Psychobiotics: An Emerging Solution for Alleviation of Psychotic Disorders

 

Tina Raju, Swathy Lakshmi N, Jisha Prems, Lal Prasanth ML

Dr. Moopen’s College of Pharmacy, Naseera Nagar, Meppadi P.O., Wayanad - 673577, Kerala, India.

*Corresponding Author E-mail: wajidahmad806@gmail.com

 

ABSTRACT:

The covid-19 pandemic has made a profound impact on the mental and physical well-being of people worldwide. Apart from just treatment and prevention of such diseases which keep on emerging through mutation, it is also necessary to focus on mental health of patients. An emerging trend in this regard is psychobiotics. These are defined as probiotics that impart mental health comfort to the host when consumed in a particular quantity through the interaction with commensal gut bacteria. Depression and anxiety are disorders with greater number of cases worldwide. Although there are many treatment strategies, undesirable effects are seen. The highlight of this review is to spotlight on importance of psychobiotics in maintaining psychiatric health and its correlation with gut microbiota. It also includes different proposed mechanism and researches conducted so far to ascertain its value to human kind. Researches on psychobiotics which evidently prove that they should be considered and explored in detail have been showcased in this article. A few examples of fermented foods that exhibit psychobiotic potential along with dose have also been tabulated.

 

KEYWORDS: Psychobiotic, Depression, Microbiome, Prebiotic, Neurotransmitter.

 

 


INTRODUCTION:

The communication between the gut microbiome (GM) and the central nervous system (CNS) involves a number of neuro-immune and metabolic circuits through the vagal pathway or through the gut microbiome synthesized metabolites, gut hormones, and endocrine peptides.1

 

Therefore, maintaining a healthy GM is currently referred as an essential factor for maintaining mental health. The administration of prebiotics, synbiotics, and probiotics has been researched in patients with vulnerability toward, or well-established diagnoses of psychiatric disorders and also in preclinical     models.1, 2,3

 

The diversity of GM and taxonomic abundance changes have been explored in clinical settings, and their results prove the existence of a dissimilarity between patients (e.g., those diagnosed with depressive disorders, psychotic disorders, substance use disorders, etc.) and the general population.2,3,4 The corelation between GM changes and the onset or perseverance of psychiatric disorders is difficult to explain because most of the discoveries related to GM composition are made after the onset of a specific pathology. To make things even more complicated, several psychotropics have been associated with changes in GM diversity, e.g., antipsychotics may exert a dose-related negative effect on the Shannon index (The Shannon Diversity Index, sometimes called the Shannon-Wiener Index is a way to measure the diversity of species in a community) and phylogenic diversity.5,6 Also, antidepressants produce in vitro changes in the presentation of various GM species, with most of their effects being of antimicrobial nature.6,7

 

According to the World Health Organization, depression affects more than 300 million people worldwide. Many of those suffer from anxiety. This does not only have a negative impact on the health of those suffering, but also on their quality of life. Furthermore, they also affect the economic well-being of entire areas of work due to a considerable decrease in productivity at work, and both welfare and increase in health expenses.8,9 Anxiety is marked by an uneasy feeling about the future, including fear and uncertainty. On the other hand, depression is a serious mood disorder with severe symptoms such as sad and anxious mood, pessimism, irritability, fatigue, alterations in sleeping patterns, and suicidal thoughts. Current research states that both disorders are triggered by the interaction of psychological, environmental, genetic, and biological factors. There exist many therapeutic options to treat these disorders. However, these options often take time to work, cause mood swings, alterations in sleeping patterns, dependence, addiction, and side effects in other parts of the body.8,10

 

It is common to find both intestinal and mental disorders coexisting in the same individual. This suggests a strong connection between the central nervous system and the gastrointestinal tract.11,12 By studying the complex communication system that exists between the gut and the brain, it was found that the relationship between these two organs goes further than just the maintenance of homeostasis. This association is referred to as the gut-brain axis. The gut-brain axis (GBA) consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions. It is important to note that this relationship is bidirectional and that reciprocal brain-gut communication exists. However, the understanding of this complex gut-brain interaction would be incomplete without considering the fact that gut microbiota exerts.12,13,14

 

There is proof that suggests that the enteric microbiome plays a key role in the gut-brain axis communication. In fact, these microorganisms in the gut interact so closely with the host that they form a good relationship that even controls homeostasis. Although each person has their own specific microbiota, a certain equilibrium is accountable for many essential functions. That is why when this balance is affected, some conditions that affect the gut-brain-endocrine relationship develop, and in due course result in disease.15,16 This gives rise to a new concept which is ‘gut-brain-microbiota axis’that includes a bilateral communication system that enables gut microbes to interact with the brain, and vice versa. The mechanisms underlying this interaction pathway have not been completely elucidated, but strong evidence shows the involvement of neural, endocrine, immune, and metabolic systems.16,17

 

The gut microbiota is a vast and complex collection of microorganisms that profoundly affects human health.8,9 Previously, people referred to the gut microbiota as microflora of the gut. The gut microbiota assists in a range of bodily functions, as harvesting energy from digested food, protecting against pathogens, regulating immune function and strengthening biochemical barriers of the gut and intestine. These infections include food poisoning and other GI diseases that result in diarrhea and vomiting.10,11,14 Research suggests that bacterial populations in the gastrointestinal system play a role in developing gut conditions including inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis. Low microbial diversity in the gut also has links to obesity and type 2 diabetes. The status of the gut microbiota also has links to metabolic syndrome. Changing the diet by including prebiotics, probiotics, and other supplements may reduce these risk factors.15,16,18 Disturbing the microbiota with antibiotics can also lead to disease, including infections that become resistant to antibiotics. The microbiota also plays an important role in resisting intestinal overgrowth of externally introduced populations that otherwise cause disease – the good bacteria compete with the bad, with some even releasing anti-inflammatory compounds. Researchers have been studying the gut’s impact on overall health.19,20 They have concluded that the gut should be referred to as the ‘second brain’. This is because of the large amount of nerves present in the gut. The main nerve that connects the brain and gut is called the vagus nerve. The vagus nerve is the main nerve of the parasympathetic nervous system, which plays an important role in mood regulation, heart rate, digestion and immunity.18,19

 

Proposed mechanisms of action of psychobiotics:

Neural pathway:

The human enteric nervous system (ENS) contains 200 –600 million neurons starting from the upper esophagus to the internal anal sphincter. ENS creates a connection with CNS and is supported by the pelvic nerves, vagus, and sympathetic pathways.8,9 Many researchers believe that stimulating the vagus nerve may be a promising strategy to treat depression like, the implantation of vagus nerve stimulators (VNS) into the chest or neck can ease depression symptoms and improve life quality with treatment-resistant depression (TRD).10,11 Their earlier studies also concluded that compared with normal antidepressant treatment, VNS has a long-term treatment effect on patients with TRD, including a higher response rate and lower remission and suicide rates. The use of gut microbiota to stimulate the vagus nerve can be done instead of using the surgical route. Lot of animal studies have indicated that gut microorganisms can directly activate the vagus nerve and initiate signal transmission from the ENS to CNS. Such activation mediates brain functions and behavioural changes, including emotions, anorexia, lethargy, and hyperalgesia.12,13,14 For instance, treatment with L. rhamnosus JB1 can decrease anxiety-like behaviour by altering the expression of genes encoding GABA receptors in the amygdala and hippocampus, that control fear and emotions.18,19

 

Gut bacteria regulate electrophysiological thresholds in ENS neurons. For example, myenteric neurons exposed to Bifidobacterium longum NCC3001-fermented substances showed lower generation of action potential when electrically stimulated. Also, colonic AH neurons treated with Lactobacillus rhamnosus showed increased excitability, caused by inhibition of calcium-controlled potassium gates.21,22 Research performed on neurons from the dorsal root ganglion in the colon did not show hyperexcitability in response to noxious stimulation when treated with Lactobacillus rhamnosus.23 Overall, these results provide striking evidence of direct, bacteria-induced modulation of the enteric nervous system. Moreover, the influence of the microbiome on the ENS extends beyond neurons, with recent findings indicating that gut bacteria also play a crucial role in the development and homeostasis of glial populations in the gut.

 

Vagal Signalling:

The vagus nerve plays an indispensable role in coordinating parasympathetic activity, including regulation of heart rate and gut motility. It possesses lot of sensory fibres, and is able to convey information regarding function of organs throughout the body to the brain.15,17 These behaviourcomprises of lethargy, depression, anxiety, and loss of appetite, among others. Vagus nerve stimulation exerts anti-inflammatory effects, and is used therapeutically for refractory depression, pain, and epilepsy.20,23,24 Several animal studies have concluded that the vagus nerve, channels the relationship between psychobiotics and their psychophysiological effects. This is because severing the vagus nerve (vagotomy) annihilates responses to psychobiotics.24,25,26 However, one of the researchers found that ingestion of antimicrobials increased intrinsic relative abundance of Lactobacilli in innately anxious male BALB/c mice, which was accompanied by increased exploratory behaviour and BDNFexpression. Imperatively, in conclusion, vagotomy did not eliminate these neural or behaviouralbenefits.18,24 Therefore, vagal signalling may be considered as a partial mediator of bacterial effects.

Gut bacteria also produce a range of neurotransmitters through the metabolism of indigestible fibres. These include dopamine and noradrenalin by members of the Bacillus family, GABA by the Bifidobacteria family, serotonin by the Enterococcus and Streptococcus families, noradrenalin and serotonin by the Escherichia family, and GABA and acetylcholine by the Lactobacilli family.25,26 Even though there is no direct evidence till date, it is likely that these neurotransmitters mediate synaptic activity in the proximal neurons of the enteric nervous system, and is an important area for future research.

 

The connection with the enteric nervous system, which controls the gastrointestinal tract function, widens the scope of signals that can be transmitted through the VN by microorganisms. Vagal afferent fibers can sense microbiota signals indirectly, through the diffusion of bacterial compounds or metabolites or other cells located in the epithelium that send luminal signals.20,21 For instance, it has been reported that specific bacterial strains utilize vagus nerve signaling to communicate with the brain and to alter behavior. In addition, the vagal activity imparts a protective function to the intestinal epithelial barrier. Low vagal activity makes intestinal epithelium more permeable, thus promoting systemic inflammation and chronic disease.25,26

 

Hypothalamic-Pituitary-Adrenal (HPA) Axis:

The HPA axis is the paramount neuroendocrine system that mediates physiological and physical stress in the human body. It includes the hypothalamus, pituitary gland, and adrenal cortex, as well as secreted factors and hormones, such as cortisol in humans and corticosterone in rats. Cortisol possesses immunosuppressant properties. Under chronic stress, cortisol is over-produced. However, it cannot exert its anti-inflammatory effects. As a result, cortisol’s negative feedback on the HPA axis is restricted, resulting in hypercortisolemia.18,20 This increase in glucocorticoid level inhibits immunological activity. It also increases threat sensitivity, negative mood, impairs memory, and other cognitive functions. Recent researchers suggested a strong bidirectional communication pathway between this neuroendocrine system and the gut microbiota. It has been found that HPA behavior can affect the gut microbiota composition and increase gastrointestinal permeability. It can be understood that changes in the intestinal permeability and immune system also play an important role in neuroendocrine malfunctions. Gut microbiota imbalance can lead to the stimulation of the HPA axis. Thus, restoring this balance has promising effects in downregulating the HPA axis. For instance, researchers studied the effect of a probiotic formulation containing Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 on the HPA axis response to chronic stress. They found that this probiotic supplementation significantly managed the HPA axis response to stress.26

 

Immune Response and Inflammation:

Gut microbial dysbiosis or dysbacteriosis is characterized by a disruption to the microbiome resulting in an imbalance in the microbiota, changes in their functional composition and metabolic activities, or a shift in their local distribution. It is connected to immune responses that include the overproduction of inflammatory cytokines. Microorganisms in the gut help to regulate the innate and adaptive responses mainly by the production of small molecules that modulate host-microbiota interactions. Although the epithelial barrier prevents the escape of microorganisms from the gut, the metabolites they produce can pass through this barrier and enter and accumulate in the host’s circulatory system, where they can stimulate cells from the immune system.18,19,26 Moreover, the gut microbiota has a strong influence on the population, migration, and function of various immune cells. Microglia are the primary innate immune effector cells of the central nervous system. It was recently found that the intestinal microbiota plays aoutstanding role in microglia maturation, morphology, and immunological function. This is because short-chain fatty acids (SCFA) are able to interact and regulate the correct functioning and development of the microglia. Recent evidence suggests that higher levels of inflammation increase the risk of developing psychological disorders. In fact, higher levels of inflammatory cytokines, such as interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α), have been observed in depressed patients. Additionally, it has been observed that there is a positive association between microbiota composition and serum levels of interleukin-1α and interferon-γ, which are found to be associated with depressive behavior. In a recent work, researchers investigated the long-term effect that antibiotics administration has on rodents by studying their brain neurochemistry and behavior. They concluded that the antibiotic supplementation has a lasting effect on the gut microbiota composition and, thus, increases the expression of cytokines in the frontal cortex, modifies the function of the blood-brain barrier, and even alters behavior. Further, these mice showed impaired anxiety and increased levels of aggression. But, when one experimental group was supplemented with Lactobacillus rhamnosus JB-1, it was concluded that mental alterations got corrected.23,26

 

Bacteria-Immune Interactions:

Every microbe possesses a microbe-associated molecular pattern (MAMP, previously referred to as pathogen-associated molecular patterns). Many microscopic elements can act as MAMPs, including microbial nucleic acids, molecular cell wall components (e.g., lipopolysaccharides), or bacterial flagella. Gut microbes can communicate with the enteric nervous system and the innate immune system via interactions between the MAMPs and pattern-recognition receptors embedded along the lumen.20,26 Pattern-recognition receptors includes Toll-like receptors (TLRs), C-type lectins, and inflammasomes. These receptors are able to detect the nature and potential effects of various microbes via the MAMPs and, transmits information about the microbial environment to the host, enabling specific immunological responses.11,15,16 The MAMPs of beneficial bacteria, stimulate pattern-recognition receptors, and cause secretion of anti-inflammatory cytokines such as interleukin-10. While evidence on relationship between MAMPs, pattern-recognition receptors, and reductions in inflammation are lacking, one intriguing hypothesis is that beneficial bacteria might serve as physical barriers that block pathogenic MAMPs (e.g., lipopolysaccharides) from activating host pattern-recognition receptors such as TLR2 and TLR4 by binding to them instead, thereby preventing pro-inflammatory responses.25,26

 

One mechanism for psychobiotic effects is the mitigation of low-grade inflammation, typically observed as reduction in circulating pro-inflammatory cytokine concentration. Pro-inflammatory cytokines are also capable of increasing the permeability of the blood–brain barrier, permitting access to potential pathogenic entities. Cytokines change concentrations of several neurotransmitters that regulate communication in the brain, including serotonin, dopamine, and glutamate. Cytokines can also enter the brain through active uptake, thus, stimulating secretion of pro-inflammatory substances such as prostaglandins, leading to inflammation. There is also emerging evidence of a lymphatic drainage system subserving the brain, which may allow cytokines to interact with neural tissue.34,36 A parallel mechanism underlying psychobiotic-induced reductions in inflammation is the increase of anti-inflammatory cytokines such as interleukin-10. For example, in humans, Bifidobacterium infantis 35624 and Lactobacillus GG have been shown to enhance concentrations of interleukin-10. By reducing the total quantity of pro-inflammatory cytokines, either directly or by increasing anti-inflammatory cytokines, psychobiotics may be reducing the probability of cytokines gaining access to the central nervous system, and may also be restoring inflammation-induced permeability of the blood–brain barrier.24,26

 

Brain-Derived Neurotrophic Factors (BDNF):

BDNF is a neurotrophin structurally related to nerve growth factor, neurotrophin-3, and neurotrophin-4, which regulate the viability and functional integrity of specific neuronal populations. BDNF involves functions within the CNS, including neuronal survival and differentiation. Changes in BDNF levels may contribute to the dysfunction of synaptic transmission and plasticity. Gut microbiota influences the expression of BDNF in brain regions crucially involved in the development of correct behavioral patterns. Several studies suggest that the gastrointestinal microbiota may influence behavior by modulating BDNF production in the CNS. A parasitic infection study highlighted an important mechanistic insight regarding role of cytokine in microbiome–brain signalling. Healthy male AKR mice were infected with the Trichuris muris parasite, following which they were treated with Bifidobacterium longum NCC3001 and Lactobacillus rhamnosus NCC4007, or vehicle. Infection increased anxious behaviour and reduced hippocampal BDNF mRNA levels. Bifidobacterium longum NCC3001 (but not Lactobacillus rhamnosus NCC4007) reduced anxious behaviour and normalised BDNF mRNA concentrations. However, these changes occurred in the absence of prebiotic-induced reductions in any pro-inflammatory cytokines. This may be interpreted as evidence that psychobiotic effects also occur through mechanisms other than cytokine reduction.38,39,40,41 Pro-inflammatory cytokines are also known to compromise the integrity of the gut barrier. For example, Lactobacillus rhamnosus GG ameliorates gut barrier dysfunction by inhibiting the signalling potential of pro-inflammatory cytokines such as tumour necrosis factor-α.24,25

 

Exogenous bacteria can also trigger the development of immunogenic responses by producing substances line SCFAs under certain conditions. For instance, the introduction of Helicobacter hepaticus in the presence of genetically-deficient interleukin-10 signaling systems causes an increase in pro-inflammatory marginal zone B cells of the spleen. The microbiome also controls the development of appropriate immunosuppression in response to dietary antigens through the production of immunosuppressive regulatory T-cells. These cells prevent full immunogenic reactions to normal nutritional input, whereas germ-free mice do not possess this immunosuppressive activity and show exaggerated immune responses to dietary antigens.25,26

 

Short-Chain Fatty Acids (SCFAs):

SCFAs are saturated aliphatic organic acids that consist of one to six carbons; acetate, propionate, and butyrate are the most abundant, and are present in the colon and stool. SCFA are produced by gut bacteria through saccharolytic fermentation of carbohydrates that get spared from digestion and absorption in the small intestine. The different types and amounts of nondigestible carbohydrates that reach the cecum and large intestine depend on the daily intake and type of food, mainly fiber. The amount and type of fiber consumed have major impact on the intestinal microbiota composition and, therefore, the type and amount of SCFAs produced.21,26 Regarding its role in the organism, SCFAs act as metabolic substrates regulating host cellular metabolism, also they appear to play an important role in regulating the integrity of the epithelial barrier, regulating the immune system and inflammatory response, and eliciting effects on lipid metabolism and adipose tissue. Moreover, SCFAs might directly influence neural function by reinforcing blood-brain barrier integrity, modulating neurotransmission, influencing levels of neurotrophic factors, and promoting memory consolidation. Researchers have also given evidence that suggests a key role of SCFAs in gut-brain axis signaling. The human gut is incapable of digesting macronutrients such as plant polysaccharides.21,22 While these frequently appear in the diet, the human genome does not code the required enzymes for their digestion, which are supplied by the microbiome. The metabolisation of these fibres produces short-chain fatty acids (SCFAs). They enter the circulatory system through the large intestine, where the greater proportion are directed into the liver and muscle. There are a few evidencesfocusingon psychotropic properties of SCFAs at pharmacological concentrations. For instance, systemic sodium butyrate injections (200 mg/kg body weight) in rats produce antidepressant effects, and increase central serotonin neurotransmission and BDNF expression.25 Here, the action of butyrate as an epigenetic modifier is predominant as compared to action as an agonist at a free fatty acid receptor (FFAR). However, it should be noted that the SCFAs display pleiotropy (independent effects produced by a single gene), and also stimulate the HPA axis or have direct effects on the mucosal immune system, which may indirectly affect central neurotransmission. A conclusion of recent rodent investigation said that the SCFA acetate plays a causal role in obesity. Acetate generated by the gut bacteria in response to high-fat diets triggers parasympathetic activity and promotes increases in ghrelin, glucose-stimulated insulin, and further nutrition intake, creating a positive feedback loop that increases the likelihood of obesity.24,25

 

SCFAs also influence secretion of satiety peptides, including cholecystokinin (CCK), peptide tyrosine tyrosine (PYY) and glucagon-like peptide-1 (GLP-1), from gut mucosal enteroendocrine cells which express FFARs. For instance, propionic acid mediates the release of GLP-1 and PYY through activation of FFAR2. significant role in the central effects of prebiotics compared to probiotics. Furthermore, circulating PYY and GLP-1 have brain-penetrant properties, and their administration to rodents have significant effects on neurotransmitters and their behaviour.20,24 The microbiome has also been shown to possess a significant role in generating metabolites that enter circulation and exert a range of consequences outside the gut. A study that compared germ-free mice to normally colonised mice found emerging effects of the microbiome on the diversity and quantity of blood metabolites. For instance, germ-free mice had 40% greater plasma tryptophan concentrations than normal mice, but the normal mice had 2.8 times greater plasma serotonin levels than the germ-free mice.24 This suggests that gut bacteria crucially affect the metabolism of tryptophan into serotonin in Enterochromaffin cells (serotonin-secreting cells embedded in the luminal epithelium). It can be said that these metabolites are sensitive to psychobiotic action. However, the relationships between the microbiome, bacteria-derived metabolites, and the central nervous system, as well as the role of psychobiotics in modulating this network, remain unexplored.

 

Neurohormones and Neurotransmitters:

The microbiome can produce a range of neuroactive compounds. Some neurochemicals that have been isolated from gut bacteria are gamma-aminobutyric acid (GABA), noradrenaline, serotonin, dopamine, and acetylcholine, which may affect the brain activity directly. Other bacterial metabolites with neuroactive functions include long and short-chain fatty acids. Hence, the capacity of some bacteria within the human gastrointestinal tract to produce and deliver neurotransmitters and neuromodulators has been suggested as a novel treatment option for neuropsychiatric diseases.21,22,24

 

Serotonin:

Serotonin (5-HT) is a neurotransmitter that is involved in regulating behavioral and biological functions in the body like the mood. Additionally, it plays a major role in both psychological processes in the central nervous system (CNS) and peripheral tissues such as the bone and gut. 5-HT is primarily found in the intestinal mucosa, 90%–95% of it is contained in two primary reservoirs i.e., In the intestinal epithelium, where it is produced by enterochromaffin cells (ECs), and in neurons of the enteric nervous system. It is said that it may play a role in normal gut functions, including intestinal motility, absorption, and transit. Microbiota trigger 5-HT biosynthesis from ECs, and it has been observed that microbiota-dependent effects on gut 5-HT modulated GI motility and platelet function. Changes in the supply and availability of tryptophan have many implications in the enteric nervous system, CNS, and brain-gut axis signaling. Some reports suggest that concentrations of tryptophan increased in the plasma of male germ-free animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission.

 

Dopamine and Epinephrine:

Catecholamine (CA) neurotransmitters (dopamine (DA), norepinephrine (NE), and epinephrine (EP)) are biogenic amines derived from the amino acid tyrosine. They play pivotal roles in motor control, learning, memory formation and in stress relief. They also have greater effects on the cardiovascular system, by regulating the carbohydrate and fatmetabolism in the body. NE and DA stand out as prefrontal cortex-dependent function regulators, which monitor attention, decision making, and inhibitory control. Prefrontal cortex dysfunction has been recognized as a basic feature of many psychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and drug addiction. Gut microbiota plays a critical role in the generation of free CA in the gut lumen.

 

Gamma-Aminobutyric Acid (GABA) and Glutamate:

GABA and glutamate are the primary neurotransmitters of the mammalian CNS, whose role is to control excitatory and inhibitory neurotransmission. Coordination between these two neurotransmitters is essential for the proper working of complex brain processes such as neuronal excitability, synaptic plasticity, and cognitive functions such as learning and memory. Multiple studies have reported the role of GABA-producing microorganisms, predominantly lactic acid bacteria (LAB). For instance, Lactobacillus paracasei PF6, Lactobacillus delbrueckii subsp. bulgaricus PR1, Lactococcus lactis PU1, and Lactobacillus brevis PM17 isolated from Italian cheeses were found to produce high GABA concentrations during the fermentation of reconstituted skimmed milk.43,44 Recently, researchers examined the ability to produce GABA in laboratory strains isolated from traditional dairy products made from raw milk. It was reported that more than 1 mM of GABA was produced by strains of Lactococcuslactis subsp. lactis and Streptococcus thermophilus. Moreover, it was found that GABA receptors are present in gut microbiome and that glutamic acid decarboxylase genes are distributed among Lactobacillus plantarum, Lactobacillus brevis, Bifidobacterium adolescentis, Bifidobacterium angulatum, Bifidobacterium dentium, and other gut-derived bacterial species. This is the reason thay have ability to produce GABA. Also, it was reported that Lactobacillus brevis CRL 2013 is able to grow and produce high amounts of GABA in hexoses-supplemented MRS broth, such as glucose or fructose. Finally, a transcriptome analysis of human stool samples from healthy individuals showed that GABA-producing pathways are actively expressed by Bacteroides.

 

Acetylcholine:

Acetylcholine (ACh) plays a role as the primary excitatory neurotransmitter in the periphery. It acts as a neuromodulator in the brain: Influences synaptic plasticity, reinforces neuronal loops and cortical dynamics during learning, changes neuronal excitability, and can also differ the firing of neurons on a rapid time scale in response to changing environmental conditions. However, ACh and the enzymes participating in the acetylcholine synthesis have been well identified as components of bacteria. Its production was discovered for the first time in a strain of Lactobacillus plantarum.

 

CONCLUSION:

Any substance that shows a microbiome-mediated psychological effect can be considered as a psychobiotic, or at least said to possess psychobiotic properties. Antibiotic mixtures have been shown to induce neurochemical and behavioural changes through effects on the microbiome, and chronic ingestion of antibiotics can permanently alter microbiome composition and metabolism. Therefore, both antibiotics and antipsychotics may also be classified as psychobiotics. Antibiotic and antipsychotic effects on commensal bacteria showcase the importance of considering microbiome in side-effect assessments during clinical trials, which is not much explored by researchers till date. Of course, many substances may exert secondary psychobiotic effects through the microbiome alongwith their primary intended effects. Some of these areas are of interest in the emerging field of pharmacomicrobiomics.

Especially because psychobiotics belong to microbiota naturally found in the intestinal tract, they have lower risk of allergies and less dependence than psychotropic drugs. one of the biggest gaps is the lack of systemic studies that evaluate the psychobiotic effect of strains from in vitro studies all the way to clinical studies. This type of studies that contemplate the psychobiotic extent at different levels would allow a better understanding not only of the potential itself, but also of the mechanism behind it.

 

ACKNOWLEDGEMENTS:

We thank our institution for providing us with the required facility and resources for completion of this review article.

 

CONFLICTS OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 07.02.2024      Revised on 15.07.2024

Accepted on 07.10.2024      Published on 18.11.2024

Available online from December 19, 2024

Res.  J. Pharma. Dosage Forms and Tech.2024; 16(4):357-364.

DOI: 10.52711/0975-4377.2024.00056

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