Over time, the field of psychology has made significant strides in the treatment of psychiatric conditions, including major depressive disorder (MDD), schizophrenia, and Alzheimer’s disease (AD). Depression, also known as clinical depression, is a prevalent mental health condition defined by persistent feelings of sadness, hopelessness, and emptiness, all of which significantly impact the quality of life. According to the World Health Organization (WHO), approximately 3.8% of the global population experiences depression, with 15% of those affected dying by suicide. This review focuses on the emerging role of psychobiotics in treating clinical depression. Recent studies indicate that psychobiotics, which combine probiotics and prebiotics, offer potential therapeutic benefits. These compounds not only introduce beneficial bacteria to the gut but also support the growth of existing gut microbiota. Research on the gut-brain axis has revealed its key role in the effectiveness of psychobiotics, offering promising results for improving mental health. Beyond treating psychological disorders, psychobiotics also contribute to overall health by enhancing gut function.
Depression, also known as major depressive disorder (MDD) or clinical depression, is a significant mental health condition characterized by persistent sadness, hopelessness, and a sense of emptiness, all of which severely impact an individual’s quality of life [1]. This mood disorder is characterized by at least 2 weeks of noticeable changes in emotions, cognition, and neurovegetative functions, such as reduced appetite and energy levels [2]. Globally, approximately 280 million people are affected by depression, with 1.9 million children aged 3 to 17 years diagnosed with the condition. Individuals with depression often experience anhedonia (the inability to derive pleasure from activities), alongside physical and behavioral symptoms such as fatigue, loss of energy, low self-esteem, and, in some cases, suicidal ideation. Depression is diagnosed through tools like the Patient Health Questionnaire (PHQ-9) score and physician assessment of patient-reported symptoms [3].
Standard treatment for clinical depression typically includes antidepressants such as selective serotonin reuptake inhibitors (SSRIs), including escitalopram, fluoxetine, and sertraline; serotonin and norepinephrine reuptake inhibitors (SNRIs) like duloxetine and venlafaxine; and Tricyclic Antidepressants (TCAs) such as imipramine and nortriptyline. However, these medications alone often show a high failure rate, posing significant clinical challenges [4]. Psychotherapies, such as cognitive-behavioral therapy (CBT) and interpersonal therapy, offer additional benefits and are commonly used alongside pharmacological treatments.
A relatively new class of medication in the treatment of depression is psychobiotics. Psychobiotics are live beneficial bacteria that, when ingested, positively influence mental health by interacting with the gut microbiota [5]. The term “psychobiotics” was coined by Dinan and colleagues in 2013 to describe a novel class of probiotics with potential therapeutic applications for psychiatric disorders [6, 7]. Psychobiotics include both probiotics and prebiotics, which promote the growth of beneficial gut bacteria. Research into the mechanism of action of psychobiotics suggests that they impact the gut-brain axis, a bidirectional communication pathway between the gut and the brain. Understanding how psychobiotics affect this axis can help clarify their role in alleviating symptoms of clinical depression.
This review aims to explore the potential of psychobiotics in treating clinical depression and their broader implications for overall human health.
This review focuses on synthesizing existing knowledge about the role of psychobiotics in the treatment of clinical depression. The screening of articles was guided by keywords such as “clinical depression,” “psychobiotics,” and related terms. Full-text articles were meticulously reviewed by the authors for relevance and eligibility, particularly those that discuss the therapeutic role of psychobiotics in clinical depression and other psychiatric disorders. Articles examining the practical use of psychobiotics across various conditions, as well as studies on probiotics and prebiotics, were included in the review. After selecting the relevant articles, the data were extracted and assessed for consistency across studies. The findings were then organized to provide a clear understanding of psychobiotics, their mechanisms, and their potential benefits in treating clinical depression. Various research trials support the content of this review and review articles investigating psychobiotics and their effects on major depressive states.
A limited comprehension of mental health issues often complicates recognizing disease symptoms and hinders the proper implementation of therapeutic strategies [8]. Depression’s origins stem from a complex interplay of biological, psychological, and social factors. The brain-gut-microbiota axis, a multifaceted system involving neural, immune, and chemical interactions, plays a critical role in the development of depression [9]. Biological elements, such as brain chemical imbalances and hormonal disruptions, as well as psychological factors like low self-esteem or exposure to stressors (e.g., personal loss or career failures), can lead to depression in varying degrees. Social isolation, traumatic experiences, substance abuse, and poor lifestyle habits also contribute to the condition. Diet further influences depression: high-fat, high-sugar Western diets increase the risk of depression, while the Mediterranean diet has protective effects [10, 11].
The frequent use of antibiotics in treating common infections has been linked to a decrease in gut microbiota diversity, which may elevate the risk of developing mental disorders. Research has also shown that a lack of physical activity can negatively affect immune function, stress regulation, and energy balance by altering the gut-brain axis [12]. Another key factor contributing to depression is the disruption of serotonin signaling, a vital neurotransmitter in mood regulation [13]. Stress can dysregulate the hypothalamic-pituitary-adrenal (HPA) axis, which affects cortisol and corticotropin-releasing hormone (CRH) levels, and is thought to be a significant factor in the development of depression. Hormonal imbalances, such as elevated noradrenaline levels, may also play a role [14].
Although the pathogenesis of major depressive disorder (MDD) due to gut microbiota imbalances remains unclear, emerging research increasingly connects the gut-brain axis to the development of depression [15]. Disruption of the gut microbiota leads to an overgrowth of pro-inflammatory bacteria and a reduction in anti-inflammatory species such as Blautia, Faecalibacterium, and Coprococcus. This imbalance affects microbial metabolites, such as bile acids (BAs), leading to inflammation in the gut and contributing to the onset of depression. Furthermore, disruptions in the intestinal barrier (commonly referred to as “leaky gut”) cause systemic inflammation, with elevated levels of inflammatory markers like regulatory T cells (Th17), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-alpha (TNF-α), all of which are implicated in the development of depression [16-18].
Most current antidepressants target brain neurotransmitters but are associated with delayed action and potential side effects, such as headaches, nausea, drowsiness, and sexual dysfunction [19, 20]. Despite their popularity, these treatments often fail to resolve the widespread nature of mental illness, resulting in treatment-resistant major depressive disorder (TRD). TRD leads to recurring depressive episodes, increasing the risk of relapse, chronicity, cognitive impairments, and, in some cases, suicidal thoughts [21].
Traditional antidepressants primarily focus on brain abnormalities, overlooking other organ dysfunctions that may contribute to depression. Expanding our understanding of depression’s mechanisms by considering the role of different organ systems could provide new insights into treatment options. Nutritional psychiatry, a growing field, explores the relationship between diet and mental health, suggesting that dietary patterns could play a key role in mitigating depression. The evidence presented in this review indicates that probiotic therapies may help reduce inflammation and boost serotonin levels, offering a promising alternative to traditional antidepressants. By addressing the underlying causes of depression without the stigma, delay, and side effects of conventional treatments, probiotics could be a novel addition to the therapeutic landscape of clinical depression [22].
The “gut-brain axis” (GBA), also referred to as the microbiota-gut-brain axis (MGBA), is the primary site through which psychobiotics exert their therapeutic effects on clinical depression [23, 24]. Recent research has expanded our understanding of the role of psychobiotics in influencing the gut-brain connection, revealing an already existing biochemical interaction between humans and their gut bacteria [25]. This axis represents a complex signaling pathway linking the gastrointestinal (GI) tract to the central nervous system. This discovery has gained traction in neuro-gastrointestinal research over the past decade. The gut microbiota, often referred to as the “second brain,” is crucial in regulating brain functions [26]. The trillions of microbes residing in the human gut interact with the brain through multiple communication channels, including neurological, immune, and humoral pathways. The enteric nervous system (ENS), specific to the gut, maintains a direct connection with the brain via nerve signals. These microbes are essential for immune function, with an adult’s gastrointestinal tract housing around 100 trillion microorganisms [27]. These microbes significantly influence human health, both through their interactions with one another and with the host [28]. Research has also established the role of gut microbiota in neurodevelopment and neuropsychiatric disorders [29]. It’s worth noting that the mucous layer separating the ENS from the microbiota in the gut helps prevent direct contact with the local nervous system [30].
The theoretical foundations, combined with emerging applications, have paved the way for groundbreaking approaches in medicine, particularly concerning the bidirectional communication within the microbiome-gut-brain axis. This concept has garnered significant attention from both researchers and clinicians for its potential in addressing mental health disorders. Probiotics, live microorganisms that confer health benefits upon ingestion, are increasingly recognized for their impact on both mental and physical well-being. Available in fermented dairy products and vegetables, or as supplements, probiotics have shown promise when used alongside traditional antidepressant and anxiolytic treatments, especially when incorporated into a balanced diet. The term “probiotic” derives from the Greek “bios” (life) and the Latin “pro” (for), underscoring their beneficial effects. Recent studies suggest that certain gut bacteria can influence serotonin production in the gut, with specific strains affecting the enterochromaffin cells that synthesize this neurotransmitter. Probiotic supplementation has been linked to improvements in mood, reductions in anxiety, and enhanced sleep, with few side effects, suggesting that these supplements are well tolerated. This raises the need for further exploration into how probiotics may function as psychobiotics. Compared with prebiotics, probiotics have demonstrated greater efficacy in reducing symptoms of clinical depression [31]. Common strains used in probiotic formulations include Lactobacillus, Bifidobacterium, Bacillus, Streptococcus, Enterococcus, and Escherichia.
The action of psychobiotics is strain-dependent, with each strain potentially influencing depression through different mechanisms. Three mechanisms by which gut microbiota may impact the GBA include: (1) stimulating the release of neuroactive chemicals from the intestinal epithelium, (2) altering cytokine levels in the serum, and (3) activating the vagus nerve directly [32]. When administered either alone or in combination, these strains have demonstrated a capacity to alleviate depressive symptoms in humans. Beyond their role in regulating the hypothalamic-pituitary-adrenal (HPA) axis, the sympathoadrenal medullary (SAM) axis, and the inflammatory reflex, psychobiotics also influence cognitive functions such as learning, memory, and behavior [33], with these effects mediated by changes in glial cells [34]. Psychobiotics help restore balance to the MGBA, a balance often disrupted by stress and anxiety, and maintaining this equilibrium can help mitigate depressive symptoms [35].
C-reactive protein (CRP) levels, when assessed at baseline, play an essential role in tracking improvements in depression. One of the primary mechanisms by which probiotics may alleviate depressive symptoms is through their anti-inflammatory effects. Several preclinical studies highlight the benefits of using probiotics alone in managing depression, but their effects are often amplified when used alongside traditional antidepressants [36]. The therapeutic benefits of probiotics have been demonstrated in clinical settings through depression assessments using validated scales and monitoring depression-related biomarkers, such as cortisol, pro-inflammatory cytokines, and brain-derived neurotrophic factor (BDNF). Research indicates that the combination of probiotics with antidepressants is linked to increased expression of GABA receptors and restoration of BDNF, serotonin, and noradrenaline levels, contributing to the alleviation of depressive symptoms [17].
Psychobiotics have shown significant promise in improving mental health outcomes in patients with depression [37]. A 2021 meta-analysis of seven randomized clinical trials (RCTs) involving 404 patients revealed that probiotics, when taken with antidepressants, can reduce depressive symptoms. Further studies in animal models, where chronic immobilization stress (IS) was used to induce depressive and anxious behaviors—linked to both brain and intestinal inflammation—showed that administering probiotics like Lactobacillus reuteri, Bifidobacterium adolescentis, Lactobacillus mucosae, or Bifidobacterium longum led to improved performance in several behavioral tests, including forced swimming, elevated plus maze, and light/dark transition tests. Additionally, these probiotic strains increased BDNF levels, reduced microglial cell infiltration, and decreased NF-B activation in the hippocampus. Lactobacillus mucosae was particularly effective in improving cognitive function, reducing anxiety and depressive symptoms, and restoring intestinal health in an animal model of colitis induced by Escherichia coli. Probiotic combinations, including strains of Lactobacillus and Bifidobacterium, have also shown the potential to reduce depressive behaviors by reestablishing equilibrium between the gut and brain [38]. Consequently, Bifidobacterium and Lactobacillus probiotics are now widely used to alleviate depressive symptoms [39], demonstrating a noticeable impact on mood.
In a study conducted by Tillisch et al., healthy female volunteers who consumed a fermented milk product containing a blend of probiotics, including Bifidobacterium animalis subsp. lactis, Streptococcus thermophilus, Lactobacillus bulgaricus, and Lactococcus lactis subsp. lactis exhibited changes in brain activity related to emotional processing. Participants who consumed a milk beverage containing Lactobacillus casei Shirota for 3 weeks reported improved mood and greater happiness.
Another study using the Hospital Anxiety and Depression Scale (HADS) evaluated participants’ levels of anxiety and depression. Participants with scores indicating potential anxiety or depression were included in the study, which involved no psychiatric medications. After one month of taking multispecies probiotics, significant improvements were observed in both HADS and EQ-5D-5L scores, with these improvements continuing into the second month. Probiotic supplementation was also linked to increased levels of neurotransmitters associated with depression, such as 5-hydroxytryptamine (5-HT), norepinephrine (NE), and Gamma-aminobutyric acid (GABA). This mode of action resembles the therapeutic effects of some antidepressants, highlighting the potential of probiotics as a complementary treatment for depression.
Steenbergen’s study involved administering lyophilized Bifidobacterium probiotics to participants and assessing their mental health before and after treatment using tools such as the revised Leiden Depression Sensitivity Scale (LEIDS-r), the Beck Depression Inventory II (BDI-II), and the Beck Anxiety Inventory (BAI). After four weeks of probiotic supplementation, participants showed a significant improvement in cognitive responses related to depression, especially in terms of aggressive and ruminative thought patterns. This study offers early evidence that a 4-week regimen of multispecies probiotics positively influences cognitive responses linked to mood fluctuations, even in individuals without mental health conditions [40].
Probiotics also affect neuroendocrine pathways and neuronal communication, thereby stabilizing the hypothalamic-pituitary-adrenal (HPA) axis. Evidence supporting this includes reduced 5-hydroxyindoleacetic acid (5-HIAA) levels in patients on SSRIs, with similar effects observed in mice treated with Lactobacillus plantarum. Furthermore, there were no reports of adverse effects from psychobiotics, demonstrating their safety and tolerability as potential treatments for depression [41].
Psychobiotics may serve as complementary treatments alongside antidepressants to alleviate symptoms of depression. Probiotics that enhance GABA production have shown promise in treating various mental disorders, such as depression, bipolar disorder, and schizophrenia. Probiotics also influence anxiety by reducing oxidative stress, regulating pain-related hormones, and lowering circulating cytokines. The gut microbiota is highly responsive to stress, leading to a reduction in Firmicutes, particularly Bifidobacterium strains and other Lactobacillaceae. Prolonged stress elevates HPA-axis activity, increases corticosteroid secretion, and disrupts the sympathetic nervous system, often leading to deficits in prefrontal cortex function, immune responses, and behavioral regulation [42].
Probiotics like Lactobacillus helveticus and Bifidobacterium longum can help relieve gastrointestinal issues caused by stress, as stress can severely impact gut health. There is also growing interest in the potential of probiotics to treat conditions like autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) [43]. The influence of gut microbiota on neurological diseases like depression, Alzheimer’s, and Parkinson’s is becoming increasingly evident. Studies have shown that people with depression often have altered gut microbiota composition, reinforcing the importance of gut health in mental well-being [44].
This review focused on the role of psychobiotics in the treatment of clinical depression and their potential to enhance overall human health. Psychobiotics, a relatively new class of therapeutic agents, have shown promise not only in alleviating depression but also in managing various other psychiatric conditions. The therapeutic effects of psychobiotics are primarily mediated through the microbiota-gut-brain axis, a bidirectional communication pathway linking the gut and brain. Psychobiotics influence mental health in several ways:
Neurotransmitter production: Certain bacteria in the gut produce essential neurotransmitters such as serotonin, dopamine, and gamma-aminobutyric acid (GABA), which are crucial for regulating emotions like anxiety and mood.
Inflammation regulation: Psychobiotics have anti-inflammatory properties that help reduce systemic inflammation, including in the brain. This reduction in inflammation may contribute to improved mood and mental health.
Hormonal regulation: Cortisol, a key hormone in mood and stress regulation, is partially influenced by gut microbiota. Psychobiotics may help regulate cortisol levels, promoting emotional stability.
Immune system modulation: An imbalance in gut bacteria can disrupt immune system function, which is linked to various psychiatric disorders. Psychobiotics can modulate the immune response, potentially reducing the risk of mental health conditions.
The overall contribution of psychobiotics to the treatment of clinical depression is promising. However, more research is needed to understand their mechanisms fully and to explore their potential benefits in treating other psychiatric disorders. Given the current evidence, it is reasonable to conclude that psychobiotics can be effectively used in conjunction with traditional antidepressants as an adjunct therapy for managing mental health conditions.
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