Depression is a major concern, as it greatly adds to the burden of disease on a global scale. According to World Health Organization (2018), there are more than 300 million depressed individuals of all ages and the numbers are expected to increase. Thus, effective treatment methods for major depressive disorder should be a priority. There is a variety of treatments currently available, with antidepressants being most commonly used, as they target the emotional neural system. While they are effective in most cases, they also produce pharmacotherapeutic side effects (Balikci et al, 2014). Cognitive Behavioral Therapy is another frequently used method, which is primarily focused on psychological interventions. However, it is expensive and time-consuming (Lepping et al, 2017). With that being said, alternatives for major depressive disorder are needed.
Psychobiotics has been placed as a subject of interest and extensively explored by scientists and researchers over the past couple of years. Our gut microbiota hosts a commensal relationship of beneficial bacteria known as probiotics, which are stimulated by growth promoting non-digestible food components called prebiotics. These microbiome constituents are termed psychobiotics. They induce a bacterially-mediated impact on the brain, which consequently influences the immune and nervous systems of the body (Sarkar et al, 2016).
Psychobiotics are probiotics, or live bacteria, that produce beneficial mental effects when ingested in adequate amounts. These live microorganisms are typically found in the gut. Interestingly, the human gut is connected to the brain through the gut-brain axis, a bidirectional communication system, which is mediated by both neural and humoral mechanisms. There are various neural pathways in this particular axis, including autonomic and enteric pathways, and hypothalamic-pituitary-adrenal (HPA) axis. The slow humoral route combined with the rapid neural pathways facilitates gut microbiota’s effects on brain and behavior (Bruce-Keller, Salbaum, & Berthoud, 2018). This allows the microbiota to have a significant effect on the symptoms of mental disorders.
Psychobiotics could treat a variety of mental disorders effectively, which include disorders of mood, behavior, and cognition. In fact, psychobiotics “exert anxiolytic and antidepressant effects characterized by changes in emotional, cognitive, systemic, and neural indices” (Sarkar et al, 2016). More importantly, psychobiotics can help alleviate the symptoms of depression since they can reduce inflammation, its microbial composition has a relationship with mental disorders, and can relieve anxiety-like behavior.
Reduction of Inflammation
Psychobiotics can alleviate symptoms of depression, particularly by reducing inflammation. Elevated levels of proinflammatory cytokines have been correlated with serious mood disorders, such as major depressive disorder. Cytokines are a type of proteins secreted by immune cells, which act as chemical messengers. They play a major role in regulating inflammatory responses. A proinflammatory cytokine is a cytokine that promotes inflammatory responses, which play a role in the process of pathological pain. Intestinal dysbiosis, a process caused by the association between an altered state of intestinal microbiota and a peripheral and central inflammation, is thought to be involved in pathophysiology of major depressive disorder. In fact, interleukin and Tumor Necrosis Factor which are also known as pro-inflammatory cytokines, are found to be very elevated in the blood of individuals with depressive behavior and other inflammatory and mood disorders (Park et al, 2018).
Interestingly, psychobiotics can decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines (Sarkar et al, 2016). For instance, participants who displayed an abnormal ratio of interleukin-10 to interleukin-12, were supplemented with Bifidobacterium infantis which generated a therapeutic action by reducing plasma inflammatory cytokines. C-reactive protein levels, which serve as an indicator for inflammation status, are found to be increased in 45% of individuals resistant to antidepressant treatment. There is a significant link between live bacteria that are naturally found in our gut, known as probiotics, and their ability to reestablish a balanced and healthy set-up of intestinal microbiota (Park et al, 2018). Moreover, a study was conducted on Sprague–Dawley rats to test the effects of microbiota on inflammation. A stress factor was introduced to their physiology by disconnecting them from their mothers. Due to their evident anxious and depressive symptoms that were accompanied with reduced levels of noradrenaline, elevated inflammation and stress markers such as corticotropin-releasing hormone, a group of rats were injected with antidepressants and others with the microbiota Bifidobacterium infantis. Ultimately, the introduction of a probiotic has regularized the altered psychophysiological state resulting in an analogous effect to that exerted by antidepressants (Sarkar et al, 2016). Thus, by normalizing the gut microbiota composition and reducing the inflammation, psychobiotics alleviate the symptoms of depression.
Gut Microbial Composition
The importance of gut microbial composition is evident, as the diversity of gut microbiota varies from healthy individuals to patients diagnosed with major depressive disorder. The human gut serves as a natural habitat for the complex microbiome population. When an individual reaches adulthood, a relative equilibrium of bacterial abundance and diversity is reached in the microbiome. Typically, the abundance and diversity remain unchanged under stable health or environmental conditions. However, the microbiome could be affected by several factors such as disease, infection, and diet (Dinan, Stanton, & Cryan, 2013), which in turn, disrupt its composition.
Using animal models, the alteration of microbial diversity has been proven to contribute to the pathology of various neurodevelopmental disorders. More specifically, evidence suggests that microbial diversity may play a role in the risk of depression. For instance, a study has shown that there’s a significant difference in the beta-diversity between the gut microbiota of major depressive disorder and the gut microbiota of healthy individuals. More Actinobacteria and less Bacteroidetes were evident in the microbial population of a depressed individual relative to that of a healthy individual (Zheng et al, 2016). The fact that there is less bacterial richness and diversity in the microbial populations of depressed individuals indicates that an abnormal microbial composition may be involved the development of major depressive disorder. Additionally, psychobiotics can decrease the risk of depression, as studies have shown that these live microorganisms can help restore the microbial composition and maintain a healthy community of microbiota (Park et al, 2018).
Also, gut microbial composition has been linked to depression in an experiment done on germ-free rats. The transfer of microbiota from depressed individuals to microbiota-deficient rats, lead to the transfer of the corresponding behavioral and physiological phenotype (Kelly et al, 2016). In other words, after the transfer, the germ-free rat developed anhedonia, decreased interest in pleasure, and anxiety-like behaviors as well as a similar physiological state as the depressed patient. The results suggest that gut microbiota may be highly correlated to the process that underlies the development of depression, as the alteration in the microbial composition was enough to disrupt behavioral and physiological homeostasis in rats that lacked microbiota.
Regulation of HPA Stress Response
Psychobiotics can also help treat symptoms of depression by reducing stress through the regulation of HPA stress response and by synthesizing neurotransmitters that are typically deficient in individuals suffering from depression. Elevated cortisol levels may serve as a trait marker for the susceptibility of depression, as a dysregulation of the HPA axis has often been found in individuals diagnosed with depression (Ancelin et al, 2017). The gut-brain axis, a network of bidirectional communication between the brain and gut, allows microbiota to have significant effects on the symptoms of neurodevelopmental disorders, such as major depressive disorder. The dysregulation of microbiota-gut-brain axis leads to the stress response, particularly cortisol, which is produced by a complex interaction among the hypothalamus, the pituitary gland, and adrenal glands. Recall that the hypothalamic-pituitary-adrenal (HPA) axis is a neural pathway in the gut-brain axis, which happens to be a major output of cortisol. Essentially, when the brain detects a threat, it signals the hypothalamus to produce a hormone, which stimulates the pituitary gland to produce another hormone that causes the adrenal gland to release cortisol (Burokas, Moloney, Dinan, & Cryan, 2015).
The microbiota-gut-brain connection allows microbiota to shape an organism’s responsiveness to stress. In fact, studies have shown that treatment with gut microbiota Lactobacillus rhamnosus JB-1 was effective in decreasing anxiety-like behavior in rats that were caused by stress (Bharwani, Mian, Surette, Bienenstock, & Forsythe, 2017). Thus, a gut-microbiota-based treatment can indeed reverse the alterations in HPA axis that cause elevated levels of cortisol, which in turn, reduces the symptoms of depression.
Neurotransmitters GABA & Serotonin
Moreover, a dysfunction in GABA production is often reported in the pathophysiology of various chronic disorders, such as anxiety and major depressive disorder (Rieder, Wisniewski, Alderman, & Campbell, 2017). GABA is an inhibitory neurotransmitter that is responsible for regulating psychological and physiological processes. GABA is known to play a very important role in aiding the brain to control stress, which is a major vulnerability factor in mood disorders. Interestingly, psychobiotics produce major alterations in the expressions of GABA receptors in the brain. When the structures of the receptors are altered, their functions and pharmacological characteristics also change. Indeed, the exposure to early gut microbiota disturbance decreased the expressions of GABA receptors in the hippocampus (Liang, Zhou, Zhang, Yuan, & Wu, 2017). The decreased expression of the receptors, particularly the emotional behavior regulating receptors in the hippocampus, creates a deficit in the transmission of GABA. Thus, the deficit of GABA in the hippocampus prevents it from controlling the stress response, leading to depressive symptoms. Notably, psychobiotics have shown to increase of GABA receptor expression in the hippocampus in an experiment (Burokas et al, 2017). With that being said, psychobiotics can alleviate depressive symptoms by synthesizing GABA in the brain.
In addition, gut microbiota synthesizes serotonin, a neurotransmitter that is typically involved in the regulation of a number of bodily functions. Research indicates that “over 90% of serotonin in the human body is synthesized from tryptophan by enterochromaffin cells of the gut” (Wiley et al, 2017). The synthesis of serotonin in the brain depends on the availability of its precursor, tryptophan. Depressive behaviors are most likely to occur when the availability of tryptophan is inadequate for normal synthesis of serotonin. Interestingly, gut microbiota regulates plasma tryptophan and hippocampal serotonin, which are typically elevated in germ-free animals. Based on experiments done, it is apparent that psychobiotics normalize these levels (Foster, Rinaman, & Cryan, 2017). It’s worth noting that the symptoms of depression are due to insufficient levels of neurotransmitters, including serotonin (Liang et al, 2018). Thus, psychobiotics can reduce the symptoms of depression by regulating tryptophan expression, which is responsible for serotonin production.
Are Psychobiotics Truly Effective?
Nevertheless, there are opposers who claim that although the usage of animal models is important, they are not enough to prove the effectiveness of psychobiotics on humans. They think that more clinical trials need to be implemented on individuals diagnosed with psychological disorders to get an accurate representation of the therapeutic applicability of psychobiotics.
Indeed, animal models are important to study effect of microbiota on the physiology of the host. Germ-free mice enable researchers to study the transplantation of fecal human microbiota or animal models of disease by colonizing the mice with microorganisms of recognized anatomy and configuration. The inception of germ-free models has enabled scientists to study the correlation between the deprivation or absenteeism of gut microorganisms and the physiological outcomes on the developmental trajectory of the immune system and neurological functions (Luczynski, Neufeld, Clarke, Dinan, & Cryan, 2016).
However, according to Sarkar et al, the utilization of psychobiotics in animals with neurodevelopmental diseases or infection yields a pertinent understanding of the clinical diseases and physiology of humans (2016). Although it’s a new area of research, most scientists agree that psychobiotics have a very strong potential and have approved its testing on humans with particular precautions. In fact, psychobiotics have been tested on humans through the administration of probiotics to those who were clinically diagnosed with depression and inflammatory diseases influenced by the dysregulation of the gut-brain axis. The obtained results revealed that humans were responsive to the introduction of probiotics through management of cytokine levels (Sarkar et al, 2016).
Other critics claim that not all microbiota have been proven to be effective since the human gut colonizes more than 100 trillion microorganisms. Thus, the gut constitutes of various types of non-beneficial microorganisms such as viruses, protozoa and algae resulting in about 3.3 million unnecessary microorganisms.
Nonetheless, there are particular strains of gut microbiota that have been clinically proven to reduce anxiety-like behavior in humans. For instance, specific types of Lactobacillus and Bifidobacterium microorganisms have been tested on alleviating the symptoms of anxiety and depression through the production and regulation of neurotransmitters such as acetylcholine and GABA. The ingestion of Bifidobacterium infantis by germ-free mice has been proved to acquire antidepressant properties through influencing the gut-brain axis and secreting serotonin neurotransmitters. Also, another experiment has demonstrated the anti-inflammatory and immunoregulatory properties of Lactobacillus bacterium through its ability to modulate IL-10 cytokines in the blood. Thus, clinical experiments have proven that daily specific probiotic treatment can significantly reduce negative moods, such as anxiety and distress in humans (Dinan, Stanton, & Cryan, 2013).
Moreover, some people think that seeking an effective treatment for major depressive disorder is not a major concern, as there are various options out there to treat it. The nature of the current treatments vary from psychological to medical.
However, the most commonly used treatments, Cognitive Behavioral Therapy and antidepressants, typically have significant disadvantages. Cognitive Behavioral Therapy (CBT) is a treatment that is commonly used to treat mental disorders, particularly major depressive disorder. CBT is a psycho-social intervention that aims to modify emotions and behaviors. While it has been proven to be effective, it is demanding as it requires cooperation from patients over several months, it is expensive, and labor intensive. It is also most effective combined with antidepressants, as its therapeutic effects are not as significant on their own (Lepping et al, 2017). Furthermore, Cognitive Behavioral Therapy does not benefit every depressed individual. In fact, the average improvement in depressed patients using routine clinical practices ranges between 20% and 50% (Aafjes-van Doorn & Barber, 2017).
Unlike Cognitive Behavioral Therapy, antidepressants are a type of medication that are primarily used to treat mental disorders by balancing the neurotransmitters in the brain and regulating mood. Antidepressants are highly unreliable, as clinical trials have shown that the consumption of antidepressants has produced inconsistent therapeutic responses. It’s also worth noting that the therapeutic effects of antidepressants vary from one individual to another. This could be highly problematic because it is difficult for psychiatrists to prescribe suitable antidepressants, and the trial-and-error switching often causes distress for patients (Clark et al, 2012). In addition, they produce pharmacotherapeutic side effects that could cause a patient to avoid or stop the treatment. In fact, in a study done on the side effects that cause patient non-compliance, 28.6% of patients stopped the administration of antidepressants due to their side effects (Balikci et al, 2014).
Unlike any other treatment method, psychobiotics are “well-adapted to intestinal environment and naturally modulate gut-brain axis, reducing the chance of adverse reactions” (Kali, 2016). Therefore, psychobiotics treat mental disorders effectively and in a healthy way, with almost no side effects. This is one of the many qualities of psychobiotics that further indicates that it has what it takes to be a treatment of value for major depressive disorder.
In a time needed more than ever, psychobiotics are a relatively new subject of interest in research in the field of psychoneuroimmunology and they have proved to be very powerful candidates to treat major depressive disorder. The qualities of psychobiotics, such as its ability to reduce inflammation, its microbial composition’s relationship with mental disorders, and its ability to reduce anxiety-like behavior, qualifies it to become an actual treatment for major depressive disorder. Psychobiotics are more than just probiotics ingested, they exert powerful antidepressant qualities, especially when ingested in the right, sufficient amount. Considering the increasing prevalence of major depressive disorder and the therapeutic effects of psychobiotics, the addition of psychobiotics to the treatments of mental disorders such as major depressive disorder may be just what is needed to alleviate this epidemic.
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