deficits and immune changes in chronic social stress. BMC Med. 2017;15(1):7. PubMed, PubMed, CrossRef
  43. Bharwani A, Mian MF, Foster JA, Surette MG, Bienenstock J, Forsythe P. Structural & functional consequences of chronic psychosocial stress on the microbiome & host. Psychoneuroendocrinology. 2016;63:217-227. PubMed, CrossRef
  44. Cummings JH, Macfarlane GT. Collaborative JPEN-Clinical Nutrition Scientific Publications Role of intestinal bacteria in nutrient metabolism. JPEN J Parenter Enteral Nutr. 1997;21(6):357-365. PubMed, CrossRef
  45. Dinan TG, Cryan JF. Gut-brain axis in 2016: Brain-gut-microbiota axis – mood, metabolism and behaviour. Nat Rev Gastroenterol Hepatol. 2017;14(2):69-70. PubMed, CrossRef
  46. Burokas A, Arboleya S, Moloney RD, Peterson VL, Murphy K, Clarke G, Stanton C, Dinan TG, Cryan JF. Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice. Biol Psychiatry. 2017;82(7):472-487. PubMed, CrossRef
  47. Desbonnet L, Clarke G, Traplin A, O’Sullivan O, Crispie F, Moloney RD, Cotter PD, Dinan TG, Cryan JF. Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. Brain Behav Immun. 2015;48:165-173. PubMed, CrossRef
  48. Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, Jafari P, Akbari H, Taghizadeh M, Memarzadeh MR, Asemi Z, Esmaillzadeh A. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Nutrition. 2016;32(3):315-320. PubMed, CrossRef
  49. Dinan TG, Stanton C, Long-Smith C, Kennedy P, Cryan JF, Cowan CSM, Cenit MC, van der Kamp JW, Sanz Y. Feeding melancholic microbes: MyNewGut recommendations on diet and mood. Clin Nutr. 2019;38(5):1995-2001. PubMed, CrossRef
  50. Mason BL, Li Q, Minhajuddin A, Czysz AH, Coughlin LA, Hussain SK, Koh AY, Trivedi MH. Reduced anti-inflammatory gut microbiota are associated with depression and anhedonia. J Affect Disord. 2020;266:394-401. PubMed, cr id=”https://doi.org/10.1016/j.jad.2020.01.137″]
  51. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, Dinan TG, Cryan JF. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013;18(6):666-673. PubMed, CrossRef
  52. Kelly JR, Borre Y, O’ Brien C, Patterson E, El Aidy S, Deane J, Kennedy PJ, Beers S, Scott K, Moloney G, Hoban AE, Scott L, Fitzgerald P, Ross P, Stanton C, Clarke G, Cryan JF, Dinan TG. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016;82:109-118. PubMed, CrossRef
  53. Lurie I, Yang YX, Haynes K, Mamtani R, Boursi B. Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study. J Clin Psychiatry. 2015;76(11):1522-1528. PubMed, CrossRef
  54. Köhler O, Petersen L, Mors O, Mortensen PB, Yolken RH, Gasse C, Benros ME. Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. Acta Psychiatr Scand. 2017;135(2):97-105. PubMed, CrossRef
  55. Bercik P, Collins SM. The Effects of Inflammation, Infection and Antibiotics on the Microbiota-Gut-Brain Axis. In: Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease. Edited by: Lyte M, Cryan JF. New York, NY: Springer New York; 2014. Vol. 817. P. 279-289. CrossRef
  56. Mackos AR, Maltz R, Bailey MT. The role of the commensal microbiota in adaptive and maladaptive stressor-induced immunomodulation. Horm Behav. 2017;88:70-78. PubMed, PubMed, CrossRef
  57. Wiley CD, Flynn JM, Morrissey C, Lebofsky R, Shuga J, Dong X, Unger MA, Vijg J, Melov S, Campisi J. Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell. 2017;16(5):1043-1050. PubMed, PubMed, CrossRef
  58. Brink LR, Matazel K, Piccolo BD, Bowlin AK, Chintapalli SV, Shankar K, Yeruva L. Neonatal diet impacts bioregional microbiota composition in piglets fed human breast milk or infant formula. J Nutr. 2019;149(12):2236-2246. PubMed, PubMed, CrossRef
  59. Garcia K, Ferreira G, Reis F, Viana S. Impact of dietary sugars on gut microbiota and metabolic health. Diabetology. 2022;3(4):549-560. CrossRef
  60. Bisgaard TH, Allin KH, Keefer L, Ananthakrishnan AN, Jess T. Depression and anxiety in inflammatory bowel disease: epidemiology, mechanisms and treatment. Nat Rev Gastroenterol Hepatol. 2022;19(11):717-726. PubMed, CrossRef
  61. Frolkis AD, Vallerand IA, Shaheen AA, Lowerison MW, Swain MG, Barnabe C, Patten SB, Kaplan GG. Depression increases the risk of inflammatory bowel disease, which may be mitigated by the use of antidepressants in the treatment of depression. Gut. 2019;68(9):1606-1612. PubMed, CrossRef
  62. Wei P, Bao R, Lv Z, Jing B. Weak but Critical Links between Primary Somatosensory Centers and Motor Cortex during Movement. Front Hum Neurosci. 2018;12:1. PubMed, PubMed, CrossRef
  63. Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Linløkken A, Wilson R, Rudi K. Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil. 2014;26(8):1155-1162. PubMed, CrossRef
  64. Neuendorf R, Harding A, Stello N, Hanes D, Wahbeh H. Depression and anxiety in patients with Inflammatory Bowel Disease: A systematic review. J Psychosom Res. 2016;87:70-80. PubMed, CrossRef
  65. Mikocka-Walus A, Knowles SR, Keefer L, Graff L. Controversies Revisited: A Systematic Review of the Comorbidity of Depression and Anxiety with Inflammatory Bowel Diseases. Inflamm Bowel Dis. 2016;22(3):752-762. PubMed, CrossRef
  66. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottière HM, Doré J, Marteau P, Seksik P, Langella P. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA. 2008;105(43):16731-16736. PubMed, PubMed, CrossRef
  67. D’Mello C, Swain MG. Immune-to-Brain Communication Pathways in Inflammation-Associated Sickness and Depression. Curr Top Behav Neurosci. 2017;31:73-94. PubMed, CrossRef
  68. Rea K, Dinan TG, Cryan JF. The microbiome: A key regulator of stress and neuroinflammation. Neurobiol Stress. 2016;4:23-33. PubMed, PubMed, CrossRef
  69. Van Oudenhove L, Levy RL, Crowell MD, Drossman DA, Halpert AD, Keefer L, Lackner JM, Murphy TB, Naliboff BD. Biopsychosocial aspects of functional gastrointestinal disorders: how central and environmental processes contribute to the development and expression of functional gastrointestinal disorders. Gastroenterology. 2016;150(6):1355-1367.e2. PubMed, PubMed, CrossRef
  70. Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, Martin FP, Cominetti O, Welsh C, Rieder A, Traynor J, Gregory C, De Palma G, Pigrau M, Ford AC, Macri J, Berger B, Bergonzelli G, Surette MG, Collins SM, Moayyedi P, Bercik P. Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome. Gastroenterology. 2017;153(2):448-459.e8. PubMed, CrossRef
  71. Salem I, Ramser A, Isham N, Ghannoum MA. The Gut Microbiome as a Major Regulator of the Gut-Skin Axis. Front Microbiol. 2018;9:1459.
    PubMed, PubMed, CrossRef
  72. Logan AC, Jacka FN, Craig JM, Prescott SL. The Microbiome and Mental Health: Looking Back, Moving Forward with Lessons from Allergic Diseases. Clin Psychopharmacol Neurosci. 2016;14(2):131-147. PubMed, PubMed, CrossRef
  73. Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BW, Zitman FG. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry. 2010;67(3):220-229. PubMed, CrossRef
  74. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022-1023. PubMed, CrossRef
  75. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480-484. PubMed, PubMed, CrossRef
  76. Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci. 2015;9:392. PubMed, PubMed, CrossRef
  77. Zamani M, Alizadeh-Tabari S, Zamani V. Systematic review with meta-analysis: the prevalence of anxiety and depression in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2019;50(2):132-143. PubMed, CrossRef
  78. Czéh B, Lucassen PJ. What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur Arch Psychiatry Clin Neurosci. 2007;257(5):250-260. PubMed, CrossRef
  79. Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, Scheimann J, Myers B. Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr Physiol. 2016;6(2):603-621. PubMed, PubMed, CrossRef
  80. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389. PubMed, CrossRef
  81. Raison CL, Borisov AS, Woolwine BJ, Massung B, Vogt G, Miller AH. Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry. 2010;15(5):535-547. PubMed, PubMed, CrossRef
  82. Angst J, Gamma A, Gastpar M, Lépine JP, Mendlewicz J, Tylee A; Depression Research in European Society Study. Gender differences in depression. Epidemiological findings from the European DEPRES I and II studies. Eur Arch Psychiatry Clin Neurosci. 2002;252(5):201-209. PubMed, CrossRef
  83. Jeon SW, Kim YK. Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness? World J Psychiatry. 2016;6(3):283-293. PubMed, PubMed, CrossRef
  84. Li Z, Ruan M, Chen J, Fang Y. Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications. Neurosci Bull. 2021;37(6):863-880. PubMed, PubMed, CrossRef
  85. Nemeroff CB. The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry. 1996;1(4):336-342. PubMed
  86. Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna). 2014;121(8):799-817. PubMed, PubMed, CrossRef
  87.  Cui W, Ning Y, Hong W, Wang J, Liu Z, Li MD. Crosstalk Between Inflammation and Glutamate System in Depression: Signaling Pathway and Molecular Biomarkers for Ketamine’s Antidepressant Effect. Mol Neurobiol. 2019;56(5):3484-3500. PubMed, CrossRef
  88. Inoshita M, Umehara H, Watanabe SY, Nakataki M, Kinoshita M, Tomioka Y, Tajima A, Numata S, Ohmori T. Elevated peripheral blood glutamate levels in major depressive disorder. Neuropsychiatr Dis Treat. 2018;14:945-953. PubMed, PubMed, CrossRef
  89. Smith RS. The macrophage theory of depression. Med Hypotheses. 1991;35(4):298-306. PubMed, CrossRef
  90. Szelényi J. Cytokines and the central nervous system. Brain Res Bull. 2001;54(4):329-338. PubMed, CrossRef
  91. Ménard C, Hodes GE, Russo SJ. Pathogenesis of depression: Insights from human and rodent studies. Neuroscience. 2016;321:138-162. PubMed, PubMed, CrossRef
  92. Jacka FN, Pasco JA, Mykletun A, Williams LJ, Hodge AM, O’Reilly SL, Nicholson GC, Kotowicz MA, Berk M. Association of Western and traditional diets with depression and anxiety in women. Am J Psychiatry. 2010;167(3):305-311. PubMed, CrossRef
  93. Lassale C, Batty GD, Baghdadli A, Jacka F, Sánchez-Villegas A, Kivimäki M, Akbaraly T. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Mol Psychiatry. 2019;24(7):965-986. PubMed, PubMed, CrossRef
  94. Ding Y, Bu F, Chen T, Shi G, Yuan X, Feng Z, Duan Z, Wang R, Zhang S, Wang Q, Zhou J, Chen Y. A next-generation probiotic: Akkermansia muciniphila ameliorates chronic stress-induced depressive-like behavior in mice by regulating gut microbiota and metabolites. Appl Microbiol Biotechnol. 2021;105(21-22):8411-8426. PubMed, CrossRef
  95. Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part I – autointoxication revisited. Gut Pathog. 2013;5(1):5. PubMed, PubMed, CrossRef
  96. Kohler O, Krogh J, Mors O, Benros ME. Inflammation in Depression and the Potential for Anti-Inflammatory Treatment. Curr Neuropharmacol. 2016;14(7):732-742. PubMed, PubMed, CrossRef
  97. Schneider E, Doll JPK, Schweinfurth N, Kettelhack C, Schaub AC, Yamanbaeva G, Varghese N, Mählmann L, Brand S, Eckert A, Borgwardt S, Lang UE, Schmidt A. Effect of short-term, high-dose probiotic supplementation on cognition, related brain functions and BDNF in patients with depression: a secondary analysis of a randomized controlled trial. J Psychiatry Neurosci. 2023;48(1):E23-E33. PubMed, PubMed, CrossRef
  98. Schaub AC, Schneider E, Vazquez-Castellanos JF, Schweinfurth N, Kettelhack C, Doll JPK, Yamanbaeva G, Mählmann L, Brand S, Beglinger C, Borgwardt S, Raes J, Schmidt A, Lang UE. Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: a randomized controlled trial. Transl Psychiatry. 2022;12(1):227. PubMed, PubMed, CrossRef
  99. Winiarska-Mieczan A, Kwiecień M, Jachimowicz-Rogowska K, Donaldson J, Tomaszewska E, Baranowska-Wójcik E. Anti-Inflammatory, Antioxidant, and Neuroprotective Effects of Polyphenols-Polyphenols as an Element of Diet Therapy in Depressive Disorders. Int J Mol Sci. 2023;24(3):2258. PubMed, PubMed, CrossRef
  100. Vogelzangs N, Duivis HE, Beekman AT, Kluft C, Neuteboom J, Hoogendijk W, Smit JH, de Jonge P, Penninx BW. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry. 2012;2(2):e79. PubMed, PubMed, CrossRef
  101. Macedo D, Filho AJMC, Soares de Sousa CN, Quevedo J, Barichello T, Júnior HVN, Freitas de Lucena D. Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness.
    J Affect Disord. 2017;208:22-32. PubMed, CrossRef
  102. Zhu F, Tu H, Chen T. The Microbiota-Gut-Brain Axis in Depression: The Potential Pathophysiological Mechanisms and Microbiota Combined Antidepression Effect. Nutrients. 2022;14(10):2081. PubMed, PubMed, CrossRef
  103. Zhai S, Qu Y, Zhang D, Li T, Xie Y, Wu X, Zou L, Yang Y, Tao F, Tao S. Depressive symptoms predict longitudinal changes of chronic inflammation at the transition to adulthood. Front Immunol. 2023;13:1036739. PubMed, PubMed, CrossRef
  104. Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2018;23(2):335-343. PubMed, PubMed, CrossRef
  105. Vittengl JR, Jarrett RB, Ro E, Clark LA. Associations of antidepressant medication consumption with changes in personality pathology and quality of life among community-dwelling adults. Int J Risk Saf Med. 2024;35(1):5-18. PubMed, CrossRef
  106. Huang R, Wang K, Hu J. Effect of probiotics on depression: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2016;8(8):483. PubMed, PubMed, CrossRef
  107. Koopman M, El Aidy S; MIDtrauma consortium. Depressed gut? The microbiota-diet-inflammation trialogue in depression. Curr Opin Psychiatry. 2017;30(5):369-377. PubMed, CrossRef
  108. Shafiei F, Salari-Moghaddam A, Larijani B, Esmaillzadeh A. Adherence to the Mediterranean diet and risk of depression: a systematic review and updated meta-analysis of observational studies. Nutr Rev. 2019;77(4):230-239. PubMed, PubMed, CrossRef
  109. Parletta N, Zarnowiecki D, Cho J, Wilson A, Bogomolova S, Villani A, Itsiopoulos C, Niyonsenga T, Blunden S, Meyer B, Segal L, Baune BT, O’Dea K. A Mediterranean-style dietary intervention supplemented with fish oil improves diet quality and mental health in people with depression: A randomized controlled trial (HELFIMED). Nutr Neurosci. 2019;22(7):474-487. PubMed, CrossRef
  110. Martin SE, Kraft CS, Ziegler TR, Millson EC, Rishishwar L, Martin GS. The Role of Diet on the Gut Microbiome, Mood and Happiness. medRxiv [Preprint]. 2023;2023.03.18.23287442. PubMed, PubMed, CrossRef
  111. Ng QX, Peters C, Ho CYX, Lim DY, Yeo WS. A meta-analysis of the use of probiotics to alleviate depressive symptoms. J Affect Disord. 2018;228:13-19. PubMed, CrossRef
  112. Grosso G, Galvano F, Marventano S, Malaguarnera M, Bucolo C, Drago F, Caraci F. Omega-3 fatty acids and depression: scientific evidence and biological mechanisms. Oxid Med Cell Longev. 2014;2014:313570. PubMed, PubMed, CrossRef
  113. McNamara RK, Carlson SE. Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins Leukot Essent Fatty Acids. 2006;75(4-5):329-349. PubMed, PubMed, CrossRef
  114. Sinn N, Bryan J. Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHD. J Dev Behav Pediatr. 2007;28(2):82-91. PubMed, CrossRef
  115. Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013;202:100-107. PubMed, CrossRef
  116. Solati Z, Jazayeri S, Tehrani-Doost M, Mahmoodianfard S, Gohari MR. Zinc monotherapy increases serum brain-derived neurotrophic factor (BDNF) levels and decreases depressive symptoms in overweight or obese subjects: a double-blind, randomized, placebo-controlled trial. Nutr Neurosci. 2015;18(4):162-168. PubMed, CrossRef
  117. Young SN. The effect of raising and lowering tryptophan levels on human mood and social behaviour. Philos Trans R Soc Lond B Biol Sci. 2013;368(1615):20110375. PubMed, PubMed, CrossRef
  118. Serefko A, Szopa A, Wlaź P, Nowak G, Radziwoń-Zaleska M, Skalski M, Poleszak E. Magnesium in depression. Pharmacol Rep. 2013;65(3):547-554. PubMed, CrossRef
  119. Markus CR, Olivier B, de Haan EH. Whey protein rich in alpha-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects. Am J Clin Nutr. 2002;75(6):1051-1056. PubMed, CrossRef
  120. Booij L, Van der Does AJ, Riedel WJ. Monoamine depletion in psychiatric and healthy populations: review. Mol Psychiatry. 2003;8(12):951-973.
    PubMed, CrossRef
  121. Appleton KM, Rogers PJ, Ness AR. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2010;91(3):757-770. PubMed, CrossRef
  122. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584. PubMed, PubMed, CrossRef
  123. Ginty AT, Conklin SM. Short-term supplementation of acute long-chain omega-3 polyunsaturated fatty acids may alter depression status and decrease symptomology among young adults with depression: A preliminary randomized and placebo controlled trial. Psychiatry Res. 2015;229(1-2):485-489. PubMed, CrossRef
  124. Gilbody S, Lightfoot T, Sheldon T. Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. J Epidemiol Community Health. 2007;61(7):631-637. PubMed, PubMed, CrossRef
  125. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69(2):228-232. PubMed, PubMed, CrossRef
  126. Chandrakumar A, Bhardwaj A, ‘t Jong GW. Review of thiamine deficiency disorders: Wernicke encephalopathy and Korsakoff psychosis. J Basic Clin Physiol Pharmacol. 2018;30(2):153-162. PubMed, CrossRef
Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.