Abstract
Depression is a prevalent mental illness, affecting a significant portion of the global population. Recent research has highlighted the crucial role of the gut microbiota in both metabolic and central nervous health. By reviewing literature from various databases, including Pubmed, Science Direct, Web of Science, and Scopus, spanning the years 2005–2023, a comprehensive search was conducted using keywords such as "Depression" and "Gut Microbiota". The gut microbiota acts as a "second brain" in humans and can communicate bidirectionally with the brain through the Brain-gut-microbiota axis pathway. This communication involves the immune and nervous systems. However, there are challenges in detecting and treating depression effectively. To address these limitations, researchers have been exploring the relationship between gut microbiota and depression. Studies have shown that gut microbial metabolites, such as lipopolysaccharides and short-chain fatty acids, can induce pro-inflammatory cytokines that contribute to neuroinflammation and increase the risk of depression. The kynurenine pathway, triggered by gut microbial metabolites, has also been associated with neuroinflammation. Thus, investigating these microbial metabolites can provide insights into depression treatment. This review focuses on analyzing the connection between gut microbial metabolites, inflammation, and depression. It explores novel mechanisms contributing to depression, specifically focusing on the mediation of inflammation through the release of pro-inflammatory cytokines. The objective is to provide valuable insights into the mechanisms underlying depression and to propose potential treatments.
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References
Abdel-Haq R, Schlachetzki JCM, Glass CK, Mazmanian SK (2019) Microbiome-microglia connections via the gut-brain axis. J Exp Med 216:41–59. https://doi.org/10.1084/jem.20180794
Aguirre-García MM et al (2023) Neuroinflammation, microbiota-gut-brain axis, and depression: the vicious circle. J Integr Neurosci. https://doi.org/10.31083/j.jin2203065
Alli SR, Gorbovskaya I, Liu JA-O, Kolla NJ, Brown LA-O, Müller DJ (2022a) The gut microbiome in depression and potential benefit of prebiotics, probiotics and synbiotics: a systematic review of clinical trials and observational studies. Int J Mol Sci 23:4494. https://doi.org/10.3390/ijms23094494
Alli SR, Gorbovskaya I, Liu JCW, Kolla NJ, Brown L, Muller DJ (2022b) The gut microbiome in depression and potential benefit of prebiotics, probiotics and synbiotics: a systematic review of clinical trials and observational studies. Int J Mol Sci. https://doi.org/10.3390/ijms23094494
Anand NA-O, Gorantla VR, Chidambaram SA-OX (2023) The role of gut dysbiosis in the pathophysiology of neuropsychiatric disorders. Cells 12:54. https://doi.org/10.3390/cells12010054
Association AP (2015) Diagnostic and statistical manual of mental disorders DSM-5. Peking University Press
Bermúdez-Humarán LA-O, Salinas EA-O, Ortiz GG, Ramirez-Jirano LA-O, Morales JA-O, Bitzer-Quintero OK (2019) From probiotics to psychobiotics: live beneficial bacteria which act on the brain-gut axis. Nutrients 11:890. https://doi.org/10.3390/nu11040890
Beurel E, Toups M, Nemeroff CB (2020) The bidirectional relationship of depression and inflammation: double trouble. Neuron 107:234–256. https://doi.org/10.1016/j.neuron.2020.06.002
Boku S, Nakagawa S, Toda H, Hishimoto A (2018) Neural basis of major depressive disorder: beyond monoamine hypothesis. Psychiatry Clin Neurosci 72:3–12. https://doi.org/10.1111/pcn.12604
Chang L, Wei Y, Hashimoto K (2022) Brain-gut-microbiota axis in depression: a historical overview and future directions. Brain Res Bull 182:44–56. https://doi.org/10.1016/j.brainresbull.2022.02.004
Chen L et al (2019a) Forsythiaside prevents beta-amyloid-induced hippocampal slice injury by upregulating 2-arachidonoylglycerol via cannabinoid receptor 1-dependent NF-kappaB pathway. Neurochem Int 125:57–66. https://doi.org/10.1016/j.neuint.2019.02.008
Chen L et al (2019b) Forsythiaside prevents β-amyloid-induced hippocampal slice injury by upregulating 2-arachidonoylglycerol via cannabinoid receptor 1-dependent NF-κB pathway. Neurochem Int 125:57–66. https://doi.org/10.1016/j.neuint.2019.02.008
Cheung SG, Goldenthal AR, Uhlemann AC, Mann JJ, Miller JM, Sublette ME (2019) Systematic review of gut microbiota and major depression. Front Psychiatry 10:34. https://doi.org/10.3389/fpsyt.2019.00034
Dethloff F et al (2020) Paroxetine administration affects microbiota and bile acid levels in mice. Front Psychiatry 11:518. https://doi.org/10.3389/fpsyt.2020.00518
Doroszkiewicz J, Groblewska M, Mroczko B (2021) The role of gut microbiota and gut-brain interplay in selected diseases of the central nervous system. Int J Mol Sci. https://doi.org/10.3390/ijms221810028
Drevets WC, Wittenberg GM, Bullmore ET, Manji HK (2022) Immune targets for therapeutic development in depression: towards precision medicine. Nat Rev Drug Discov 21:224–244. https://doi.org/10.1038/s41573-021-00368-1
Duman CH, Duman RS (2015) Spine synapse remodeling in the pathophysiology and treatment of depression. Neurosci Lett 601:20–29. https://doi.org/10.1016/j.neulet.2015.01.022
Edinoff AN et al (2021) Selective serotonin reuptake inhibitors and adverse effects: a narrative review. Neurol Int 13:387–401. https://doi.org/10.3390/neurolint13030038
Evrensel A, Tarhan KN (2021) Emerging role of Gut-microbiota-brain axis in depression and therapeutic implication. Prog Neuro Psychopharmacol Biol Psychiatry. https://doi.org/10.1016/j.pnpbp.2020.110138
Fock E, Parnova R (2023) Mechanisms of blood-brain barrier protection by microbiota-derived short-chain fatty acids. Cells. https://doi.org/10.3390/cells12040657
Foster JA, Baker GB, Dursun SM (2021) The relationship between the gut microbiome-immune system-brain axis and major depressive disorder. Front Neurol. https://doi.org/10.3389/fneur.2021.721126
Frenois F et al (2007) Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32:516–531. https://doi.org/10.1016/j.psyneuen.2007.03.005
Góralczyk-Bińkowska A, Szmajda-Krygier D, Kozłowska E (2022a) The microbiota–gut–brain axis in psychiatric disorders. Int J Mol Sci. https://doi.org/10.3390/ijms231911245
Góralczyk-Bińkowska A, Szmajda-Krygier DA-O, Kozłowska E (2022b) The microbiota-gut-brain axis in psychiatric disorders. Int J Mol Sci 23:11245. https://doi.org/10.3390/ijms231911245
Guo B, Zhang M, Hao W, Wang Y, Zhang T, Liu C (2023) Neuroinflammation mechanisms of neuromodulation therapies for anxiety and depression. Transl Psychiatry 13:5. https://doi.org/10.1038/s41398-022-02297-y
Han YM et al (2021) Decoding the temporal nature of brain GR activity in the NFkappaB signal transition leading to depressive-like behavior. Mol Psychiatry 26:5087–5096. https://doi.org/10.1038/s41380-021-01016-1
Hassamal S (2023) Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Front Psychiatry. https://doi.org/10.3389/fpsyt.2023.1130989
Kang M-X, Jia H (2008) Progress in mechanisms of visceral hypersensitivity in irritable bowel syndrome. Baishideng Publ Group 16(14):1554–1558. https://doi.org/10.11569/wcjd.v16.i14.1554
Khawam EA, Laurencic G, Malone DA (2006) Side effects of antidepressants: an overview. Clevel Clin J Med 73:351–353. https://doi.org/10.3949/ccjm.73.4.351
Klein DCG et al (2015) CD14, TLR4 and TRAM show different trafficking dynamics during LPS stimulation. Traffic 16:677–690. https://doi.org/10.1111/tra.12274
Kohler-Forsberg O, NL C, Hjorthoj C, Nordentoft M, Mors O, Benros ME (2019) Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand 139:404–419. https://doi.org/10.1111/acps.13016
Kunugi H (2021) Gut microbiota and pathophysiology of depressive disorder. Ann Nutr Metab 2:11–20. https://doi.org/10.1159/000518274
Li B, Yang W, Ge T, Wang Y, Cui R (2022a) Stress induced microglial activation contributes to depression. Pharmacol Res 179:106145. https://doi.org/10.1016/j.phrs.2022.106145
Li D, Li Y, Yang S, Lu J, Jin X, Wu M (2022b) Diet-gut microbiota-epigenetics in metabolic diseases: From mechanisms to therapeutics. Biomed Pharmacother. https://doi.org/10.1016/j.biopha.2022.113290
Li X et al (2022c) Sorafenib inhibits LPS-induced inflammation by regulating Lyn-MAPK-NF-kB/AP-1 pathway and TLR4 expression. Cell Death Discov 8:281. https://doi.org/10.1038/s41420-022-01073-7
Liu S, Guo R, Liu F, Yuan Q, Yu Y, Ren F (2020) Gut microbiota regulates depression-like behavior in rats through the neuroendocrine-immune-mitochondrial pathway. Neuropsychiatr Dis Treat 16:859–869. https://doi.org/10.2147/NDT.S243551
Liu H et al (2022) Muscone with attenuation of neuroinflammation and oxidative stress exerts antidepressant-like effect in mouse model of chronic restraint stress. Oxid Med Cell Longev 2022:1–10. https://doi.org/10.1155/2022/3322535
Liu L, Wang H, Chen X, Zhang Y, Zhang H, Xie P (2023) Gut microbiota and its metabolites in depression: from pathogenesis to treatment. EBioMedicine 90:104527. https://doi.org/10.1016/j.ebiom.2023.104527
Maes M, Kubera M, Fau - Leunis J-C, Leunis JC, (2008) 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 29(1):117–124
Margolis KG, Cryan JF, Mayer EA (2021) The microbiota-gut-brain axis: from motility to mood. Gastroenterology 160:1486–1501. https://doi.org/10.1053/j.gastro.2020.10.066
McGuinness AJ et al (2022) A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia. Mol Psychiatry 27:1920–1935. https://doi.org/10.1038/s41380-022-01456-3
Mikulska J, Juszczyk G, Gawrońska-Grzywacz M, Herbet M (2021) HPA axis in the pathomechanism of depression and schizophrenia: new therapeutic strategies based on its participation. Brain Sci. https://doi.org/10.3390/brainsci11101298
Nikolova VL, Smith MRB, Hall LJ, Cleare AJ, Stone JM, Young AH (2021) Perturbations in gut microbiota composition in psychiatric disorders. JAMA Psychiat. https://doi.org/10.1001/jamapsychiatry.2021.2573
Outhred T, Hawkshead BE, Wager TD, Das P, Malhi GS, Kemp AH (2013) Acute neural effects of selective serotonin reuptake inhibitors versus noradrenaline reuptake inhibitors on emotion processing: implications for differential treatment efficacy. Neurosci Biobehav Rev 37:1786–1800. https://doi.org/10.1016/j.neubiorev.2013.07.010
Palepu MSK, Dandekar MP (2022) Remodeling of microbiota gut-brain axis using psychobiotics in depression. Eur J Pharmacol. https://doi.org/10.1016/j.ejphar.2022.175171
Paul ER et al (2022) Peripheral and central kynurenine pathway abnormalities in major depression. Brain Behav Immun 101:136–145. https://doi.org/10.1016/j.bbi.2022.01.002
Perez-Caballero L, Torres-Sanchez S, Romero-Lopez-Alberca C, Gonzalez-Saiz F, Mico JA, Berrocoso E (2019) Monoaminergic system and depression. Cell Tissue Res 377:107–113. https://doi.org/10.1007/s00441-018-2978-8
Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S (2016) From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry 21:738–748. https://doi.org/10.1038/mp.2016.50
Sanada K et al (2020) Gut microbiota and major depressive disorder: a systematic review and meta-analysis. J Affect Disord 266:1–13. https://doi.org/10.1016/j.jad.2020.01.102
Savitz J et al (2014) Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder. Neuropsychopharmacology 40:463–471. https://doi.org/10.1038/npp.2014.194
Savitz J et al (2015) Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder. Brain Behav Immun 46:55–59. https://doi.org/10.1016/j.bbi.2015.02.007
Scassellati C et al (2021) The complex molecular picture of gut and oral microbiota-brain-depression system: what we know and what we need to know. Front Psychiatry. https://doi.org/10.3389/fpsyt.2021.722335
Slyepchenko A et al (2016) Intestinal dysbiosis, gut hyperpermeability and bacterial translocation: missing links between depression, obesity and type 2 diabetes. Curr Pharm Des 22:6087–6106. https://doi.org/10.2174/1381612822666160922165706
Socała K et al (2021) The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacol Res 172:105840. https://doi.org/10.1016/j.phrs.2021.105840
Strandwitz P (2018) Neurotransmitter modulation by the gut microbiota. Brain Res 1693:128–133. https://doi.org/10.1016/j.brainres.2018.03.015
Tang M, Liu T, Jiang P, Dang R (2021) The interaction between autophagy and neuroinflammation in major depressive disorder: from pathophysiology to therapeutic implications. Pharmacol Res. https://doi.org/10.1016/j.phrs.2021.105586
Triantafilou M, Triantafilou K (2002) Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol 23:301–304. https://doi.org/10.1016/s1471-4906(02)02233-0
Trzeciak PA-O, Herbet MA-O (2021) Role of the intestinal microbiome, intestinal barrier and psychobiotics in depression. Nutrients 13:927. https://doi.org/10.3390/nu13030927
Wang H et al (2022) Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression. J Neuroinflammation 19:132. https://doi.org/10.1186/s12974-022-02492-0
Wang C et al (2023) A comprehensive review on pharmacological, toxicity, and pharmacokinetic properties of phillygenin: current landscape and future perspectives. Biomed Pharmacother 166:115410. https://doi.org/10.1016/j.biopha.2023.115410
Won E, Na K-S, Kim Y-K (2021) Associations between melatonin, neuroinflammation, and brain alterations in depression. Int J Mol Sci. https://doi.org/10.3390/ijms23010305
Wu L et al (2020a) Targeting oxidative stress and inflammation to prevent ischemia-reperfusion injury. Front Mol Neurosci 13:28. https://doi.org/10.3389/fnmol.2020.00028
Wu M et al (2020b) Associations between disordered gut microbiota and changes of neurotransmitters and short-chain fatty acids in depressed mice. Transl Psychiatry 10:350. https://doi.org/10.1038/s41398-020-01038-3
Xu R, Ma L, Chen T, Wang J (2022) Sophorolipid suppresses LPS-induced inflammation in RAW264.7 cells through the NF-κB signaling pathway. Molecules. https://doi.org/10.3390/molecules27155037
Yang JW et al (2020) Corticosteroids alleviate lipopolysaccharide-induced inflammation and lung injury via inhibiting NLRP3-inflammasome activation. J Cell Mol Med 24:12716–12725. https://doi.org/10.1111/jcmm.15849
Yu S, Wang L, Jing X, Wang Y, An C (2023) Features of gut microbiota and short-chain fatty acids in patients with first-episode depression and their relationship with the clinical symptoms. Front Psychol. https://doi.org/10.3389/fpsyg.2023.1088268
Zhang L, Zhang J, You Z (2018) Switching of the microglial activation phenotype is a possible treatment for depression disorder. Front Cell Neurosci. https://doi.org/10.3389/fncel.2018.00306
Zhao X et al (2019) Behavioral, inflammatory and neurochemical disturbances in LPS and UCMS-induced mouse models of depression. Behav Brain Res 364:494–502. https://doi.org/10.1016/j.bbr.2017.05.064
Zheng H, Zhang C, Zhang J, Duan L (2023) “Sentinel or accomplice”: gut microbiota and microglia crosstalk in disorders of gut-brain interaction. Protein Cell 14:726–742. https://doi.org/10.1093/procel/pwad020
Zhu Z, Wang L, Hao R, Zhao B, Sun L, Ye RD (2016) Cutting edge: a cullin-5–TRAF6 interaction promotes TRAF6 polyubiquitination and lipopolysaccharide signaling. J Immunol 197:21–26. https://doi.org/10.4049/jimmunol.1600447
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Yunxiang Tan wrote the main manuscript text and Mengyu Xu prepared figures 1-2. All authors reviewed the manuscript.
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Tan, Y., Xu, M. & Lin, D. Review of research progress on intestinal microbiota based on metabolism and inflammation for depression. Arch Microbiol 206, 146 (2024). https://doi.org/10.1007/s00203-024-03866-z
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DOI: https://doi.org/10.1007/s00203-024-03866-z