By Raida Aldosari, Nutrition Science (Biology option) ’18
Author’s Note: I wrote this literature review as part of my UWP 104F class with Dr. Lisa Sperber. The assignment was to choose a clinically-relevant topic, review the existing body of literature on this topic, and choose a specific area to write on. My topic of interest was about the relationship between gut microbiome and the brain. I became interested in this topic after reading an article about the differences between the microbial composition of individuals with depression. By the end of the quarter, my research question evolved from “how does our diet affect our brain or mood?” to “how does modulation of gut microbiome affect depression pathophysiology?” I enjoyed the flexibility of the assignment, and I greatly benefited from the guidance provided by Dr. Sperber. I would recommend this class to anyone interested in health-related fields, especially in research!
Depression is a stress-related disorder affecting more than 350 million people and is one of the leading causes of disability worldwide (1). Development of depression is strongly correlated with the prognosis of chronic diseases like diabetes, asthma, and heart diseases (2). Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of medications for depression (3). However, 30% of patients develop resistance to treatment over time, and more than 68% of patients discontinue the use after 3 months due to lack of improvement or development of adverse effects (3, 4). The exact mechanism of SSRIs is not fully understood, which is limiting researchers from adequately addressing these problems (4). Therefore, understanding the pathophysiology of depression is crucial to developing more effective treatments (1).
The gut-brain axis is a topic of growing discussion that can provide means for depression treatment (5). The gut-brain axis refers to the bidirectional communication between the central nervous system and the gastrointestinal tract regulated by the gut microbiome (5). The gut microbiome plays a significant role in the pathogenesis of many physiological and psychological disorders such as irritable bowel syndrome (5), autism spectrum disorder (6), Parkinson’s disease (7), and depression (5). Microbiome composition is influenced by genetics, use of antibiotics, smoking habits, diet, and age, and disruption of microbial composition inducing changes in behavior and mood (9,10). Gut-brain interactions occur through the neuroendocrine, nervous, and immune systems (9). However, the mechanism through which microbiome affects depression status is unclear (11).
In this review, I will provide a comprehensive overview of the three pathways involved in the gut-brain axis: the hypothalamic-pituitary-adrenocortical (HPA) axis pathway involving the neuroendocrine system, the cytokines pathway involving the immune system, and the neurotransmitter pathways involving the nervous system. Then, I will describe how microbiome modulation affects these pathways and consequently depression symptoms.
The HPA axis is hyperactive in 40-60% of patients diagnosed with Major Depressive Disorder (14). It is the central reactivity response system in the brain (12). Corticotropin-releasing hormone (CRH) and vasopressin (VAP) are normally released from the hypothalamus, which subsequently trigger the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. In response to ACTH, glucocorticoids, like cortisol, are released from the adrenal cortex to regulate immunity, metabolism, and mood (13).
The hyperactivity of HPA is indicated by three markers: 1) enlargement of the pituitary and adrenal glands, 2) elevated CRH levels in the cerebrospinal fluid, and 3) elevated glucocorticoids levels in plasma, saliva, and urine (15). Sudo et al. used germ-free mice to test the effects of microbiome on the HPA axis (16). Germ-free mice had significantly higher responses to stress compared to control as indicated by the elevated levels of ACTH and corticosterone (16). However, the introduction of Bifidobacterium infantis, a common bacterial species usually found in the guts of most mammals, restored the normal levels (16). Interestingly, childhood traumatic life events like physical or sexual abuse are also associated with higher cortisol release accompanied by alteration in fecal microbiota (17, 18). This demonstrates a top-down relationship in which the brain indirectly influences the gut, thus corroborating the bidirectionality of the gut-brain axis (13).
Depression is associated with the hyperactivation of the immune system, indicated by overproduction of immune cells and pro-inflammatory cytokines (19). Pro-inflammatory cytokines are biomarkers usually elevated during infection and inflammation (20). Cytokines like TNF-a and IL-6 are found at levels significantly higher in depressed individuals (19, 21). A recent study investigated the causal relationship between depression and cytokines levels (8). First, stress was induced to mice using the Maternal Separation model, a standardized method to study mental health in rodents where a brief maternal absence in early life significantly alters behavior (8). Then, depression levels were assessed using the Forced Swim Test, a method to study depression in rodents (22). In this test, development of depression is indicated by 1) increased immobility and 2) increased swimming time (22). Mice that were exposed to early maternal separation exhibited higher depression-like behavior, which triggered the release of pro-inflammatory cytokines (8). To measure the effects of probiotics on cytokines levels, the study administered Bifidobacteria infantis to depressed mice, then compared it to a group treated with Citalopram, an antidepressant (8). After chronic probiotic treatment, decreased immobility in the Forced Swim Test and restoration of pro-inflammatory cytokines levels were observed with effects comparable to Citalopram (8).
The monoamine hypothesis is the most accepted model for pathogenesis of depression (23). It states that depression is caused by deficiency in neurotransmitters like serotonin, dopamine, and norepinephrine, which have been major targets for most antidepressants (23). A study by Wikoff et al. tested a possible mechanism by which gut microbiome modulation influences serotonin levels in germ-free mice (24). The introduction of microbiome increased plasma serotonin levels 2.8 fold (24). This increase may be attributed to the regulatory effects of microbiome on the serotonin that is usually stored in gut tissues upon birth (25). However, more studies are needed to determine the mechanism of release.
Gamma-aminobutyric acid (GABA) is a neurotransmitter involved in regulating the central nervous system (26). A reduction or an increase in GABA receptors is correlated with depression (26). To observe the effects of gut microbiome on GABA receptors and depression-like behavior, Lactobacillus and Bifidobacterium bacterial strains were fed to two groups of stress-induced mice (27). The first group was only stress-induced, while the second group was stress-induced and vagotomized, which refers to cutting part or all of the vagus nerve (27). The first group had altered GABA receptor expression and reduced depression-like behavior after probiotics administration as observed using the Forced Swim Test (27). The vagotomized mice, however, did not exhibit the same effects (27). This suggests that the vagus nerve is a possible way of interaction between the brain and the gut microbiome (27). This study did not use germ-free mice or mice with modified gut microbiome, which makes it more applicable to free-living mammals, including humans (27).
This review investigated possible pathways by which the microbiome affects depression status in mice. Such pathways involve the HPA axis, cytokines, serotonin, and GABA. The findings can be utilized to develop medications specifically targeting depression markers in the gut or to further investigate the possible antidepressant properties of probiotics, which can be included in parallel with standard depression therapy. More studies on this topic are necessary to understand how these pathways relate to the etiology of depression in humans.
- Forsythe P, Sudo N, Dinan T, Taylor VH, Bienenstock J. Mood and gut feelings. Brain, Behavior, and Immunity 2010;24(1):9-16. doi: https://doi.org/10.1016/j.bbi.2009.05.058.
- Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. The Lancet 2007;370(9590):851-8. doi: https://doi.org/10.1016/S0140-6736(07)61415-9.
- Anderson HD, Pace WD, Libby AM, West DR, Valuck RJ. Rates of 5 Common Antidepressant Side Effects Among New Adult and Adolescent Cases of Depression: A Retrospective US Claims Study. Clinical Therapeutics 2012;34(1):113-23. doi: https://doi.org/10.1016/j.clinthera.2011.11.024.
- Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D project results: A comprehensive review of findings. Current Psychiatry Reports 2007;9(6):449-59. doi: 10.1007/s11920-007-0061-3.
- Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. The Journal of Clinical Investigation 2015;125(3):926-38. doi: 10.1172/JCI76304.
- Mayer EA, Padua D, Tillisch K. Altered brain-gut axis in autism: Comorbidity or causative mechanisms? BioEssays 2014;36(10):933-9. doi: 10.1002/bies.201400075.
- de Vos WM, de Vos EAJ. Role of the intestinal microbiome in health and disease: from correlation to causation. Nutrition Reviews 2012;70(suppl_1):S45-S56. doi: 10.1111/j.1753-4887.2012.00505.x.
- Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 2010;170(4):1179-88. doi: https://doi.org/10.1016/j.neuroscience.2010.08.005.
- Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends in Neurosciences 2013;36(5):305-12. doi: https://doi.org/10.1016/j.tins.2013.01.005.
- Cryan JF, O’Mahony SM. The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterology & Motility 2011;23(3):187-92. doi: 10.1111/j.1365-2982.2010.01664.x.
- Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Linløkken A, Wilson R, Rudi K. Correlation between the human fecal microbiota and depression. Neurogastroenterology & Motility 2014;26(8):1155-62. doi: 10.1111/nmo.12378.
- Gotlib IH, Joormann J, Minor KL, Hallmayer J. HPA Axis Reactivity: A Mechanism Underlying the Associations Among 5-HTTLPR, Stress, and Depression. Biological Psychiatry;63(9):847-51. doi: 10.1016/j.biopsych.2007.10.008.
- Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends in Neurosciences 2008;31(9):464-8. doi: https://doi.org/10.1016/j.tins.2008.06.006.
- Parker KJ, Schatzberg AF, Lyons DM. Neuroendocrine aspects of hypercortisolism in major depression. Hormones and Behavior 2003;43(1):60-6. doi: https://doi.org/10.1016/S0018-506X(02)00016-8.
- Dinan TG. Glucocorticoids and the Genesis of Depressive Illness a Psychobiological Model. British Journal of Psychiatry 2018;164(3):365-71. doi: 10.1192/bjp.164.3.365.
- Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu X-N, Kubo C, Koga Y. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. The Journal of Physiology 2004;558(Pt 1):263-75. doi: 10.1113/jphysiol.2004.063388.
- Heim C, Mletzko T, Purselle D, Musselman DL, Nemeroff CB. The Dexamethasone/Corticotropin-Releasing Factor Test in Men with Major Depression: Role of Childhood Trauma. Biological Psychiatry 2008;63(4):398-405. doi: https://doi.org/10.1016/j.biopsych.2007.07.002.
- O’Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho A-M, Quigley EMM, Cryan JF, Dinan TG. Early Life Stress Alters Behavior, Immunity, and Microbiota in Rats: Implications for Irritable Bowel Syndrome and Psychiatric Illnesses. Biological Psychiatry 2009;65(3):263-7. doi: https://doi.org/10.1016/j.biopsych.2008.06.026.
- Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL. A Meta-Analysis of Cytokines in Major Depression. Biological Psychiatry 2010;67(5):446-57. doi: https://doi.org/10.1016/j.biopsych.2009.09.033.
- Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience 2008;9:46. doi: 10.1038/nrn2297.
- Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. European Neuropsychopharmacology;25(10):1532-43. doi: 10.1016/j.euroneuro.2015.06.007.
- Cryan JF, Page ME, Lucki I. Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment. Psychopharmacology 2005;182(3):335-44. doi: 10.1007/s00213-005-0093-5.
- Meyer JH, Ginovart N, Boovariwala A, et al. Elevated monoamine oxidase a levels in the brain: An explanation for the monoamine imbalance of major depression. Archives of General Psychiatry 2006;63(11):1209-16. doi: 10.1001/archpsyc.63.11.1209.
- Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proceedings of the National Academy of Sciences 2009;106(10):3698.
- Uribe A, Alam M, Johansson O, Midtvedt T, Theodorsson E. Microflora modulates endocrine cells in the gastrointestinal mucosa of the rat. Gastroenterology 1994;107(5):1259-69. doi: https://doi.org/10.1016/0016-5085(94)90526-6.
- Cryan JF, Kaupmann K. Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences 2005;26(1):36-43. doi: https://doi.org/10.1016/j.tips.2004.11.004.
- Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America 2011;108(38):16050-5. doi: 10.1073/pnas.1102999108.