Abstract
Introduction: Gut dysbiosis has been recognized as a relevant factor in the etiology of neuropsychiatric disorders such as depression and anxiety. Although the relationship between altered gut microbiota and these disorders is well documented, the underlying molecular mechanisms remain incompletely understood. This study reviews recent literature to analyze the biological pathways that may explain this connection.
Materials and methods: A narrative review of the available literature was conducted using biomedical databases, selecting studies that address the relationship between gut dysbiosis and affective disorders. The involved mechanisms were classified into three categories: the vagal pathway, intestinal permeability, and the effects of bacterial metabolites. Both animal and human studies were included.
Results: The review identified that gut dysbiosis affects the central nervous system through three main mechanisms: the vagal pathway acts as a bridge between the gut microbiota and the brain, increased intestinal permeability allows the translocation of bacterial products, and bacterial metabolites such as lipopolysaccharides induce neuroinflammation and neurotransmission alterations.
Discussion: The findings suggest that gut dysbiosis plays a critical role in modulating systemic and cerebral inflammation, contributing to the emergence of depressive and anxiety symptoms. Disruption of the intestinal barrier and the effects of bacterial metabolites are key elements in this relationship.
Conclusions: Gut dysbiosis and alterations in the gut-brain axis are key determinants in the manifestation of affective disorders, highlighting the potential of the microbiota as a therapeutic target in managing depression and anxiety.
References
Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305-12. https://doi.org/10.1016/j.tins.2013.01.005
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
Kumar A, Pramanik J, Goyal N, Chauhan D, Sivamaruthi BS, Prajapati BG, et al. Gut microbiota in anxiety and depression: unveiling the relationships and management options. Pharmaceuticals. 2023;16(4):565. https://doi.org/10.3390/ph16040565
American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-5. 5.a ed. Estados Unidos: APA; 2014.
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;21:786-96. https://doi.org/10.1038/mp.2016.44
Koopman M, El Aidy S. Depressed gut? The microbiota-diet-inflammation trialogue in depression. Curr Opin Psychiatry. 2017;30(5):369-77. https://doi.org/10.1097/yco.0000000000000350
Malhi GS, Mann JJ. Depression. Lancet. 2018;392(10161):2299-312. https://doi.org/10.1016/s0140-6736(18)31948-2
World Health Organization. Global burden of mental disorders and the need for a comprehensive, coordinated response from health and social sectors at the country level [internet]. Ginebra, Suiza: WHO; 2011 [citado 2023 jun. 5]. https://apps.who.int/gb/ebwha/pdf_files/EB130/B130_9-en.pdf
Chisholm D, Sweeny K, Sheehan P, Rasmussen B, Smit F, Cuijpers P, et al. Scaling-up treatment of depression and anxiety: a global return on investment analysis. Lancet Psychiatry. 2016;3(5):415-24. https://doi.org/10.1016/S2215-0366(16)30024-4
Ministerio de Salud y Protección Social. Boletín de salud mental depresión subdirección de enfermedades no transmisibles [internet]. Bogotá, Colombia: Minsalud; 2017. [citado 2023 jun. 5]. https://www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/VS/PP/ENT/boletin-depresion-marzo-2017.pdf
World Health Organization. Mental disorders [internet]. Ginebra, Suiza: WHO; 2022. [citado 2023 jun. 5]. https://www.who.int/news-room/fact-sheets/detail/mental-disorders
Simon NM. Generalized anxiety disorder and psychiatric comorbidities such as depression, bipolar disorder, and substance abuse. J Clin Psychiatry. 2009;70(supl. 2):10-4. https://doi.org/10.4088/jcp.s.7002.02
Kelly JR, Keane VO, Cryan JF, Clarke G, Dinan TG. Mood and microbes: gut-to-brain communication in depression. Gastroenterol Clin North Am. 2019;48(3):389-405. https://doi.org/10.1016/j.gtc.2019.04.006
Kelly JR, Borre Y, O' Brien C, Patterson E, El Aidy S, Deane J, et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016;82:109-18. https://doi.org/10.1016/j.jpsychires.2016.07.019
ESNM - European Society of Neurogastroenterology and Motility - ESNM [internet]. Viena, Austria: ESNM; 2023 [citado 2023 jun. 5]. https://www.esnm.eu
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
Agostoni E, Chinnock JE, de Burgh Daly M, Murray JG. Functional and histological studies of the vagus nerve and its branches to the heart, lungs and abdominal viscera in the cat. J Physiol. 1957;135(1):182-205. https://doi.org/10.1113%2Fjphysiol.1957.sp005703
Powley TL, Spaulding RA, Haglof SA. Vagal afferent innervation of the proximal gastrointestinal tract mucosa: chemoreceptor and mechanoreceptor architecture. J Comp Neurol. 2011;519(4):644-60. https://doi.org/10.1002/cne.22541
Näslund E, Hellström PM. Appetite signaling: from gut peptides and enteric nerves to brain. Physiol Behav. 2007;92(1-2):256-62. https://doi.org/10.1016/j.physbeh.2007.05.017
Lal S, Kirkup AJ, Brunsden AM, Thompson DG, Grundy D. Vagal afferent responses to fatty acids of different chain length in the rat. Am J Physiol Gastrointest Liver Physiol. 2001;281(4):G907-15. https://doi.org/10.1152/ajpgi.2001.281.4.g907
Goehler LE, Park SM, Opitz N, Lyte M, Gaykema RPA. Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain Behav Immun. 2008;22(3):354-66. https://doi.org/10.1016/j.bbi.2007.08.009
Hosoi T, Okuma Y, Matsuda T, Nomura Y. Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion. Auton Neurosci. 2005;120(1-2):104-7. https://doi.org/10.1016/j.autneu.2004.11.012
Goehler LE, Gaykema RPA, Opitz N, Reddaway R, Badr N, Lyte M. Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun. 2005;19(4):334-44. https://doi.org/10.1016/j.bbi.2004.09.002
Bercik P, Verdu EF, Foster JA, Macri J, Potter M, Huang X, et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology. 2010;139(6):2102-2112.e1. https://doi.org/10.1053/j.gastro.2010.06.063
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 U S A. 2011;108(38):16050-5. https://doi.org/10.1073/pnas.1102999108
Bluthé RM, Walter V, Parnet P, Layé S, Lestage J, Verrier D, et al. Lipopolysaccharide induces sickness behavior in rats via a vagal-mediated mechanism. C R Acad Sci III. 1994;317(6):499-503.
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):1132-9. https://doi.org/10.1111/j.1365-2982.2011.01796.x
Tan C, Yan Q, Ma Y, Fang J, Yang Y. Recognizing the role of the vagus nerve in depression from microbiota-gut brain axis. Front Neurol. 2022;13:1015175. https://doi.org/10.3389%2Ffneur.2022.1015175
Simpson CA, Mu A, Haslam N, Schwartz OS, Simmons JG. Feeling down? A systematic review of the gut microbiota in anxiety/depression and irritable bowel syndrome. J Affect Disord. 2020;266:429-46. https://doi.org/10.1016/j.jad.2020.01.124
Capuco A, Urits I, Hasoon J, Chun R, Gerald B, Wang JK, et al. Current perspectives on gut microbiome dysbiosis and depression. Adv Ther. 2020;37(4):1328-46. https://doi.org/10.1007/s12325-020-01272-7
Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: an interface between health and disease. J Gastroenterol Hepatol. 2003;18(5):479-97. https://doi.org/10.1046/j.1440-1746.2003.03032.x
Gill N, Wlodarska M, Finlay BB. Roadblocks in the gut: barriers to enteric infection: Barriers to enteric infection. Cell Microbiol. 2011;13(5):660-9. https://doi.org/10.1111/j.1462-5822.2011.01578.x
Chelakkot C, Ghim J, Ryu SH. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med. 2018;50(8):1-9. https://doi.org/10.1038/s12276-018-0126-x
Dicksved J, Schreiber O, Willing B, Petersson J, Rang S, Phillipson M, et al. Lactobacillus reuteri maintains a functional mucosal barrier during DSS treatment despite mucus layer dysfunction. PLoS One. 2012;7(9):e46399. https://doi.org/10.1371/journal.pone.0046399
Allam-Ndoul B, Castonguay-Paradis S, Veilleux A. Gut microbiota and intestinal trans-epithelial permeability. Int J Mol Sci. 2020;21(17):6402. https://doi.org/10.3390/ijms21176402
Stevens BR, Goel R, Seungbum K, Richards EM, Holbert RC, Pepine CJ, et al. Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut. 2018;67(8):1555-7. https://doi.org/10.1136/gutjnl-2017-314759
Iordache MM, Tocia C, Aschie M, Dumitru A, Manea M, Cozaru GC, et al. Intestinal permeability and depression in patients with inflammatory bowel disease. J Clin Med. 2022;11(17):5121. https://doi.org/10.3390/jcm11175121
Gaus OV, Livzan MA. Zonulin levels are associated with cortisol, dopamine, and serotonin levels in irritable bowel syndrome. Exp Clin Gastroenterol. 2023;4:37-48. https://doi.org/10.31146/1682-8658-ecg-212-4-37-48
Verma A, Inslicht SS, Bhargava A. Gut-Brain axis: role of microbiome, metabolomics, hormones, and stress in mental health disorders. Cells. 2024;13(17):1436. https://doi.org/10.3390/cells13171436
Mhanna A, Martini N, Hmaydoosh G, Hamwi G, Jarjanazi M, Zaifah G, et al. The correlation between gut microbiota and both neurotransmitters and mental disorders: a narrative review. Medicine. 2024;103(5):e37114. https://doi.org/10.1097/md.0000000000037114
Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. 2010;10(2):131-44. https://doi.org/10.1038/nri2707
Kim KA, Gu W, Lee IA, Joh EH, Kim DH. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One. 2012;7(10):e47713. https://doi.org/10.1371/journal.pone.0047713
Maes M, Twisk FNM, Kubera M, Ringel K, Leunis JC, Geffard M. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord. 2012;136(3):909-17. https://doi.org/10.1016/j.jad.2011.09.010
Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489(7415):220-30. https://doi.org/10.1038%2Fnature11550
Macfarlane S, Macfarlane GT. Regulation of short-chain fatty acid production. Proc Nutr Soc. 2003;62(1):67-72. https://doi.org/10.1079/pns2002207
Roshchina VV. Evolutionary considerations of neurotransmitters in microbial, plant, and animal cells. En: Lyte M, Freestone PPE, editores. Microbial Endocrinology. Nueva York, Estados Unidos: Springer New York; 2010. p. 17-52.
Erny D, Hrab? de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965-77. https://doi.org/10.1038%2Fnn.4030
Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun. 2013;4:1829. https://doi.org/10.1038/ncomms2852
Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003;278(13):11312-9. https://doi.org/10.1074/jbc.m211609200
Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun. 2014;5(1):3611. https://doi.org/10.1038/ncomms4611
Macfabe DF. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis. 2012;23. https://doi.org/10.3402/mehd.v23i0.19260
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):4923-44. https://doi.org/10.1113/jp276431
Yu S, Wang L, Jing X, Wang Y, An C. Features of gut microbiota and short-chain fatty acids in patients with first-episode depression and their relationship with the clinical symptoms. Front Psychol. 2023;14:1088268. https://doi.org/10.3389/fpsyg.2023.1088268
Archana, Gupta AK, Noumani A, Panday DK, Zaidi F, Sahu GK, et al. Gut microbiota derived short-chain fatty acids in physiology and pathology: An update. Cell Biochem Funct. 2024;42(7):e4108. https://doi.org/10.1002/cbf.4108
Gupta S, Dinesh S, Sharma S. Bridging the mind and gut: uncovering the intricacies of neurotransmitters, neuropeptides, and their influence on neuropsychiatric disorders. Cent Nerv Syst Agents Med Chem. 2024;24(1):2-21. https://doi.org/10.2174/0118715249271548231115071021
Barandouzi ZA, Starkweather AR, Henderson WA, Gyamfi A, Cong XS. Altered composition of gut microbiota in depression: a systematic review. Front Psychiatry. 2020;11:541. https://doi.org/10.3389/fpsyt.2020.00541
Cooke MB, Catchlove S, Tooley KL. Examining the influence of the human gut microbiota on cognition and stress: a systematic review of the literature. Nutrients. 2022;14(21):4623. https://doi.org/10.3390%2Fnu14214623
Santos J, Benjamin M, Yang PC, Prior T, Perdue MH. Chronic stress impairs rat growth and jejunal epithelial barrier function: role of mast cells. Am J Physiol Gastrointest Liver Physiol. 2000;278(6):G847-54. https://doi.org/10.1152/ajpgi.2000.278.6.g847
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.