The role of the gut–brain axis in the pathogenesis of depression and anxiety disorders: The significance of microbiota, bacterial metabolites, and vagus nerve signalling — A systematic review
DOI:
https://doi.org/10.12775/QS.2026.65.73951Keywords
gut–brain axis, gut microbiota, short-chain fatty acids, vagus nerve, depression, anxiety disordersAbstract
Introduction and aim: Depression and anxiety disorders are leading causes of disability worldwide, and many patients respond inadequately to conventional treatment. The microbiota–gut–brain axis has emerged as a candidate contributor to their pathogenesis. This review aimed to synthesise mechanistic and clinical evidence linking gut microbiota, bacterial metabolites, and vagal signalling to depression and anxiety. Material and methods: A systematic search of PubMed, Embase, and Scopus (2011–2025) was performed following PRISMA principles, using terms for the gut–brain axis, microbiota, short-chain fatty acids, tryptophan, vagus nerve, depression, and anxiety. Studies were synthesised narratively across three mechanistic pillars. Results: Patients with depression and anxiety show reduced short-chain-fatty-acid-producing taxa and enrichment of pro-inflammatory bacteria. Bacterial metabolites—short-chain fatty acids, tryptophan catabolites, and gamma-aminobutyric acid—modulate neuroinflammation, blood–brain-barrier integrity, and neurotransmission. Several anxiolytic and antidepressant-like microbial effects are abolished by vagotomy, confirming a vagal route. Randomised trials of psychobiotics show small but significant reductions in depressive symptoms. Conclusions: The gut–brain axis is a biologically plausible, therapeutically tractable contributor to mood and anxiety disorders, though heterogeneity and causal uncertainty remain.
References
1. Asad A, Kirk M, Zhu S, Dong X, Gao M. Effects of prebiotics and probiotics on symptoms of depression and anxiety in clinically diagnosed samples: systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2024;83(7):e1504-e1520. https://doi.org/10.1093/nutrit/nuae177
2. Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011;23(12):1132-1139. https://doi.org/10.1111/j.1365-2982.2011.01796.x
3. Bonaz B, Bazin T, Pellissier S. The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci. 2018;12:49. https://doi.org/10.3389/fnins.2018.00049
4. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, et al. 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. https://doi.org/10.1073/pnas.1102999108
5. Clarke G, Kennedy PJ, Groeger JA, Quigley EMM, Dinan TG, Cryan JF. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology. 2016;112(Pt B):399-412. https://doi.org/10.1016/j.neuropharm.2016.07.002
6. Correia AS, Vale N. Tryptophan metabolism in depression: a narrative review with a focus on serotonin and kynurenine pathways. Int J Mol Sci. 2022;23(15):8493. https://doi.org/10.3390/ijms23158493
7. Czachor A, Kotula A. The link between gut microbiota and depression: exploring the correlation. J Educ Health Sport. 2025;77:55276. https://doi.org/10.12775/JEHS.2025.77.55276
8. Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol. 2019;16(8):461-478. https://doi.org/10.1038/s41575-019-0157-3
9. Deng Y, Zhou M, Wang J, Yao J, Yu J, Liu W, et al. Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain. Gut Microbes. 2021;13(1):1-16. https://doi.org/10.1080/19490976.2020.1869501
10. Fock E, Parnova R. Mechanisms of blood-brain barrier protection by microbiota-derived short-chain fatty acids. Cells. 2023;12(4):657. https://doi.org/10.3390/cells12040657
11. Han W, Tellez LA, Perkins MH, Perez IO, Qu T, Ferreira J, et al. A neural circuit for gut-induced reward. Cell. 2018;175(3):665-678. https://doi.org/10.1016/j.cell.2018.08.049
12. Kaur H, Bose C, Mande SS. Tryptophan metabolism by gut microbiome and gut-brain-axis: an in silico analysis. Front Neurosci. 2019;13:1365. https://doi.org/10.3389/fnins.2019.01365
13. Kim JK, Han SK, Joo MK, Kim DH. Short-chain fatty acids and gut microbiota in the regulation of anxiety and depression. Front Neurosci. 2024;18:1501134. https://doi.org/10.3389/fnins.2024.1501134
14. Komasara P, Niewczas K, Brzozowska A, et al. Gut microbiota in postpartum depression: pathogenesis and treatment perspectives—a review. J Educ Health Sport. 2025;82:60357. https://doi.org/10.12775/JEHS.2025.82.60357
15. Kosyra K, Drabczyk M, Marczyńska Z, Zyśk A, Magda I. Microbiota and depressive disorders—a review. J Educ Health Sport. 2024;60:013. https://doi.org/10.12775/JEHS.2024.60.013
16. Li H, Wang P, Zhou Y, et al. Short-chain fatty acids ameliorate depressive-like behaviors of high fructose-fed mice by rescuing hippocampal neurogenesis decline and blood-brain barrier damage. Nutrients. 2022;14(9):1882. https://doi.org/10.3390/nu14091882
17. Lin P, Ding B, Feng C, Yin S, Zhang T, Qi X, et al. Prevotella and Klebsiella proportions in fecal microbial communities are potential characteristic parameters for patients with major depressive disorder. J Affect Disord. 2017;207:300-304. https://doi.org/10.1016/j.jad.2016.09.051
18. Liu H, Wang D, Wan X, Chen X, Liu Y, Chen Z, et al. Efficacy of probiotic intervention in unmedicated depression: a systematic review and meta-analysis. Front Psychiatry. 2026;16:1608238. https://doi.org/10.3389/fpsyt.2025.1608238
19. Liu L, Wang H, Chen X, Zhang Y, Zhang H, Xie P. Gut microbiota and its metabolites in depression: from pathogenesis to treatment. EBioMedicine. 2023;90:104527. https://doi.org/10.1016/j.ebiom.2023.104527
20. Lukić I, Ivković S, Mitić M, Adžić M. Tryptophan metabolites in depression: modulation by gut microbiota. Front Behav Neurosci. 2022;16:987697. https://doi.org/10.3389/fnbeh.2022.987697
21. Ma L. Microbiome-gut-brain axis as a novel hotspot in depression. Brain-X. 2024;2(3):e43. https://doi.org/10.1002/brx2.43
22. Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R. The new '5-HT' hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs). Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):702-721. https://doi.org/10.1016/j.pnpbp.2010.12.017
23. Obi-Azuike C, Ebiai R, Gibson T, Hernandez A, Khan A, Anugwom G, et al. A systematic review on gut–brain axis aberrations in bipolar disorder and methods of balancing the gut microbiota. Brain Behav. 2023;13(6):e3037. https://doi.org/10.1002/brb3.3037
24. Petakh P, Oksenych V, Kamyshnyi A. The role of the gut microbiota-gut-brain axis in psychiatric disorders. Front Neurosci. 2024;18:1394953. https://doi.org/10.3389/fnins.2024.1394953
25. Qu Y, Zhang K, Pu Y, et al. Brain short-chain fatty acids induce ACSS2 to ameliorate depressive-like behavior via PPARγ-TPH2 axis. Research (Wash DC). 2024;7:0400. https://doi.org/10.34133/research.0400
26. Sarkar A, Harty S, Lehto SM, Moeller AH, Dinan TG, Dunbar RIM, et al. Effectiveness of psychobiotics in the treatment of psychiatric and cognitive disorders: a systematic review of randomized clinical trials. Nutrients. 2024;16(9):1352. https://doi.org/10.3390/nu16091352
27. Silva YP, Bernardi A, Frozza RL. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol. 2020;11:25. https://doi.org/10.3389/fendo.2020.00025
28. Simpson CA, Diaz-Arteche C, Eliby D, Schwartz OS, Simmons JG, Cowan CSM. The gut microbiota in anxiety and depression - a systematic review. Clin Psychol Rev. 2021;83:101943. https://doi.org/10.1016/j.cpr.2020.101943
29. Siopi E, Galerne M, Rivagorda M, et al. Gut microbiota changes require vagus nerve integrity to promote depressive-like behaviors in mice. Mol Psychiatry. 2023;28(7):3002-3012. https://doi.org/10.1038/s41380-023-02071-6
30. Tian P, Chen Y, Zhu H, Wang L, Qian X, Zou R, et al. Bifidobacterium breve CCFM1025 attenuates major depression disorder via regulating gut microbiome and tryptophan metabolism: a randomized clinical trial. Brain Behav Immun. 2022;100:233-241. https://doi.org/10.1016/j.bbi.2021.11.023
31. Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol. 2019;4(4):623-632. https://doi.org/10.1038/s41564-018-0337-x
32. Van de Wouw M, Boehme M, Lyte JM, Wiley N, Strain C, O'Sullivan O, et al. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations. J Physiol. 2018;596(20):4923-4944. https://doi.org/10.1113/JP276431
33. Wojciechowska K, Zajkowska I, Zabrocka P, Martowska J, Choroszewska E, Baran J, et al. The role of gut microbiota in the pathophysiology of depression: a narrative review. Qual Sport. 2026;49:67803. https://doi.org/10.12775/QS.2026.49.67803
34. Wójcik ZM, Kamińska-Omasta K, Omasta B, Krupa O, Pietrukaniec PD, Romańczuk KB, et al. Gut microbiota and its impact on brain function and mental health. Qual Sport. 2025;38:58196. https://doi.org/10.12775/QS.2025.38.58196
35. Wang Y, Ding K, Liu Y, et al. Cefaclor causes vagus nerve-mediated depression-like symptoms with gut dysbiosis in mice. Sci Rep. 2023;13:15320. https://doi.org/10.1038/s41598-023-42302-y
36. Xiong R, Li W, Li Y, et al. Gut microbiota variations in depression and anxiety: a systematic review. BMC Psychiatry. 2025;25:412. https://doi.org/10.1186/s12888-025-06871-8
37. Yang LL, Millischer V, Rodin S, MacFabe DF, Villaescusa JC, Lavebratt C. Plasma short-chain fatty acid concentrations in social anxiety disorder and changes after cognitive behavioral therapy. Transl Psychiatry. 2026;16:12. https://doi.org/10.1038/s41398-026-04134-y
38. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264-276. https://doi.org/10.1016/j.cell.2015.02.047
39. Zhang J, Ma L, Chang L, Pu Y, Qu Y, Hashimoto K. A key role of the subdiaphragmatic vagus nerve in the depression-like phenotype and abnormal composition of gut microbiota in mice after lipopolysaccharide administration. Transl Psychiatry. 2020;10:186. https://doi.org/10.1038/s41398-020-00878-3
40. Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Mol Psychiatry. 2016;21(6):786-796. https://doi.org/10.1038/mp.2016.44
41. Zhou L, Chen Y, Liu Z, et al. Gut microbiota as a novel target for treating anxiety and depression: from mechanisms to multimodal interventions. Front Microbiol. 2025;16:1664800. https://doi.org/10.3389/fmicb.2025.1664800
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Dominika Grzybowska, Maria Leśniak, Hubert Bednarz, Agnieszka Anna Gaczoł, Weronika Grzyb-Kurnik, Kamil Idzik, Michał Kawa, Tomasz Kilian, Paulina Kopcińska, Michał Kurnik, Magdalena Mortka, Gabriela Piotrowska, Aleksander Urbaś
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 21
Number of citations: 0
