The Gut–Brain Axis and Psychosis: A Systematic Review of Microbial Metabolites and Their Impact on Dopaminergic Pathways in Schizophrenia
DOI:
https://doi.org/10.58445/rars.3106Keywords:
Cognitive and negative symptoms, Dopaminergic dysfunction, Gut–brain axis (GBA), Microbiota dysbiosis, Schizophrenia, Tryptophan–kynurenine pathwayAbstract
Schizophrenia is a psychiatric disorder that has psychotic, cognitive, and negative symptoms, with dopaminergic dysfunction. The gut–brain axis is identified as an important modulator for neurochemical function. Following PRISMA 2020 guidelines, this systematic review is conducted through searches (PubMed, Scopus, SpringerLink, Taylor & Francis, and Google Scholar). After removing duplicates and screening, six studies included three clinical studies, two translational studies involving fecal microbiota transplantation (FMT), and one rodent model. The findings highlighted three main themes:(1) the dysregulation of the tryptophan–kynurenine pathway, with elevated kynurenine and reduced kynurenic acid linked to disrupted dopaminergic and glutamatergic signaling; (2) changes of microbiota composition and metabolite imbalances, which included fewer butyrate producers and more succinate generators, which were associated with neurotransmitter dysregulations; and (3) relationships within clinical symptoms, in which metabolites correlated with comprehension of negative/cognitive deficits. Collectively, microbial dysbiosis and metabolite imbalance influence dopamine biosynthesis, receptor activity, immune, metabolic, and neurochemical signaling.
References
Chen, J., Xu, M., Li, L., Lu, Y., Luo, Y., & Cao, J. (2025). Chronic fluoride induces neurotoxicity in zebrafish through the gut-brain axis. Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology, 110157. https://doi.org/10.1016/j.cbpc.2025.110157
Cichon, N., Szelenberger, R., Stela, M., Podogrocki, M., Gorniak, L., & Bijak, M. (2025). Flavanones as modulators of gut microbiota and cognitive function. Molecules, 30(10), 2203. https://doi.org/10.3390/molecules30102203
Cipriani, E., & Juster, R. (2024). Psychoneuroimmunology and Allostatic Load in Schizophrenia: Insights from Social and Biomedical Perspectives. In Integrated science (pp. 287–322). https://doi.org/10.1007/978-3-031-72079-6_12
Crotchett, B. L., Reighard, S. D., & Nasrallah, H. A. (2025). GABA dysfunction in schizophrenia: the GABAA receptor as a potential therapeutic target. Biomarkers in Neuropsychiatry, 100130. https://doi.org/10.1016/j.bionps.2025.100130
Ghorbani, M., Joseph, G. B. S., Mei, T. M., Ramly, S. S., Rasat, M. a. M., Croft, L., Parimannan, S., Rajandas, H., & Lee, S. Y. (2024). Functional associations of the gut microbiome with dopamine, serotonin, and BDNF in schizophrenia: a pilot study. The Egyptian Journal of Neurology Psychiatry and Neurosurgery, 60(1). https://doi.org/10.1186/s41983-024-00901-0
Gubert, C., Kong, G., Shadani, S., Connell, S., Masson, B. A., Van De Garde, N., Narayana, V. K., Renoir, T., & Hannan, A. J. (2025). Prebiotics rescue gut microbiome dysregulation and enhance cognitive and gastrointestinal function in a mouse model of schizophrenia. Schizophrenia Bulletin. https://doi.org/10.1093/schbul/sbaf056
Hadrich, I., Turki, M., Chaari, I., Abdelmoula, B., Gargouri, R., Khemakhem, N., Elatoui, D., Abid, F., Kammoun, S., Rekik, M., Aloulou, S., Sehli, M., Mrad, A. B., Neji, S., Feiguin, F. M., Aloulou, J., Abdelmoula, N. B., & Sellami, H. (2025). Gut mycobiome and neuropsychiatric disorders: insights and therapeutic potential. Frontiers in Cellular Neuroscience, 18. https://doi.org/10.3389/fncel.2024.1495224
Jamerlan, A. M., An, S. S. A., & Hulme, J. P. (2025). Microbial diversity and fitness in the gut–brain axis: influences on developmental risk for Alzheimer’s disease. Gut Microbes, 17(1). https://doi.org/10.1080/19490976.2025.2486518
Kong, L., Wang, X., Chen, G., Zhu, Y., Wang, L., Yan, M., Zeng, J., Zhou, X., Lui, S. S. Y., & Chan, R. C. K. (2025). Gut microbiome characteristics in individuals across different stages of schizophrenia spectrum disorders: A systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews, 106167. https://doi.org/10.1016/j.neubiorev.2025.106167
Kurhaluk, N., Kamiński, P., Bilski, R., Kołodziejska, R., Woźniak, A., & Tkaczenko, H. (2025). Role of antioxidants in modulating the Microbiota–Gut–Brain axis and their impact on neurodegenerative diseases. International Journal of Molecular Sciences, 26(8), 3658. https://doi.org/10.3390/ijms26083658
Liu, J., Yu, H., Li, R., Zhou, C., Shi, Q., Guo, L., & He, H. (2023). A Preliminary Comparison of Plasma Tryptophan Metabolites and Medium- and Long-Chain Fatty Acids in Adult Patients with Major Depressive Disorder and Schizophrenia. Medicina, 59(2), 413. https://doi.org/10.3390/medicina59020413
Marder, S. R., & Cannon, T. D. (2019). Schizophrenia. New England Journal of Medicine, 381(18), 1753–1761. https://doi.org/10.1056/nejmra1808803
Marutani, T., Chhim, S., Taing, S., & Nishio, A. (2022). Causal beliefs regarding schizophrenia and help-seeking behaviors among patients with schizophrenia and family caregivers attending psychiatric clinics in Cambodia. Transcultural Psychiatry, 136346152211072. https://doi.org/10.1177/13634615221107207
Mousavinejad, S. N., Hosseini, S. A., Mohammadpour, M., Ferdosi, F., Dadgostar, E., Abdolghaderi, S., & Khatami, S. H. (2025). Long non-coding RNAs in schizophrenia. Clinica Chimica Acta, 574, 120340. https://doi.org/10.1016/j.cca.2025.120340
Nafe, R., Arendt, C. T., & Hattingen, E. (2025). Morphological alterations in schizophrenia — An interdisciplinary review. Journal of Integrative Neuroscience, 24(5). https://doi.org/10.31083/jin27061
Ouzzani, M., Hammady, H., Fedorowicz, Z., & Elmagarmid, A. (2016). Rayyan—a web and mobile app for systematic reviews. Systematic Reviews, 5(1). https://doi.org/10.1186/s13643-016-0384-4
Paniagua, G., Couce-Sánchez, M., González-Blanco, L., Sabater, C., García-Fernández, A., Rodríguez-Revuelta, J., Sáiz, P. A., Bobes, J., Margolles, A., & García-Portilla, M. P. (2025). Comparative analysis of gut microbiome-derived short-chain fatty acids in patients with severe mental disorder: Insights from schizophrenia and bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 111345. https://doi.org/10.1016/j.pnpbp.2025.111345
Petrut, S., Bragaru, A. M., Munteanu, A. E., Moldovan, A., Moldovan, C., & Rusu, E. (2025). Gut over Mind: Exploring the Powerful Gut–Brain Axis. Nutrients, 17(5), 842. https://doi.org/10.3390/nu17050842
Randeni, N., & Xu, B. (2025). Critical review of the Cross-Links between dietary components, the gut microbiome, and depression. International Journal of Molecular Sciences, 26(2), 614. https://doi.org/10.3390/ijms26020614
Sekine, A., Kuroki, Y., Urata, T., Mori, N., & Fukuwatari, T. (2016). Inhibition of large neutral amino acid transporters suppresses kynurenic acid production via inhibition of kynurenine uptake in rodent brain. Neurochemical Research, 41(9), 2256–2266. https://doi.org/10.1007/s11064-016-1940-y
Van Der Walt, E., Brink, C. B., & Van Vuren, E. J. (2025). Changes in schizophrenia symptoms, tryptophan metabolism, neuroinflammation and the GABA-glutamate loop: A pilot study. South African Journal of Psychiatry, 31. https://doi.org/10.4102/sajpsychiatry.v31i0.2407
Vascellari, S., Palmas, V., Melis, M., Pisanu, S., Cusano, R., Uva, P., Perra, D., Madau, V., Sarchioto, M., Oppo, V., Simola, N., Morelli, M., Santoru, M. L., Atzori, L., Melis, M., Cossu, G., & Manzin, A. (2020). Gut Microbiota and Metabolome Alterations Associated with Parkinson’s Disease. mSystems, 5(5). https://doi.org/10.1128/msystems.00561-20
Vellucci, L., Mazza, B., Barone, A., Nasti, A., De Simone, G., Iasevoli, F., & De Bartolomeis, A. (2025). The role of astrocytes in the molecular pathophysiology of schizophrenia: Between neurodevelopment and neurodegeneration. Biomolecules, 15(5), 615. https://doi.org/10.3390/biom15050615
Wei, N., Ju, M., Su, X., Zhang, Y., Huang, Y., Rao, X., Cui, L., Lin, Z., & Dong, Y. (2024). Transplantation of gut microbiota derived from patients with schizophrenia induces schizophrenia-like behaviors and dysregulated brain transcript response in mice. Schizophrenia, 10(1). https://doi.org/10.1038/s41537-024-00460-6
Ye, N., Wang, Q., Li, Y., & Zhen, X. (2024). Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities. Medicinal Research Reviews. https://doi.org/10.1002/med.22086
Zhang, Y., Liu, C., Zhu, Q., Wu, H., Liu, Z., & Zeng, L. (2025). Relationship Between Depression and Epigallocatechin Gallate from the Perspective of Gut Microbiota: A Systematic Review. Nutrients, 17(2), 259. https://doi.org/10.3390/nu17020259
Downloads
Posted
Categories
License
Copyright (c) 2025 Farida Said
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.