Depression is a mental disorder that affects more than 264 million people of all ages worldwide. Understanding its mechanisms is vital for the development of effective therapeutic strategies.
Scientists from the Institut Pasteur, Inserm and the CNRS recently conducted a study showing that an imbalance in the gut bacterial community can cause a reduction in some metabolites, resulting in depressive-like behaviors.
These findings, which show that a healthy gut microbiota contributes to normal brain function, were published in Nature Communications on December 11, 2020.
The bacterial population in the gut, known as the gut microbiota, is the largest reservoir of bacteria in the body.
Research has increasingly shown that the host and the gut microbiota are an excellent example of systems with mutually beneficial interactions. Recent observations also revealed a link between mood disorders and damage to the gut microbiota.
This was demonstrated by a consortium of scientists from the Institut Pasteur, the CNRS and Inserm, who identified a correlation between the gut microbiota and the efficacy of fluoxetine, a molecule frequently used as an antidepressant.
But some of the mechanisms governing depression, the leading cause of disability worldwide, remained unknown.
Using animal models, scientists recently discovered that a change to the gut microbiota brought about by chronic stress can lead to depressive-like behaviors, in particular by causing a reduction in lipid metabolites (small molecules resulting from metabolism) in the blood and the brain.
These lipid metabolites, known as endogenous cannabinoids (or endocannabinoids), coordinate a communication system in the body which is significantly hindered by the reduction in metabolites. Gut microbiota plays a role in brain function and mood regulation
Endocannabinoids bind to receptors that are also the main target of THC, the most widely known active component of cannabis.
The scientists discovered that an absence of endocannabinoids in the hippocampus, a key brain region involved in the formation of memories and emotions, resulted in depressive-like behaviors.
The scientists obtained these results by studying the microbiotas of healthy animals and animals with mood disorders. As Pierre-Marie Lledo, Head of the Perception and Memory Unit at the Institut Pasteur (CNRS/Institut Pasteur) and joint last author of the study, explains:
“Surprisingly, simply transferring the microbiota from an animal with mood disorders to an animal in good health was enough to bring about biochemical changes and confer depressive-like behaviors in the latter.”
The scientists identified some bacterial species that are significantly reduced in animals with mood disorders. They then demonstrated that an oral treatment with the same bacteria restored normal levels of lipid derivatives, thereby alleviating the depressive-like behaviors.
These bacteria could therefore serve as an antidepressant. Such treatments are known as “psychobiotics”.
“This discovery shows the role played by the gut microbiota in normal brain function,” continues Gérard Eberl, Head of the Microenvironment and Immunity Unit (Institut Pasteur/Inserm) and joint last author of the study.
If there is an imbalance in the gut bacterial community, some lipids that are vital for brain function disappear, encouraging the emergence of depressive-like behaviors.
In this particular case, the use of specific bacteria could be a promising method for restoring a healthy microbiota and treating mood disorders more effectively.
Depression: a multifaceted mood disorder
The history of Western medicine’s understanding of depression dates back as far as ancient Greek physician Hippocrates, whose humoral theory of pathology identified black bile as the cause of what we today refer to as depression (Hippocrates, 1931). The Greek term for black bile μέλαινα χολή, transliterates to melaina chole, the origin of the words melancholy and melancholia. In 1621, renaissance scholar Robert Burton published “The Anatomy of Melancholy,” an encyclopedic tome that was one of the first published works to combine history, cause, and treatment in a single volume. While Burton’s treatments varied widely, including practices such as blood-letting, Burton did suggest changes in diet as being connected with melancholia, changes that are pertinent to the current review (Burton, 1621). By the late 19th century, British Psychiatrist Charles Mercier is credited as one of the first to propose the idea that melancholia was a brain disorder, a concept that would go on to shape the field of mental health for the next century (Lawlor, 2012).
In the tradition of viewing depressed mood as a brain disorder, psychiatrist Adolph Meyer (1866–1950) pushed for a transition from using the term “melancholia” to “depression” in medicine, partially to promote moving away from previous treatment practices in favor of developing what he termed “somatic therapies,” including early psychopharmacology and shock treatment. This new, medical perspective on depression would go on to influence the formation of the first Diagnostic and Statistical Manual for Mental Disorders (DSM-I) in 1952.
While the DSM-I and its successor, the DSM-II, were still strongly grounded in the psychoanalytic approach, pioneered by Freud in the early 20th century, the DSM-III in 1980 would transform the United States’ (and the global perspective, to a large extent) perspective on mental health. The DSM-III was the first modern diagnostic guide to organize around observable symptoms, rather than theoretical constructs, creating a shared language for health care professionals.
The DSM-IV (1994), and now the current DSM-5 (Association American Psychiatric, 2013) would go on to clarify MDD as requiring a single major depressive episode with at least five depression-related symptoms (Lawlor, 2012). This common language has fueled an explosion of research that has made cross-study comparisons standardized and much simpler to carry out. The biotechnology revolution beginning in the 1980s and the development of functional magnetic resonance imaging (fMRI) as a technique in psychology research in the 1990s catapulted our understanding of depression etiology in the domain of the brain (Faro and Mohamed, 2010; Ogawa et al., 1992).
However, a decade into the 21st century, a completely brain-based understanding of depression was in question. The popular “chemical imbalance” theory of depression, stating that depression was related to an imbalance of specific neurotransmitters, was proving less effective both in explaining the etiology of depression and in developing novel treatments (Malenka, 2012).
The current understanding of MDD has come to encompass not just changes in neurotransmitters, but shifts in neural circuits, as well as alterations in both immune and endocrine functioning (Irwin and Miller, 2007; see Fig. 1). This broadened scope is now beginning to inform a vast array of new, personalized treatments that are beginning to show great promise in a new holistic approach to depression (Henter et al., 2017).
reference link: https://www.sciencedirect.com/science/article/pii/S0969996119302463#bb1570
The human gut microbiome, comprised of approximately 1800 different phyla and 40,000 bacterial species, has been implicated in numerous aspects of human health and disease [1]. It partakes in a bidirectional communication pathway with the central nervous system (CNS), aptly named the microbiota–gut–brain axis.
The microbiota–gut–brain axis is believed to modulate various central processes through the vagus nerve as well as production of microbial metabolites and immune mediators which trigger changes in neurotransmission, neuroinflammation, and behavior [2–5]. Disruptions to the gut microbiome have been correlated with several neuropsychiatric disorders, including Parkinson’s disease, autism, schizophrenia, and depression [6–9].
The exact mechanism by which the gut microbiota causes or alters neuropsychiatric disease states is not fully understood. Further studies are required to elucidate the role of the microbiota–gut–brain axis, with the goal of preventing disease, identifying new therapeutic targets, and improving treatments. In this review, we focus on recent studies investigating the relationship between gut microbiome dysbiosis and the pathogenesis of depression.
Epidemiology
Depression is one of the most prevalent mental health disorders in the USA and the second leading cause of disability worldwide [10]. A major depressive episode is defined as a depressed mood and/or loss of interest or pleasure in life activities for at least 2 weeks, with at least five symptoms that disrupt social interactions, work, or other important areas of daily life [11].
This may include symptoms such as unintentional weight change, insomnia or hypersomnia, agitation or psychomotor retardation, fatigue, or feelings of worthlessness or guilt. In 2017, 17.3 million adults (6.8%) and 3.2 million adolescents (13.3%) in the USA experienced at least one major depressive episode [12].
In addition to causing significant functional impairment, depression is also associated with substantial economic burden. From 2005 to 2010, the economic burden of individuals with major depressive disorders (MDD) in adults increased from $173.2 to $210.5 billion [13].
Medical and pharmaceutical services directly related to the treatment of MDD accounted for $27.7 billion of the $210.5 billion total cost in 2010. The remaining costs were primarily those associated with comorbidities incurred by persons with MDD, though suicide-related and workplace costs also contributed to the total economic burden.
In light of these estimates, it evident that depression is a complex disorder that greatly impacts both individuals and society. Implementation of preventative measures and effective interventions are required in order to address the challenges that depression presents.
Risk Factors for Dysbiosis
Numerous risk factors have been proposed in the pathogenesis of gut dysbiosis. The use of antibiotics has been well documented, resulting in both short-term and long-term alterations in the composition of the gut microbiome [14–17]. Reproducible gut microbiome alterations have also been demonstrated with obesity as well as high-fat and high-sugar diets [18–21].
Environmental factors at various stages of life are also believed to influence the development of gut dysbiosis. Changes in microbiome diversity at infancy have been linked to the mode of delivery, feeding type, and hospital environment [22, 23]. Exposure to xenobiotics, such as heavy metals and pesticides, as well as social stressors is also associated with gut dysbiosis [24, 25]. In addition to environmental factors, twin studies have revealed a genetic component in the development of the gut microbiome.
Human Studies
Altered Fecal Microbiota in Major Depressive Disorders
Jiang et al. analyzed fecal microbiota compositions in active MDD (A-MDD), responding MDD (R-MDD), and healthy controls (HC) to determine alterations in active episodes of MDD and possible dysbiosis in response to antidepressant treatment [29]. Forty-six patients were recruited and screened by one psychiatrist with the Mini-International Neuropsychiatric Interview for pre-existing psychiatric conditions, and the presence of MDD was verified using the Structured Clinical Interview for the Diagnosis and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV).
Severity of disease was determined with Hamilton Depression Rating Scale (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS). Severity scores were used to separate A-MDD (HAM-D score ≥ 20) and R-MDD (baseline HAM-D score ≥ 20). On the basis of the results of examination, subjects were divided into an A-MDD group (n = 29) and R-MDD group (n = 17). HC (n = 30) subjects were also selected from the same cohort.
Fecal and serum samples were collected when HAM-D scores were reduced by 50% post-treatment. Surprisingly, analysis of bacterial diversity and richness showed significant increases in bacterial diversity in A-MDD relative to HC as evaluated by the Shannon Index.
While it is conventionally considered beneficial to have greater gut microbiome diversity, this diversity is untested in regards to its effects on CNS functions, and may not be universally beneficial. The authors cite studies by Fan et al. and Roger et al. which show increases in microbiome diversity in CNS altered populations such as autism, alluding to a potentially negative impact of increased microbiome diversity [39, 40].
Serum samples were evaluated for inflammatory biomarkers TNFα, IL-1β, IL-6, and BDNF, as inflammation has been associated with dysbiosis and MDD. Notably, serum analysis showed no significant differences between A-MDD, H-MDD, and HC subjects with regards to IL-6, TNFα, and IL-1β. BDNF levels were lower in A-MDD and R-MDD compared to HC. Further studies are needed to determine causation, to better elucidate the role of the gut microbiome in CNS disorders such as MDD.
Short Chain Fatty Acid Profile Alterations in Depressed Polish Women
SCFAs are produced by gut bacteria from dietary fiber. In a study by Skonieczna-Żydeka et al. SCFAs in the stool of depressed and non-depressed women were used as an indicator of microbiome dysbiosis, potentially affecting gut–brain axis signaling as a possible pathogenic cause of depression [41]. A total of 116 Polish women were recruited for this study.
Sociodemographic and health-related data were collected by survey. The Beck Depression Inventory (BDI) was used to determine presence and severity of depressive symptoms. BDI scores of up to 11 indicated no depressive symptoms, 12–19 indicated mild depression, 20–25 indicated moderate depression, and 26–63 indicated heavy depression.
After evaluation, 35, five, and seven patients were identified to have mild, moderate, and severe depression, respectively. Depressive severity groups were pooled into one depressive symptom group of 47 patients as a result of small sample sizes. Survey results indicated no significant differences in socioeconomic or health statuses. Stool samples were collected during overnight fasting.
Analysis of the stool samples revealed that non-depressive women had higher concentrations of all SCFAs except C6:0. The SCFA isocaproic acid was increased in the depressive group. Fiber intake was measured as a potential factor affecting SCFAs levels. Food frequency questionnaires were used instead of food diaries, and the fiber consumption differed from worldwide recommended values. Women with depression ingested less fiber, though this difference was not significant. Accordingly, fiber intake did not correlate with SCFAs concentration and BDI score.
Breakdown by SCFA type revealed predominantly acetate and propionate populations in both groups. Acetate and propionate showed a negative correlation with severity of depression symptoms. Acetic acid, propionic acid, and caproic acids have been shown to partly contribute to the origin of depressive symptoms through the gut–brain axis. Acetate is described as preventative for enteropathogenic infections and maintains gut barrier integrity, thereby maintaining gut–brain axis signaling.
The lower levels of acetate observed in depressive patients cause a decrease in butyric acid. Butyric acid typically inhibits histone deacetylation and prevents hippocampal microglia activation. Decreased butyric acid may cause depressive-like behaviors secondary to neuroinflammation due to increased microglial activation.
Of note, many SCFA act as histone deacetylation inhibitors and may contribute to this pathway though to a lesser extent than acetate. Propionate has been demonstrated to dampen innate immune cell response to bacteria, and may also have roles in maintaining proper intestinal permeability [39, 42]. Lower levels may contribute to dysbiosis and neuroinflammation in the CNS leading to depressive symptoms. Through these proposed mechanisms, the authors concluded that SCFAs may partly contribute to women’s emotional health.
Prebiotics, Probiotics, Cytokines, and Cortisol
Dysbiosis and resulting inflammation via cytokine release is one proposed mechanism of MDD, and therefore a potential site for intervention. Kazemi et al. conducted a double-blind, placebo-controlled study to evaluate the effects of probiotics and prebiotics on inflammatory markers and urinary cortisol levels in patients with MDD [43].
A total of 110 patients were recruited and randomly assigned to the prebiotic group (n = 36), the probiotic group (n = 38), and the placebo group (n = 36). Prebiotics were defined as dietary, non-viable food components and probiotics were defined as live microorganisms that, when administered in adequate amounts, confer a health benefit to the host. Baseline testing showed no significant differences between the three groups. Serum cytokine levels for TNFα, IL-1, IL-6, and IL-10 were measured, alongside urine cortisol levels. BDI was used to evaluated depressive symptoms.
There were no statistically significant differences between any groups in cytokine or urine cortisol levels. The authors acknowledge similarly conflicting results in the literature. There is previous evidence that antidepressants may affect gut microbiota by potentially masking possible effects of probiotics and prebiotics on cytokine levels.
Even after adjustment for confounding factors, no statistical differences were observed for inflammatory markers. Another reason for the lack of change in cytokine levels may be due to the method of collection. Serum cytokine levels were measured in this study, though serum levels may not account for total cytokine levels in the body.
Urinary cortisol levels did decrease in the probiotic group, though the effect was not statistically significant. BDI scores were improved compared to the placebo group. Scores for the prebiotic group demonstrated no statistical difference. Improvement in BDI scores suggest that depressive symptoms may be improved by probiotic use through mechanisms other than reducing cytokine release. The limitations in this study include a small sample size, a lack of fecal microbiome analyses to account for baseline differences in patients, and a focus on serum cytokine levels. Such limitations can be overcome in larger-scale studies.
Probiotics and Sad Mood Reactivity
Steenbergen et al. evaluated the use of multispecies probiotics in cognitive reactivity scores of healthy patients in a blinded study [44]. Cognitive reactivity has been indicated in the development of depression and has been a target for prevention of depression. In adherence to the conventional theory that dysbiosis leads to increased inflammation from a leaky gut, bacterial strains that improve epithelial barrier function were chosen.
Forty healthy patients were recruited and screened with the Mini International Neuropsychiatric Interview (MINI) for pre-existing psychiatric disorders. Then the subjects were randomly assigned to the placebo group (n = 20) or the probiotic group (n = 20). Patients were evaluated by questionnaire for cognitive reactivity, sad mood, and symptoms of depression and anxiety.
The probiotic group showed significantly decreased scores for overall cognitive reactivity, and dramatically reduced scores for the subtypes rumination and aggression. Rumination, or recurrent thoughts about consequences and causes of distress, has been indicated in perpetuating sad moods into depressive episodes. Reduction in rumination may reduce the development of depression. Aggressive thoughts have been associated with suicidal ideation. Reducing suicidal ideation or action is also a positive intervention in depression and may be another benefit for probiotic use.
Biological mechanisms of action for probiotics were not tested in this study, though the authors hypothesized three potential mechanisms. The first hypothesis includes increased serotonin levels. Increasing gut microbiota, especially certain species, has been shown to increase plasma tryptophan levels. Higher tryptophan levels allow for greater synthesis of serotonin. The second hypothesis involves the release of inflammatory cytokines as a major contributor to depression.
Probiotics are thought to decrease intestinal epithelial permeability thereby decreasing immune stimulation and release of inflammatory cytokines. The third hypothesis proposed by the authors relates to increased stimulation of the vagus nerve. There is no proposed mechanism of action for this in human studies. A number of animal models have shown vagal stimulation playing a role in depressive and anxiety behaviors. In humans, vagus nerve stimulation has been used successfully as treatment for depression.
Marital Distress, Depression, and Leaky Gut
Chronic, elevated inflammation can predispose individuals to developing an inflammation-related disorder like depression. In a study by Kiecolt-Glaser et al. married couples were evaluated for increases in inflammation markers such as LPS-binding protein (LBP), soluble CD14 (sCD14), and CRP to determine if increased gut permeability is a potential mechanism for marital distress and depression [45].
LBP and CD14 are typically released in response to bacterial translocation of endotoxins and are markers for leaky gut. Forty-three couples (n = 86) were recruited for a double-blind, randomized crossover study, during which the couples received either a high saturated fat or oleic sunflower meal after fasting for 12 h and eating three standardized meals the day prior. Baseline measurements were taken 25 min after catheter placement. Afterwards, the meal was provided to the couple. Two hours later, the couple discussed a marital problem and blood samples were taken every 2 h for 7 h.
A strong, significant correlation was seen between hostile behavior and LBP. A trend of lower sCD14 with more hostile behavior was observed; however, there was no association of sCD14 with mood disorder history. The ratio of LBP/sCD14 was statistically significantly associated with marital satisfaction in patients with a history of mood disorders. Lower marital satisfaction correlated with LBP as well.
LBP is a surrogate marker for microbial translocation and typically reflects higher endotoxin levels of gram-negative bacteria since they predominate in the gut. Episodes of dysbiosis are usually transient, and normal gut flora is returned, though prolonged dysbiosis can permanently alter the gut microbiota and can cause changes in the regulation of inflammation, immunity, and gut barrier function. Patients with a history of mood disorder are more susceptible to episodes of dysbiosis due to their chronic inflammatory state, which is reflected in the higher ratio of LBP/sCD14 ratio observed in this study.
CRP was associated with a nonsignificant increased LBP/sCD14 ratio. There was also a nonsignificant trend of higher LBP and sCD14 with IL-6 levels. CRP levels are clinically prognostic, especially when considering risk of cardiovascular disease and events. The elevated CRP seen in this study is likely due to the preference of sedentary, obese couples. CRP may not be directly associated with gut dysbiosis.
Lactobacillus Double-Blind Study
Rudzki et al. sought to assess the psychobiotic and immunomodulatory effects of the probiotic bacteria Lactobacillus plantarum 299v (LP299v) in patients with MDD also being treated with selective serotonin reuptake inhibitors (SSRIs) [46]. They completed a double-blind, placebo controlled study with 79 patients with MDD. Patients were randomized into a placebo group, which received SSRI treatment with placebo probiotic, and a probiotic group, which received SSRI treatment with LP299v probiotic. Sixty patients completed the trial with 30 patients in each group. Severity of psychiatric symptoms, cognitive function, and biochemical parameters were measured.
Results of the study showed decreased kynurenine concentrations (p = 0.005) alongside improved cognitive functions in the probiotic group. Baseline cognitive measurements were taken initially and then repeated at 8 weeks post-intervention. The probiotic group demonstrated significantly improved scores in attention and perceptivity as well as verbal learning tasks as compared to control groups (p = 0.006 and p = 0.023, respectively).
Kynurenines have neurotoxic and neurodegenerative effects on CNS. At physiological levels, however, they function to regulate immunomodulation and neuroprotection in the CNS. Proinflammatory cytokines are initiators of the kynurenine synthesis pathway. Several mechanisms for improved cognition and reduced kynurenine were proposed by the authors.
One relates to increased intestinal permeability due to physiological stress, leading to low grade inflammation and the production of proinflammatory cytokines. These cytokines initiate the kynurenine pathway, thereby affecting mood and cognition by neurotoxic effects. LP299v is known to reduce gut epithelial permeability, and this function may have reduced levels of kynurenine produced, thereby leading to improved cognition. LP299v adheres to the gut wall and may inhibit growth of other potentially pathogenetic bacteria while also increasing the number of potentially beneficial bacteria. This alteration could enhance SCFA synthesis to also modulate cytokine production.
Another mechanism involves modulation of indoleamine 2,3-dioxygenase (IDO) activity, an immune modulatory enzyme, by hydrogen peroxide activity. LP299v is able to accumulate hydrogen peroxide, and the accumulated hydrogen peroxide inhibits IDO activity, causing downstream inhibition of kynurenine production.
The ratio of kynurenine/tryptophan is thought to reflect IDO activity. This study did not show a significant difference in kynurenine/tryptophan ratio between placebo and probiotic groups. This ratio is dependent on available tryptophan and does not measure IDO activity directly. Therefore, this mechanism cannot be ruled out as a possible mechanism for decreased kynurenine and improved cognition.
Synthesis of 5-HT by LP299v and other beneficial gut bacteria can also modulate tryptophan and kynurenine levels. Increased synthesis of 5-HT leads to a decreased level of available tryptophan for kynurenine synthesis. Beneficial gut bacteria also play a major role in producing cofactors necessary for a large variety of biochemical reactions in the body, including kynurenine synthesis. This study observed an increase in vitamin B cofactors associated with kynurenine synthesis and metabolism. Increasing both synthesis and metabolism prevents a buildup of toxic kynurenine and potentially yields improved cognition.
This study was notable for being the first of its kind to demonstrate a link between increased cognitive function and decreased kynurenine concentrations in MDD patients via probiotic supplementation. This provides evidence for a potential role of probiotics in treating some symptoms of MDD and possibly improving cognition in a more general population of patients.
Lactobacillus plantarum and Stress
Lew et al. conducted a 12-week randomized, double-blind, placebo-controlled trial to evaluate the effects of probiotic Lactobacillus plantarum P8 in alleviating stress in adults [47]. Depression Anxiety Stress Scales (DASS-42) and Perceived Stress Scale (PSS-10) surveys were used to determine effects on memory and cognition. Physiological markers were also used to measure glucocorticoid hormone levels in the serum.
Reduced stress scores were observed with DASS-42 survey at week 4, but no difference was seen with the PSS-10 survey. Although both P8 and placebo showed significant reductions in stress and anxiety scores (p = 0.030), the P8 group showed significantly greater improvement in reported stress versus the placebo group (p < 0.05) in DASS-42 surveys given at weeks 4, 8, and 12.
The lack of significance seen with the PSS-10 may be due to the different structures of the assessment tools. The PSS-10 tool is a ten-item questionnaire used more frequently in research and focuses on circumstances and situations that may induce anxiety or stress. The DASS-42 in comparison is more robust, being a 42-item survey that is used more frequently in clinical settings and focuses on general feelings of stress and anxiety.
Cortisol levels were also found to be marginally different between the groups, though this trend was not statistically significant. This may be due to the diversity of glucocorticoids and their role in many cellular metabolic processes. A narrower target may be needed to establish trends.
Lower plasma pro-inflammatory cytokines interferon gamma (IFNγ) and TNFα were observed alongside improved cognitive and memory potential, as assessed by DASS-42, in the probiotic group. Stress has been shown to alter neuronal morphology and can suppress neuronal proliferation.
Synaptic plasticity and firing properties may also be altered. Ultimately, hippocampal volume is reduced, and memory, learning, and cognitive abilities are diminished. Correlational analysis of the proinflammatory cytokines revealed a positive correlation with the psychological traits measured by DASS-42, and psychological traits were correlated with memory and cognition.
These correlations indicate that inflammation may help to promote the subjective experience of stress and anxiety, which has been shown to decrease cognitive performance. In the probiotic group, reduced stress and anxiety improved cognition and memory, potentially by targeting these inflammatory pathways.
The probiotic Lactobacillus plantarum P8 used in this study has been associated with increased beneficial gut bacteria while inhibiting the growth of potentially harmful gut bacteria, and has increased production of SCFAs in adults, thereby mediating and reducing harmful inflammation associated with stress and dysbiosis.
Probiotics in Postpartum Patients
Postpartum depression and anxiety have few treatments that are safe and effective. To explore the role of probiotics in this population, Slykerman et al. studied the effect of Lactobacillus rhamnosus HN001 (HN001) in pregnancy and postpartum maternal depression and anxiety [48].
This randomized, double blind, placebo-controlled trial was a secondary measure in a study on eczema. Of 423 women in the trial, 380 completed the psychological measure. The experimental group (n = 193) was treated with HN001 daily for 6 months postpartum, while the placebo group (n = 187) underwent daily placebo treatments for 6 months postpartum. Modified versions of the Edinburgh Postnatal Depression Scale and State Trait Anxiety Inventory were used to assess symptoms of depression and anxiety.
The prevalence of scores for depression and anxiety above the cutoff values at 1–2 months postpartum were higher in this study than the 10–15% typically reported. Patients with a history of allergies are known to be at a higher risk for mental problems. As this study was a secondary outcome for families seeking treatment for eczema, the prevalence of depression and anxiety may be higher in this population than the general population.
Another possible cause for the increased prevalence is that patients completed the questionnaires regarding depression and anxiety retrospectively. Despite the increased prevalence, the number of women taking psychiatric medications during pregnancy was low, thereby reducing any cofounding factors for study results.
Significantly lower levels of postpartum depression (p = 0.037) and anxiety symptoms (p = 0.014) were reported in the probiotic group. While no mechanism of action was investigated in this study, the authors described two mechanisms of action shown in animal models that may explain their results. For example, in mice treated with L. rhamnosus, changes in the GABA receptors in the brain have been demonstrated alongside anxiety-related behavior.
These changes were absent in mice with regions of the vagus nerve removed, indicating a link between the gut and the brain. Another model demonstrated resolution of anxiety behaviors induced by maternal separation by treatment with Bifidobacterium infantis [48].
Infant colic has also been associated with higher depression and anxiety scores, suggesting that probiotic use in infants may benefit maternal mood by reducing infant colic. However, in this study infants were likely only indirectly exposed to small amounts of probiotic. Furthermore the prevalence of infant colic did not differ between probiotic and placebo groups. Multivariate analysis showed that probiotic supplementation and absence of infant colic were independently associated with lower postnatal depression and anxiety scores.
Probiotic vs Prebiotic vs Placebo in Major Depressive Disorders
Akkasheh et al. analyzed the effects of probiotic intake on symptoms of depression and metabolic status in patients with MDD [49]. They conducted a randomized, double blind, placebo-controlled trial of 40 patients with MDD (DSM-IV criteria). Patients were randomly assigned to either a probiotic (n = 20) or placebo group (n = 20). Probiotic supplementation consisted of combination of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum.
In the probiotic group, significantly reduced BDI scores were observed compared to placebo, along with a significant decrease in anxiety symptoms. The authors hypothesized that increased levels of tryptophan lead to decreased serotonin metabolite concentrations in the frontal cortex and decreased dopamine levels in the amygdaloid cortex.
Probiotics, through fermentation of dietary components, may be able to change the composition or activity of the normal gut flora. This may result in improved peripheral and central nervous system symptoms. Probiotics may also directly influence the enteric and central nervous systems in addition to their mucosal immune system effects.
Decreased serum insulin concentrations and HOMA-IR (homeostatic model assessment of insulin resistance) were also observed in the probiotic group. No significant changes were noted for FPG (fasting plasma glucose), HOMA-B (homeostatic model assessment for beta cells), QUICKI (quantitative insulin-sensitivity check index), or lipid profiles.
The literature supports no changes in lipid profile, though the decrease in insulin levels observed in the probiotic group is a unique finding. Insulin reduction may be due to increased hepatic natural killer T cell numbers and a reduction in inflammatory signaling. Linoleic acid is also produced by some species of Lactobacillus, which may upregulate adiponectin and downregulate inflammation to block suppression of GLUT4 transporters.
High sensitivity C-reactive protein (hs-CRP) was also decreased in the probiotic group. Hs-CRP is a marker of systemic inflammation and a predictor of adverse cardiovascular events. The anti-inflammatory effects of probiotics may be due to production of SCFAs in the colon and decreased expression of IL-6. An increase in plasma reduced glutathione (GSH) was also observed in the probiotic group. However, no changes on total antioxidant capacity levels were seen. Although the mechanism of oxidative stress is unknown, the beneficial effects of probiotics on GSH levels might be due to enhanced glutamate–cysteine ligase activity, thereby increasing synthesis of GSH.
Clinical and Metabolic Responses to Probiotics in Major Depressive Disorders
Kazemi et al. conducted a randomized, double blind, placebo-controlled study to compare the effects of probiotic and prebiotic supplementation on the BDI as a primary outcome, and the kynurenine/tryptophan ratio and tryptophan/branched chain amino acids (BCAAs) ratio as secondary outcomes in patients with MDD [43].
A total of 81 patients were enrolled in this study and randomly assigned to probiotic group (n = 28), prebiotic group (n = 27), and placebo group (n = 26). The bacteria used in the probiotic group consisted of Lactobacillus helveticus and Bifidobacterium longum; the prebiotic was galacto-oligosaccharide.
After 8 weeks of treatment, the probiotic group demonstrated a significant decrease in BDI score compared to both prebiotic and placebo groups (p = 0.042). These results were consistent with the literature, though this study is unique in that the use of probiotics was a primary method of treatment. The main mechanisms postulated for the observed probiotic BDI score reduction include modulation of neurotransmitters and inflammation.
Additionally, serum kynurenine/tryptophan ratio was significantly reduced in the probiotic group compared to the placebo group (p = 0.048). The prebiotic group did not show any significant changes. However, this result was only seen when adjusted for serum isoleucine. Tryptophan is metabolized by two main pathways, the serotonin and kynurenine pathways. Shunting of tryptophan towards the production of kynurenine leads to a serotonin deficiency.
Probiotics, however, drive tryptophan metabolism down the serotonin pathway. This increase in serotonin may therefore reduce depression and anxiety by increasing the availability of serotonin, much like the mechanism behind SSRIs.
No significant increase in tryptophan/BCAAs ratio was observed in the probiotic group. However, the prebiotic group did show a significant increase in the ratio when compared to the placebo group (p = 0.031). The authors theorize that the significance of this ratio is that BCAAs compete with tryptophan for passage through the blood–brain barrier. BCAAs are produced by some strains of gut bacteria. Notably, probiotics or prebiotics may reduce relative proportions of BCAA, thereby increasing tryptophan entry to the brain and subsequent serotonin production.
This could then theoretically decrease symptoms of depression and anxiety. Despite the fact that probiotics were shown to reduce depression in this study, they did not significantly alter the tryptophan/BCAA ratio. Conversely, while prebiotics were able to increase the ratio of these components, prebiotics were not associated with a significant change in depressive symptoms. Though limited in size and scope, the study offers promise in the study of microbiome alterations in treating depression moving forward.
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Conclusion
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140737/
More information: Grégoire Chevalier et al, Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system, Nature Communications (2020). DOI: 10.1038/s41467-020-19931-2
