The Gut-Brain Connection: How Microbiota and Diet Influence Major Depressive Disorder
Keywords:
Mental Health, Gut-Brain Axis,, Gut Microbiota, Diet, DysbiosisAbstract
Approximately 8% of Americans are diagnosed with Major Depressive Disorder (MDD) annually, with millions experiencing changes in cognitive function, memory, and emotion (Greenberg et al., 2021; Louis-Jean et al., 2023; John, 2011). Most existing literature emphasizes neurobiological mechanisms as primary contributors to MDD. However, emerging science implicates the gut-microbiota-brain (GMB) axis as a significant factor in mental health (Cryan & Leonard, 2000). Gut microbiota, the complex ecosystem of bacteria in the gastrointestinal tract, influence the brain by releasing neurotransmitters, cytokines, and microbial metabolites through the GMB axis (Misiak et al., 2020; Mayer et al., 2022). Microbial dysbiosis, marked by inflammation and immune dysfunction, has been linked to increased stress vulnerability and depressive symptoms (Severino et al., 2024; Shoubridge et al., 2022). Toxins such as Lipopolysaccharides (LPS) enter the bloodstream, triggering neuroinflammation and disrupting neurotransmitter systems – involved in MDD (Jeon & Kim, 2016). By contrast, eubiosis supports intestinal and immune function. The gut microbiota composition is primarily shaped by diet, as nutrients promote or suppress bacterial growth. Mediterranean-style diets increase Firmicutes and Bacteroidetes via fiber and fermented foods. Western diets promote Proteobacteria and inflammation (Severino et al., 2024). Examining both diets reveals a relationship between dietary choices and mental health.
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Barber, T.M., Kabisch, S., Pfeiffer, A.F.H., Weickert, M.O. (2023) The effects of the Mediterranean diet on health and gut microbiota. Nutrients, 15(9):2150. doi: https://doi.org/10.3390/nu15092150
Cryan, J.F., Leonard, B.E. (2000) 5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response. Hum Psychopharmacol, 15(2):113-35. doi: https://doi.org/10.1002/(sici)1099-1077(200003)15:2<113::aid-hup150>3.0.co;2-w
Du, Y., Gao, X.R., Peng, L., Ge, J.F. (2020) Crosstalk between the microbiota–gut–brain axis and depression. Heliyon, 6(6):e04097. doi: https://doi.org/10.1016/j.heliyon.2020.e04097
Ferrara, G., Petrillo, M., Giani, T., Marrani, E., Filippeschi, C., Oranges, T., Simonini, G., Cimaz, R. (2019) Clinical use and molecular action of corticosteroids in the pediatric age. Int J Mol Sci, 20(2):444. doi: https://doi.org/10.3390/ijms20020444
Foster, J.A., Baker, G.B., Dursun, S.M. (2021) The relationship between the gut microbiome–immune system–brain axis and major depressive disorder. Front Neurol, 12:721126. doi: https://doi.org/10.3389/fneur.2021.721126
Greenberg, P.E., Fournier, A.A., Sisitsky, T., Simes, M., Berman, R., Koenigsberg, S.H., Kessler, R.C. (2021) The economic burden of adults with major depressive disorder in the United States (2010 and 2018). Pharmacoeconomics, 39(6):653-65. doi: https://doi.org/10.1007/s40273-021-01019-4
Gulyaeva, N.V. (2024) Augmented cortisol and antiglucocorticoid therapy in mood disorders: the hippocampus as a potential drug target. J Evol Biochem Physiol, 60(4):1516-30. doi: https://doi.org/10.1134/s0022093024040203
Hashimoto, K. (2023) Neuroinflammation through the vagus nerve-dependent gut–microbiota–brain axis in treatment-resistant depression. Prog Brain Res, 278:61-77. doi: https://doi.org/10.1016/bs.pbr.2023.01.003
Iebba, V., Totino, V., Gagliardi, A., Santangelo, F., Cacciotti, F., Trancassini, M., Mancini, C., Cicerone, C., Corazziari, E., Pantanella, F., Schippa, S. (2016) Eubiosis and dysbiosis: the two sides of the microbiota. New Microbiol, 39(1):1-12. Available from: https://iris.uniroma1.it/retrieve/e3835314-b1de-15e8-e053-a505fe0a3de9/Iebba_Eubiosis%20and%20dysbiosis_2016.pdf
Jeon, S.W., Kim, Y.K. (2016) Neuroinflammation and cytokine abnormality in major depression: cause or consequence in that illness? World J Psychiatry, 6(3):283-93. doi: https://doi.org/10.5498/wjp.v6.i3.283
John, N. (2011) Western diet and inflammation. Integr Med Clin J, 10(2):50-4. Available from: https://www.proquest.com/docview/894767380
Juruena, M.F., Pariante, C.M., Papadopoulos, A.S., Poon, L., Lightman, S., Cleare, A.J. (2009) Prednisolone suppression test in depression: prospective study of the role of HPA axis dysfunction in treatment resistance. Br J Psychiatry, 194(4):342-9. doi: https://doi.org/10.1192/bjp.bp.108.050278
Khushboo, Siddiqi, N.J., Pereira, M.d.l., Sharma, B. (2022) Neuroanatomical, biochemical, and functional modifications in brain induced by treatment with antidepressants. Mol Neurobiol, 59(6):3349-62. doi: https://doi.org/10.1007/s12035-022-02780-z
Kovtun, A.S., Averina, O.V., Angelova, I.Y., Yunes, R.A., Zorkina, Y.A., Morozova, A.Y., Pavlichenko, A.V., Syunyakov, T.S., Karpenko, O.A., Kostyuk, G.P., Danilenko, V.N. (2022) Alterations of the composition and neurometabolic profile of human gut microbiota in major depressive disorder. Biomedicines, 10(9):2162. doi: https://doi.org/10.3390/biomedicines10092162
Louis-Jean, S.F., Agrawal, N., Bisht, S. (2023) Fusobacterium nucleatum pyogenic liver abscess and the role of bacterial virulence and gut microbiota dysbiosis. Cureus, 15(3):e34548. doi: https://doi.org/10.7759/cureus.34548
Madison, A., Kiecolt-Glaser, J.K. (2019) Stress, depression, diet, and the gut microbiota: human–bacteria interactions at the core of psychoneuroimmunology and nutrition. Curr Opin Behav Sci, 28:105-10. doi: https://doi.org/10.1016/j.cobeha.2019.01.011
Magne, F., Gotteland, M., Gauthier, L., Zazueta, A., Pesoa, S., Navarrete, P., Balamurugan, R. (2020) The Firmicutes/Bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients? Nutrients, 12(5):1474. doi: https://doi.org/10.3390/nu12051474
Mayer, E.A., Nance, K., Chen, S. (2022) The gut–brain axis. Annu Rev Med, 73:439-53. doi: https://doi.org/10.1146/annurev-med-042320-014032
Misiak, B., Łoniewski, I., Marlicz, W., Frydecka, D., Szulc, A., Rudzki, L., Samochowiec, J. (2020) The HPA axis dysregulation in severe mental illness: can we shift the blame to gut microbiota? Prog Neuropsychopharmacol Biol Psychiatry, 102:109951. doi: https://doi.org/10.1016/j.pnpbp.2020.109951
Moroni, F., Cozzi, A., Sili, M., Mannaioni, G. (2012) Kynurenic acid: a metabolite with multiple actions and multiple targets in brain and periphery. J Neural Transm, 119(2):133-9. doi: https://doi.org/10.1007/s00702-011-0763-x
Mohammed, H.A., Hashim, R.A., Tawfiq, K.M. (2025) Western diets implications on health, including its influence on metabolism and the immunity. SAR J Med Biochem, 6(4):63-70. doi: https://doi.org/10.36346/sarjmb.2025.v06i04.001
Mugada, V.K., Reddy, K.P., Rajesh, K., Anusha, M. (2025) Balancing your biome for better mental health: gut microbiota and depression. Indian J Nat Sci, 15(1):1-6. Available from: https://www.researchgate.net/publication/389028291
Narvión, J., Rojo-López, M.I., Martinez-Santos, P., Rossell, J., Ruiz-Alcaraz, A.J., Alonso, N., Ramos-Molina, B., Mauricio, D., Julve, J. (2023) NAD+ precursors and intestinal inflammation: therapeutic insights involving gut microbiota. Nutrients, 15(13):2992. doi: https://doi.org/10.3390/nu15132992
Notting, F., Pirovano, W., Sybesma, W., Kort, R. (2023) The butyrate-producing and spore-forming bacterial genus Coprococcus as a potential biomarker for neurological disorders. Gut Microbiome, 4:e16. doi: https://doi.org/10.1017/gmb.2023.14
Raymond, C. (2022) Investigating the influence of dietary fibre on intestinal health [Internet]. Figshare. Available from: https://doi.org/10.25949/19441622.v1
Shin, N.R., Whon, T.W., Bae, J.W. (2015) Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol, 33(9):496-503. doi: https://doi.org/10.1016/j.tibtech.2015.06.011
Severino, A., Tohumcu, E., Tamai, L., Dargenio, P., Porcari, S., Rondinella, D., Venturini, I., Maida, M., Gasbarrini, A., Cammarota, G., Ianiro, G. (2024) The microbiome-driven impact of Western diet in the development of noncommunicable chronic disorders. Best Pract Res Clin Gastroenterol, 72:101923. doi: https://doi.org/10.1016/j.bpg.2024.101923
Shoubridge, A.P., Choo, J.M., Martin, A.M., Keating, D.J., Wong, M.L., Licinio, J., Rogers, G.B. (2022) The gut microbiome and mental health: advances in research and emerging priorities. Mol Psychiatry, 27(1):423-40. doi: https://doi.org/10.1038/s41380-022-01479-w
Souery, D., Papakostas, G.I., Trivedi, M.H. (2006) Treatment-resistant depression. J Clin Psychiatry, 67 Suppl 6:16-22.
Smoak, K.A., Cidlowski, J.A. (2004) Mechanisms of glucocorticoid receptor signaling during inflammation. Mech Ageing Dev, 125(10-11):697-706. doi: https://doi.org/10.1016/j.mad.2004.06.010
Stokes, P.E. (1995) The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression. Eur Neuropsychopharmacol, 5 Suppl:77-82. doi: https://doi.org/10.1016/0924-977x(95)00039-r
Van, T.A., Verbrugghe, K., De Vuyst, L. (2006) Kinetic analysis of bifidobacterial metabolism reveals a minor role for succinic acid in the regeneration of NAD+ through its growth-associated production. Appl Environ Microbiol, 72(8):5204-10. doi: https://doi.org/10.1128/aem.00146-06
Vasques-Monteiro, I.M.L., Silva-Veiga, F.M., Miranda, C.S., Gonçalves, É.C.B., Daleprane, J.B., Souza-Mello, V. (2021) A rise in Proteobacteria is an indicator of gut-liver axis-mediated nonalcoholic fatty liver disease in high-fructose-fed adult mice. Nutr Res, 91:26-35. doi: https://doi.org/10.1016/j.nutres.2021.04.008
Wang, H.X., Wang, Y.P. (2016) Gut microbiota-brain axis. Chin Med J, 129(19):2373-80. doi: https://doi.org/10.4103/0366-6999.190667
Wichers, M.C., Maes, M. (2004) The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Neurosci, 29(1):11-7. Available from: https://www.jpn.ca/content/29/1/11
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