Skip to main content


Front. Behav. Neurosci., 06 June 2023
Sec. Emotion Regulation and Processing
Volume 17 - 2023 |

Editorial: Gut-microbiota-brain axis in depression: mechanisms and possible therapies

  • 1Universidade Federal do Pampa - Campus Uruguaiana, Uruguaiana, Brazil
  • 2Laboratory of Microbiota and Immunomodulation, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil

Some researchers have pointed out that changes in the gut microbiota, a complex ecosystem, that begins to colonize human intestines immediately after birth, would lead to a systemic alteration. These alterations that in different ways would reach the central nervous system modulating pathways, such as the inflammatory pathway, especially the microglia, which could influence responses to treatments to depression (Macedo et al., 2017; Zhang et al., 2017; Ma et al., 2022).

Depression is a psychiatric condition that affects a large number of people in the world, but its treatment is not effective for all individuals affected (World Health Organization, 2017). Thus, this Research Topic collected current knowledge and advanced studies on the role of intestinal microbiota in depression and discussed the treatments that alter the gut microbiota.

The first review published in this Research Topic by Rosa et al. discusses the potential roles of microbiota and MicroRNAs (miRNAs) on the neuropathology of depression and anxiety, and its potential as treatment strategies. The miRNAs are small non-coding ribonucleic acid (RNAs), with an average of 22 nucleotides in length, which function as the posttranscriptional regulators of gene expression, primarily through translational repression (Ha and Kim, 2014). Studies have suggested miRNAs as pharmacological targets and biomarkers for treating and diagnosing depression and anxiety (Ortega et al., 2021; Hassan et al., 2022). Taking into account some reviews and original articles, the authors suggest that gut microbiota can influence miRNAs expression in different brain regions related to depression and anxiety, suggesting the potential role of specific miRNAs as an emerging treatment for neuropsychiatric disorders.

On the other hand, Forth et al. used current literature to demonstrate that probiotic or synbiotic supplementation alleviates symptoms of some severe psychiatric disorders, such as major depressive disorder. Probiotics and symbiotic (combine probiotics and prebiotics), when administered in adequate amounts, provide health benefits on the host and may contain a variety of microorganisms (Johnson et al., 2021). Interestingly, probiotics or fecal microbiota transplants from healthy patients alleviate symptoms and induce positive outcomes in patients with psychiatric disorders (Chinna Meyyappan et al., 2020; Johnson et al., 2021).

The authors selected 8 papers to discuss the review, because it's relevant. Some articles suggest that probiotic and symbiotic adjuvant treatment with selective serotonin reuptake inhibitors is more effective in decreasing depressive symptomatology than selective serotonin reuptake inhibitors treatment alone. In contrast, for individuals with schizophrenia, adjuvant probiotic treatment was not found to be more effective in reducing clinical symptom severity than standard antipsychotic treatment alone, but was associated with a decrease of adverse events and side effects. In the end, the authors conclude there are some big limitations, such as the small number of studies for each psychiatric illness and the lack of studies investigating other psychiatric illnesses and the mechanisms of action for these beneficial effects of probiotic adjuvant treatment are not fully understood.

Another interesting study that is part of this Research Topic is an original article by Shimada et al. exploring the relationship between social isolation-induced depressive-like phenotypes, the microbiota and liver metabolism. To this, the authors established a model of weak depression, because this type of depression is more common in modern society compared to widely studied models of severe depression (Cho et al., 2019).

Studies have been demonstrated that both microbiological and physical interaction with the mother are critical for maintaining the offspring's mental health (Benner et al., 2014; Tochitani et al., 2016). The data of Shimada et al. show that single housing conditions induce weak depression-like behaviors and demonstrate that changes in the gut bacteria composition affect the behavior and metabolism of animals.

The central mechanism for these changes induced by social isolation appears to be associated with suppression of cAMP signals in the amygdala and decrease of beta-oxidation in the liver. In this context, studies have indicated the essential role of cAMP signaling to neural response to stressors in the amygdala (Tronson et al., 2012; Cowansage et al., 2013). Interestingly, the study by Shimada et al. showed a correlation of gene expression levels with the occupation of multiple genera of intestinal bacteria, such as lactobacillus and an aero stipes, and carnitine palmitoyl transferase 1A in the liver, a key beta-oxidation enzyme. Taken together, these data suggest the essential role of gut bacteria in brain and liver homeostasis. In this way, this article provides a suitable model study of weak depression, in addition to providing therapeutic targets such as the intestinal microbiota involved with this disease and the cAMP pathway.

Studies have shown that the modulation of the intestinal microbiota can improve depression symptoms (Messaoudi et al., 2011; Codagnone et al., 2019). In this context, literature data show the effect of the intestinal microbiota on the levels of neurotransmitters involved in the mechanisms of action of antidepressants (Stasi et al., 2019). Contributing to this field of research, Rukavishnikov et al. investigated the effect of antidepressants on normal gut microbiota in vitro and the consequences of their antibacterial effect on treatment outcomes. The results of their study showed that selective serotonin reuptake inhibitors, selective serotonin and noradrenaline reuptake inhibitors and noradrenergic and specific serotonergic antidepressant had an inhibitory effect on the growth of all studied microorganisms.

Interestingly, the pharmacological class of antidepressant drugs studied by Rukavishnikov et al. are most often used in clinical practice for major depression treatment. In addition, the bacterial strains used in this study continued the normal human gut microbiota and played an important role in the functioning of the host organism. This study suggests that the antidepressants affect the gut microbiota and could influence the therapeutic process. Despite the limitation of the in vitro methodology, Rukavishnikov et al. reveals new directions for optimizing the personalized therapy of patients with depression, considering individual microbiome profiles and antidepressant used in the treatment.

In conclusion, preclinical and clinical studies that show the treatment options that modify the gut microbiota, including, for example, prebiotics and probiotics, are important to science and could contribute to finding new treatments for depression.

Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Benner, S., Endo, T., Endo, N., Kakeyama, M., and Tohyama, C. (2014). Early deprivation induces competitive subordinance in C57BL/6 male mice. Physiol. Behav. 137, 42–52. doi: 10.1016/j.physbeh.2014.06.018

PubMed Abstract | CrossRef Full Text | Google Scholar

Chinna Meyyappan, A., Forth, E., Wallace, C. J. K., and Milev, R. (2020). Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review. BMC Psychiatry 20, 299. doi: 10.21203/

PubMed Abstract | CrossRef Full Text | Google Scholar

Cho, Y., Lee, J. K., Kim, D.-H., Park, J.-H., Choi, M., Kim, H.-J., et al. (2019). Factors associated with quality of life in patients with depression: a nationwide population-based study. PLoS ONE 14, e0219455. doi: 10.1371/journal.pone.0219455

PubMed Abstract | CrossRef Full Text | Google Scholar

Codagnone, M. G., Spichak, S., O'Mahony, S. M., O'Leary, O. F., Clarke, G., Stanton, C., et al. (2019). Programming bugs: microbiota and the developmental origins of brain health and disease. Biol. Psychiatry 85, 150–163. doi: 10.1016/j.biopsych.2018.06.014

PubMed Abstract | CrossRef Full Text | Google Scholar

Cowansage, K. K., Bush, D. E. A., Josselyn, S. A., Klann, E., and Ledoux, J. E. (2013). Basal variability in CREB phosphorylation predicts trait-like differences in amygdala-dependent memory. Proc. Natl. Acad. Sci. U. S. A. 110, 16645–16650. doi: 10.1073/pnas.1304665110

PubMed Abstract | CrossRef Full Text | Google Scholar

Ha, M., and Kim, V. N. (2014). Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524. doi: 10.1038/nrm3838

PubMed Abstract | CrossRef Full Text | Google Scholar

Hassan, M., Amir, A., Shahzadi, S., and Kloczkowski, A. (2022). Therapeutic implications of microRNAs in depressive disorders: a review. Int. J. Mol. Sci. 23, 13530. doi: 10.3390/ijms232113530

PubMed Abstract | CrossRef Full Text | Google Scholar

Johnson, D., Thurairajasingam, S., Letchumanan, V., Chan, K.-G., and Lee, L.-H. (2021). Exploring the role and potential of probiotics in the field of mental health: major depressive disorder. Nutrients 13, 1728. doi: 10.3390/nu13051728

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, L., Zhang, J., Fujita, Y., Shinno-Hashimoto, H., Shan, J., Wan, X., et al. (2022). Effects of spleen nerve denervation on depression-like phenotype, systemic inflammation, and abnormal composition of gut microbiota in mice after administration of lipopolysaccharide: a role of brain-spleen axis. J. Affect. Disord. 317, 156–165. doi: 10.1016/j.jad.2022.08.087

PubMed Abstract | CrossRef Full Text | Google Scholar

Macedo, D., Filho, A. J. M. C., Soares de Sousa, C. N., Quevedo, J., Barichello, T., Júnior, H. V. N., et al. (2017). Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness. J. Affect. Disord. 208, 22–32. doi: 10.1016/j.jad.2016.09.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Messaoudi, M., Lalonde, R., Violle, N., Javelot, H., Desor, D., Nejdi, A., et al. (2011). Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br. J. Nutr. 105, 755–764. doi: 10.1017/S0007114510004319

PubMed Abstract | CrossRef Full Text | Google Scholar

Ortega, M. A., Alvarez-Mon, M. A., García-Montero, C., Fraile-Martinez, O., Lahera, G., Monserrat, J., et al. (2021). MicroRNAs as critical biomarkers of major depressive disorder: a comprehensive perspective. Biomedicines 9, 1659. doi: 10.3390/biomedicines9111659

PubMed Abstract | CrossRef Full Text | Google Scholar

Stasi, C., Sadalla, S., and Milani, S. (2019). The relationship between the serotonin metabolism, gut-microbiota and the gut-brain axis. Curr. Drug Metab. 20, 646–655. doi: 10.2174/1389200220666190725115503

PubMed Abstract | CrossRef Full Text | Google Scholar

Tochitani, S., Ikeno, T., Ito, T., Sakurai, A., Yamauchi, T., and Matsuzaki, H. (2016). Administration of non-absorbable antibiotics to pregnant mice to perturb the maternal gut microbiota is associated with alterations in offspring behavior. PLoS ONE 11, e0138293. doi: 10.1371/journal.pone.0138293

PubMed Abstract | CrossRef Full Text | Google Scholar

Tronson, N. C., Wiseman, S. L., Neve, R. L., Nestler, E. J., Olausson, P., and Taylor, J. R. (2012). Distinctive roles for amygdalar CREB in reconsolidation and extinction of fear memory. Learn. Mem. 19, 178–181. doi: 10.1101/lm.025783.112

PubMed Abstract | CrossRef Full Text | Google Scholar

World Health Organization (2017). Depression and Other Common Mental Disorders: Global Health Estimates. World Health Organization.

Google Scholar

Zhang, J.-C., Yao, W., Dong, C., Yang, C., Ren, Q., Ma, M., et al. (2017). Blockade of interleukin-6 receptor in the periphery promotes rapid and sustained antidepressant actions: a possible role of gut-microbiota-brain axis. Transl. Psychiatry 7, e1138. doi: 10.1038/tp.2017.112

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: microbiota, depression, brain, probiotics, microRNAs

Citation: Pesarico AP, Vieira AT and Rosa SG (2023) Editorial: Gut-microbiota-brain axis in depression: mechanisms and possible therapies. Front. Behav. Neurosci. 17:1221141. doi: 10.3389/fnbeh.2023.1221141

Received: 11 May 2023; Accepted: 24 May 2023;
Published: 06 June 2023.

Edited and reviewed by: Richard G. Hunter, University of Massachusetts Boston, United States

Copyright © 2023 Pesarico, Vieira and Rosa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Ana Paula Pesarico,; Suzan Gonçalves Rosa,