The Diversity of Gut Bacteria and Psychological Disorders

Abstract

The human body can be considered a superorganism, containing a large number of microorganisms in symbiosis. An average human body contains about a kilogram of bacterial cells, which is about the same weight as the human brain. Majority of these bacteria resides within the gastrointestinal tract, outnumbering human cells and constituting approximately 99% of the genetic material in the human body. Human gut microbiota has been shown to have diverse effects on the host, and recent studies show that their effects extend to mental health. This review aims to understand the recent developments of the effects of gut microbiota community on mental health and potential manipulations of gut microbiota for prevention and mitigation of mental disorders by highlighting the nutritional value of diet, probiotics, prebiotics, and psychobiotics for mental health, modifying gut microbiota by fecal microbiota transplantation and antibiotics. In addition to these, providing the current knowledge on relevant neuroprotective mechanisms in the brain associated with gut microbiota and main gut microbiota modifying ways such as quorum sensing and bacteriophage was reviewed for future recommendation.

1. Introduction

Recently, humans have entered a new era of health with the discovery of antibiotics, rapid advancements in technology, worldwide flood of information, and a conscious effort on health and longevity. However, there is still much left unknown about what is beneficial for human health and what is detrimental, and the long-term consequences of things that seemingly solve many problems in the short term. The biggest alterations to the superorganism genome through the industrialization have been through the microbiota [1]. Also, the lack of understanding regarding the health of humans as a superorganism, including the microbiota that lives in symbiosis, has led to unknowing disruptions of them. For instance, many additives used widely in food industry are harmless to humans, however, they affect the gut microbiota [2].

Hygiene hypothesis states that the emergence of many allergies as well as immune and autoimmune disorders that have much prevalence in first-world countries is due to evolutionary changes in dietary choices, urbanization, attention to cleanliness, and the widespread usage of antibiotics, and the subsequent substantial reduce in the number of bacteria that average human comes into contact with [3]. On this basis, the old friends’ hypothesis suggests that the microbiota diversity has been evolving with humans over millions of years, and they are adapted and optimized for the old hunter-gatherer lifestyle. The microorganisms that are found in pollution-free water, soil and air, hard to come by in the western world, make up the human microbiota, humanity’s old friends [4, 5, 6] and with the recent recognition of the gut microbiota’s effect on human behavior, it is possible to expand the hygiene theory and include the increasing number of behavioral and mood disorders [7] as some of the resulting issues.

The past few years have seen increasingly rapid advances in the understanding of gastrointestinal microbiota, which describes the collection of various bacteria, fungi, archaea, and viruses residing in the intestines, which have access to, and communicate with, the enteric nervous system, an extensive network that also communicates back and forth with the brain. It is increasingly recognized that there is a complex, symbiotic relationship between the host and the gut microbiota. In this symbiotic relationship, the host provides the microbes with the necessary conditions for survival such as nutrition, temperature, and moisture, and in return, the diverse community of gastrointestinal bacteria contributes in various ways, including not only aiding digestion but also enhancing optimal brain development and contributing to various metabolic functions.

In this chapter, the interaction between microbiota diversity and diseases such as depression, anxiety, and stress-related disorders are briefly explained through peer-reviewed studies. Several strategies are utilized to study the effect of the gut microbiota diversity on the brain, including probiotic and antibiotic treatments, fecal transplantation, and inflammation studies. This study aims to examine and analyze the foundations of such previous studies and compile the promising treatment strategies for various psychological disorders affected by gut microbiota diversity. The research results represent a further step toward developing causal or direct relationship between gut microbiota diversity and such disorders instead of indirect or correlational relationships, as well as propose relevant studies as a strategy for treatment.

1.1 The connection between diversity of gut microbiota and mental health

There are several routes that the gut microbiota communicates with the brain. The most common pathways include interactions with the immune system, endocrine system, or neural network [8]. Many studies have shown that if this bidirectional communication does not function properly, it may cause significant psychopathological consequences [9]. Thus, preserving the homeostatic way of functioning of the gut-brain axis is a prerequisite for maintaining the psychological health of the host.

Phylogenetic diversity correlates with extraversion in younger children [10], and in adults, the presence of high levels of Gammaproteobacteria is associated with high neuroticism, and Proteobacteria with low conscientiousness. Furthermore, butyrate-producing bacteria, such as Lachnospiraceae, are correlated with high conscientiousness. The formation of the gut microbiome occurs to a great extent during the first three years of life, which continues to evolve in the later years, increasing the compositional diversity [11]. The human intestines have generally been accepted as completely sterile at birth; however, this theory has recently become controversial with recent evidence against it, which claims that colonization in the gut starts before birth [12]. Either way, the baby is exposed to mother’s microbiota during vaginal passage, and after birth, the baby is exposed to the bacteria in breast milk of the mother, which also contains specific nutrients for healthy microbial colonization [13]. Previous studies have also reported that a combination of fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS), in ratios similar to the human breast milk’s oligosaccharide composition, could trigger the increase of bifidobacteria in intestines. Thus, influencing a variety of species in the gut microbiota, mimicking the short-chain fatty acid (SCFA) production levels of breastfed infants. SCFA has direct influence over serotonin release in enterochromaffin cells that are located in gastrointestinal tract [14].

In the early postnatal weeks, this colonization has a key role in brain development. According to recent rodent studies, prebiotic supplementation with GOS and FOS may increase the expression of neuromodulators and neurotransmitters in the hippocampus, a key part of the brain involved in memory and learning [15]. The microbiota of formula-fed infants’ have been noted to be more diverse than breastfed infants, showing higher levels of Bacteroides, Enterobacteriaceae, and Clostridium [16, 17, 18], whereas infants that were breastfed showed higher levels of Bifidobacterium and Lactobacillus [19, 20].

Figure 1 shows an overview of the microbiota diversity varies with many factors such as age, region, dietary habits, sanitary practices, and lifestyle. Studies, including both industrialized and non-industrialized populations, are rapidly becoming key instruments in determining the level of diversity in human microbiota [21]. The microbiota of urbanized populations is higher in bacteria that metabolize animal fat and protein and lower in ones that metabolize fiber [22]. Several studies have shown that a loss of diversity in industrialized populations has become a common condition that has a serious impact on public health. Through these studies, it has been conclusively shown that in industrialized countries there was a decrease in the local diversity of gut microbiome compared to non-industrialized countries [21]. Another variable that affects diversity and composition of gut microbiota was revealed to be neonatal stress, which leads to long-term changes. This was observed through a study that included maternal separation. Furthermore, this can contribute to long-term changes in stress reactivity and stress-related behavior recognized in rodents [23]. Hosts with healthy microbiomes are more resistant to stress-related disorders and they cope with stress better than hosts with abnormal microbiota.

Figure 1.

The gut microbiota and brain communication.

Microbiota that resides within the gut communicate with the brain through several paths, and much of the increasing bodies of research have been descriptive about the relationship of the gut-brain axis, which is the biochemical pathway through which the gastrointestinal tract communicates with the central nervous system. Through this axis, the gut communicates with the brain and has been shown to influence mood changes [23]. Bidirectional interaction between gut microbiota and components of the gut–brain axis affects normal homeostasis and can contribute to risk of disease through changes in gastrointestinal (GI), autonomic nervous system (ANS), central nervous system (CNS), and immune systems in Figure 2. In order to form a complicated reflex network, these components interact with afferent fibers that project efferent projections to the smooth muscle and integrative CNS structures. Through this communications network, brain signals can affect the sensory, motor, and secretory modalities of the gut and in return, brain function can be influenced by visceral messages from the gut [15]. In addition, bacteria have the capacity to generate many neuromodulators and neurotransmitters, it is been shown that certain Bifidobacterium and Lactobacillus species produce gamma-aminobutyric acid (GABA); Candida, Escherichia, Streptococcus, and Enterococcus species produce 5HT; Bacillus produces dopamine (DA); Escherichia, Saccharomyces, and Bacillus species produce norepinephrine (NE); and Lactobacillus produces acetylcholine [15]. This means that the microbiota and the brain speak the same language as given in Table 1.

Figure 2.

Factors that have an effect on the gut microbiota of an individual in their day-to-day life, and the potential modes of interference and manipulation.

Neurotransmitter	Microorganism	Processes involved
Serotonin	Candida; Streptococcus; Escherichia; Enterococcus	Mood; Circadian rhythm; Anxiety; Appetite
GABA	Lactobacillus; Bifidobacterium	Vision; Motor control; Regulation of anxiety
Dopamine	Bacillus; Serratia	Reward and pleasure; Motor control
Norepinephrine	Escherichia coli; Bacillus; Saccharomyces	Stress response; Fight or flight response

Table 1.

The neurotransmitters produced by the microorganisms in the gut microbiota are shown, as well as the functions of the neurotransmitters in human systems. These chemicals are produced by the microorganisms for communication purposes, but through a hypothesized coevolution, they communicate not only with each other but also with the organism they live in.

Serotonin is a neurotransmitter involved in regulations of mood, appetite, and circadian rhythm in brain, however, it is found in higher concentrations in the gastrointestinal tract in humans, taking part in gastrointestinal secretion, pain perception, and motility there. Serotonin is produced by the gut microbiota, and the microbiota can also regulate the host production of serotonin, though the pathways have not been fully understood. Currently, two pathways are suggested, a plant-like pathway and an animal-like pathway, including the decarboxylation of tryptophan to tryptamine, and hydroxylation to 5-hydroxytryptophan, respectively. The plant-like pathway was found rarely in the genome of the gut microbiota; however, the animal-like pathway was reported to be present in 20% of gut-associated genomes. Gamma-aminobutyric acid (GABA) is a neurotransmitter, and it takes part in intracellular pH homeostasis and energy generation, produced in bulk by gut microbiota. In genome analysis, it was reported that GABA synthesis pathways were found widespread in gut microorganisms [24].

Recent studies have demonstrated that the gut microbiota is crucial to the development of a relevant stress response in a mammal’s lifetime. In a random assignment study, subjects took a combination of probiotics, including Bifidobacterium longum and Lactobacillus helveticus that has shown to be effective in prevention of caused anxiety-like mood. The combination of these two probiotics was shown to be correlated with decreased anxiety [9]. The subjects also self-evaluated their mood and the probiotic treatment subjects showed substantially less psychological stress than other subjects [23]. One major study reported that mice raised in sterile environments and as a consequence lacking indigenous bacteria, showed exaggerated physiological reactions, as depicted with an exaggerated adrenocorticotrophic (ACTH) and corticosterone (CORT) response, to stress compared to healthy controls. Through probiotic-induced bacterial recolonization, the abnormal or unusual reactions were reversible. This finding indicated the causal involvement of the microbiome in the development of the hypothalamic–pituitary–adrenal (HPA) axis. Stress induces physiological alterations in living beings, and while it is known that stress has many harmful effects on humans, recent studies show that it also contributes to gut microbiota differences. Several studies on mammalians found that postnatal stress when the babies and mothers were separated led to decrease in levels of Bifidobacterium and Lactobacillus in both rhesus monkeys and rats [25, 26]. Microbiota community has an immense effect on social behavior as well. In studies conducted with germ-free mice, they exhibit more social avoidance [27, 28, 29], and social anxiety toward unfamiliar subjects and novel environments [30].

Autism spectrum disorders are correlated with GI tract problems, and studies have shown a correlation with increased gut permeability [31, 32]. When gut permeability is increased, termed leaky gut phenotype, the molecules produced by gut microbiota end up in extraintestinal tissues, and the derivatives of such products affect many physiological traits. Leaky gut phenotype is linked to abnormal intestinal cytokine profiles, leading to altered immune responses, and also gut microbiota takes part in development, maintenance, and repair of intestinal tissues [33]. A study by Hsiao and colleagues in 2013 has shown that B. fragilis treatment of model hosts has resulted in improvement in permeability of intestines as well as cytokine expression within the intestines [34]. In the same study, they observed that the model host for ASD (maternal immune-activated mice) had 8% alterations in blood serum, and the treatment with B. fragilis caused 34% change of metabolomes in the MIA mice serum. The improved permeability of the intestines restored the level of 4-ethylphenylsulfate (4EPS), in MIA mice they found almost undetectable levels of 4EPS, and the B. fragilis treated MIA mice serum had 46-fold increase. Interestingly, they reported that the administration of 4EPS to wild-type mice induced anxiety-like behavior [34].

1.2 Strategies for modifying the microbiota diversity to improve health: Current practice

1.2.1 Diet

Under normal physiological conditions, dietary control remains the most effective way of altering and controlling the gut microbiota. Dietary fibers, sugars, and other nutrition support various forms of bacteria in the gut, therefore, leading to an increase in their population, which means the types of food ingested contribute to the diversity in the gut.

It is the responsibility of psychiatrists to consider dietary habits of their patients and offer appropriate advice in that aspect as part of the therapy the patients are subjected to. There is a high rate of correlation between poor dietary habits and mental disorders, and gut microbiota dysbiosis is a substantial part of that. An experimental study on social behavior of mice offspring related to maternal diet shows that maternal high-fat diet affects offspring’s social behavior negatively, which is retreated by addition of Lactobacillus reuteri to mice offspring’s diet [29]. The mechanism of diet gives rise to neurological changes, including high level of myelination in brain cortex of germ-free mice, these changes could be turned to tide by reorganization of microbiota [35]. Gut microbiota also affects dietary behavior, it is likely that humans crave certain and prefered tastes of the foods that are required for the sustenance of the microbiota [36].

Short-chain fatty acids (SCFA) are products of the gut microbiota during the processing of polysaccharides that humans by themselves are not able to digest. SCFAs, namely, acetate, propionate, and butyrate have functions that contribute to host health through their anti-inflammatory, anti-carcinogenic, and immune regulatory activities [37]. A study in 2015 found strong correlation between vegetable-based diets and higher levels of fecal SCFAs [38]. Vegetable-rich diets were found to increase levels of Prevotella, while protein/fat-rich diets contribute to Bacteroides and Clostridia. To conclude, fruit, vegetable, and legume-based diets correlate with an increase in the production rate of SCFAs. Recently, a study carried out by Simpson et al. revealed a decrease in bacterial species, including Faecalibacterium, Coprococcus, Clostridium XIVa, and Megamonas in depression groups by comparison to controls. The mentioned bacterial species are crucial to secrete SCFAs, including butyrate, acetate, and propionate, respectively. Therefore, dysregulated immune responses could have resulted from a reduction of SCFAs-secreting bacterial species and their metabolites [39].

In addition to broad dietary habits, polyunsaturated fatty acids are hot topics in terms of increased interest among others; as a result of laboratory animal studies, microbial composition is being changed by polyunsaturated fatty acids and the hypothalamic-pituitary–adrenal axis (HPA) activity through cognition and wetting as well as increased attachment of probiotic bacteria to the gastrointestinal tract [40]. Additionally, the level of docosahexaenoic acid, eicosapentaenoic acid, and total omega-3 polyunsaturated fatty acids in humans with major depression is lower compared to controls [41], and omega-3 fatty acids affect depression positively compared to placebo [42].

1.2.2 Probiotics, prebiotics, and psychobiotics

Probiotics are the supplements that contain viable microorganisms that provide health benefits when ingested. Probiotics are commercially available in various forms such as sprays, capsules, tablets, liquids, sprays, and fermented foods [43].

Various studies have been performed to determine probiotics’ influence on health, mood, and mental disorders such as anxiety and depression. According to a study, adult rats’ response to separation in infancy period from their mother is reported to decrease in depressive symptoms following treatment with B. infantis [23], which suggests strongly that probiotics containing B. infantis may help restore health conditions and depression [9]. In a related study, effect of probiotics against major depression has been shown that the major depression is reduced by consumption of a probiotic mix according to Beck Depression Inventory [44].

Faecalibacterium and Coprococcus species have been correlated with higher quality of life scores. These two strains are associated with the production of butyrate, which is a short-chain fatty acid that takes part in first lines of defense of the epithelia and has been correlated with intestinal inflammation, and several studies have reported that these species are lacking in patients suffering from irritable bowel syndrome and depression [45, 46].

In patients with major depression disorder, Flavonifractor strains were reported to be found in higher levels, whereas Coprococcus and Dialister species were reported to be lacking. There are conflicting reports from studies regarding the microbiota species correlations with major depression disorder, which may be due to treatment via antidepressants. Coprococcus and Dialister have been observed to replicate over several studies without treatment, across boundaries of other control factors such as age and diet, which makes them potential psychobiotic target microorganisms. Enterotypes also have been found to vary, Bacteroides enterotype 2 has been correlated with lower QoL, as well as being observed to be increased in patients with Crohn’s disease and patients who were diagnosed with depression disorders [47].

In order to utilize probiotics, they need to be prepared specifically and on a large scale, while also maintaining their viability and stability under storage, then survive in host’s gastrointestinal ecosystem and bring the host some benefit while residing within [48]. Through this harsh process, there are also certain factors that decrease the survival chance of probiotic microorganisms in the colon and the probability of becoming active in the ecological site of colonization. One challenge is the already established several hundred other bacterial species in the gut flora and competing for nutrients. Another challenge is that for continued benefits, the probiotics have to be consumed continuously, according to the research conducted by Bouhnik et al., when the consumption of the probiotic-containing product is ceased, the added bacteria are no longer harbored in the colon [49].

Prebiotics are edibles that when ingested stimulate growth or activity of specific bacteria within the colon, therefore, providing the host with beneficial effects through the alteration of the microbiota [50]. It has been shown that consumption of mixtures that combine both prebiotics and probiotics, named synbiotics, prove advantageous over either one alone. Gut microbiota community could be modulated by dietary supplementation with microalgae as prebiotics. Usage of prebiotic compounds such as microalgae Ulva lactuca, Laminaria japonica, Ascophyllum nodosum, Fucus vesiculosus, and Spirulina spp., can sustain gut microbiota homeostasis and get the development of brain disorders under control. Microalgae is a major supplier of micro- and macronutrients, including B vitamins, minerals, amino acids, etc., and phytochemical compounds associated with mental health. When dietary microalgae are taken, they first come across the microbiota localized in the gastrointestinal tract. Microalgae–microbiota symbiotic can give rise to the production of small bioactive molecules, which have potential effect on intestinal homeostatis and host brain health by growth-booster (prebiotic) effects of critical bacterial genera with the help of releasing neurotransmitters, such as GABA and serotonin. Neuronal functions could be modulated by small bioactive molecules and their derivatives [51].

The term psychobiotics were first described as probiotics that, when ingested in proper amounts, provide positive psychiatric effects in psychopathology. The term “psychobiotics” is generalized and refers to all probiotics, prebiotics, and synbiotics that take role in improving mental health. This strategy provides more efficient, cheap with less side effects than the previous artificial medicines. Thus, using intestinal bacteria as therapeutics becomes an attractive alternative to traditional drugs. However, still, not enough is known about the microbial community in human guts for these to be considered a reliable treatment option.

1.2.3 Improving microbiota diversity by fecal transplantation

Fecal transplantation is the transfer of fecal matter containing live bacteria from a healthy host to a receiving patient. It is currently used on patients that have gastrointestinal disorders. The gut microbiota composition is unique to each individual. It is known to fluctuate from time to time even within the same individual depending on their age, dietary habits, environmental conditions, and more [52].

A study by Sherwin et al. showed the relevance of fecal transplantation in mental health by transplanting fecal matter from 34 depressed patients and 33 healthy controls into rats that were made germ-free by antibiotics, and the rats that received from depressed patients showed less interest in their surroundings and showed increased anxiety-like behavior. This study, and others, show that mental disorders can be transplanted via FMT [53]. In another study published by Kurokawa and colleagues, 17 patients who were treated for gastrointestinal disorders by fecal transplantation were followed after the treatment, and the results indicated that the patients improved not only on GI aspects but also their scores on depression, anxiety, and sleep were improved [54]. Figures 3 and 4 displays human patients with gastrointestinal issues that were treated by FMT from healthy donors followed after the treatment, and aside from GI improvements, their scores on depression, anxiety, and sleep also improved.

Figure 3.

When germ-free mice receive gut microbiota from depressed patients through fecal matter transplantation, they showed increased levels of anxiety-like behavior, social avoidance, and performed worse under stress compared to controls that received gut microbiota from healthy donors.

Figure 4.

Human patients with gastrointestinal issues that were treated by FMT from healthy donors were followed after the treatment, and aside from GI improvements, their scores on depression, anxiety, and sleep also improved.

Although microbiota diversity remains a controversial topic, studies about microbiota bacterial taxa were a hint in clinical groups by comparison to controls. In patients with major depression disorder (MDD)/depressive disorders, there was a lower amount of Bacteroidetes, Prevotellaceae, Faecalibacterium, Coprococcus, and Sutterella, along with a higher amount of Actinobacteria and Eggerthella, compared to controls. In another study, it was revealed that patients with generalized anxiety disorder (GAD) had a lower amount of Firmicutes, Ruminococcaceae, Subdoligranulum, and Dialister, and a higher amount of Enterobacterales, Enterobacteriaceae, and Escherichia/Shigella. However, there were a good number of studies that reported little difference in microbiota diversity. As the authors suggest themselves, this difference could be related to control groups’ mental health statuses, ages, or diets, none of which were controlled for [55]. Either way, before fecal transplantations, whether for GI conditions or mentali the donors should additionally be screened for mental health backgrounds as well.

1.2.4 Antibiotics

Antibiotics are among the top-selling drug classes, in fact so widely used that according to a study by World Health Organization in 2018, Europe had a median defined daily dose of 17.9 per 1000 habitants, accounting for tens of millions of prescriptions per day, many used on newborn children. Many studies have targeted the dysbiosis caused by the usage of antibiotics on gut microbiota, and the common outcomes include a decrease in taxonomic and functional diversity, reduced competitive colonization resistance against pathogenic bacteria, and promotion of horizontal transfer of resistance genes among bacteria, leading to spread of antibiotic resistance [56]. The mechanisms of horizontal gene transfer could affect psychological steps by involving in production of neuroactive molecules and their metabolites and subsequently interacting with the host immune system. The effect of genetic factors on human psychology is probably related to microbial genes. Furthermore, this microbial genetic information is relevant for identifying targets for clinical intervention, given that the microbial gene pool is more readily modifiable than the human component. Considering that the human microbiota is a complex community built on relations among many species, it is not surprising that the effects of antibiotics, especially broad-spectrum antibiotics, are not yet well understood. The responses to antibiotic treatments are highly individualized, with some patients recovering from such treatments and their gut microbiota returning to their original state after a few weeks, and for some patients, there are long-lasting consequences. Pathogen infections, such as Campylobacter jejuni and Citrobacter amalonaticus, have negative impacts on anxiety-like and depression-like behavior, which could be targeted for antibiotic treatments [34].

Broad-spectrum antibiotic treatments result in antibiotic resistance sprouting in many bacterial strains and remain one of the most threatening problems in the future. Thus, the shift in public interest toward more bio-friendly methods is not surprising, and it is a significant and necessary step in order to avoid completely or at least limit the collateral damage to the microbiota caused by antibiotics. Antibiotics are reported to decrease the production of short-chain fatty acids in the gut [57], and these short-chain fatty acids are recognized to directly affect the serotonin release of some neuroendocrine cells in the GI tract [14]. Overall, antibiotics have detrimental effects on human health and environment, and they should be the last resort.

Gut microbiota community has effects on various mental processes as shown, and a study in 2014 by Chaidez et al., found more strains of Clostridium in fecal flora of children with autism than in controls [58], and when administered vancomycin, which is an antibiotic effective on Clostridium species, the children showed significant improvement. Before the children exhibited symptoms of autism, they went through antimicrobial treatment, and Clostridium species are known to be persistent when treated with antibiotics, indicating a correlation between late-onset autism and gut microbiota, which also aligns with the data that gastrointestinal symptoms are common among children with autism spectrum disorders, as high as 70% of the patients are estimated to show such symptoms [58, 59, 60] and there is a correlation with symptom severity as well [61]. Similarly, a study investigated the effects of oral bacterial treatment on maternal immune-activated (MIA) mice. MIA mice are models that are based on the large-scale reports that associate increased risk of autism with maternal infection [62, 63]. The MIA offspring display dysbiosis of microbiota as alterations in Lachnospiraceae and Ruminococcaceae of Clostridiales family, similar to the alterations in ASD patients such as increased species of Clostridium, as well as the behavioral and neuropathological features of ASD [34]. The MIA mice that were orally treated with B. fragilis and Bacteroides thetaiotaomicron showed improvement in communicative, repetitive, and anxiety-like behavior [34].

1.3 Strategies for modifying the microbiota diversity to improve health: Future recommendations

Considering the hundreds of different species that coexist in human gut as part of a community, interacting with each other and the host, it is reasonably hard to grasp the intricacies of the mechanism fully. As the uncertainty over whether the diversity of gut microbiota is beneficial remains, and antibiotics seem to be a dead end in the search for a sustainable resolution, other methods for removal of harmful pathogens become needed. In this complex ecosystem, interspecies communication and cooperation should be underlined and can be examined as a way of neutralization.

Quorum sensing is the mechanism through which bacteria communicate with the help of chemical signals, which in turn affect their mobility and other cellular functions associated with the differentiation between planktonic and biofilm-associated states. In biofilm state, bacteria attach themselves to a surface and secrete extracellular polymers, which provide structure for the community while also providing protection. This state is essential for survival of the bacterial community within an organism and through which gut microbiota survives in a highly dynamic area that is the intestine. Chemical signals called auto-inducers are used to communicate in-species and their concentration reports the size of the population. Bacteria have specific receptors for species-specific autoinducers, but also receptors for the other signals sent out by other bacteria [64]. Quorum quenching is the process through which quorum sensing is inhibited through chemicals that interfere with the autoinducers, and this method could offer a new method to remove or inhibit harmful bacteria without disrupting the whole microbiome.

As a currently widely considered alternative to antibiotics, bacteriophages are viruses that selectively infect and destroy specific bacterial strains. Phage therapy is referred to eliminating pathogenic bacteria via adding phages in gut microbiota where beneficial bacteria are located as probiotics. In this way, microbiota manipulation has an increasing popularity day by day, and microbiota reorganization are occurred by transplantation of virome. If microbiota manipulation takes place technologically with the help of phages, bacterial answers will be analyzed evolutionary. Based on this answer, the characteristics of bacteria will be definitively hit for their virulence or pathogenicity. Otherwise, investigation of the dynamic interactions between such communities (phage-bacterium) will be needed to understand in terms of phage responses to human immune system and biotic/abiotic factors, which affect phage therapy efficiency and coevolution. In conclusion, the current lack of understanding regarding the safety of phage application constitutes a problem, because the elimination of a community could disrupt or break the balance of the whole ecosystem, causing immense detrimental effects [65]. In order to secure their position in the future of psychotherapy, the bacteriophages deserve more investigation and research.

2. Conclusion

The increasing understanding regarding gut microbiota diversity, and its effect as the forgotten organ on human well-being offer a solution to the increasing levels of psychological disorders in modernized societies. While there is no consensus on the advantages of a diverse gut microbiota, the research, initially investigating correlation, is now pointing toward causation with the recent studies that were published. There have been several studies on rodents that reported increased stress response in germ-free rats, and behavior associated with depression has been observed in rats that received fecal microbiota from patients with depression. A first-of-its-kind study monitored the physiological as well as mental states of patients after fecal transplantation, and patients recovered both physiological and mental states, in aspects such as less self-reported stress and better sleep.

Probiotics, prebiotics, and synbiotics are good options, with highest efficiency when implemented together; however, retain hardships such as storage and regular consumption. Fecal microbiota transplantation is a functional method that is used to treat GI diseases, and it offers promising therapeutic benefits. Bacteriophages and quorum quenching as therapy on humans require more research relating to the dynamic ecosystem of human GI tract; however, they also stay relevant and promising in the manipulation of gut microbiome for mental benefits. As a strategy, first option is dietary regulation, and while difficult to implement, it is the most efficient step to altering gut microbiota. Putting aforementioned strategy into practice, psychiatrists could implement dietary advice along with other therapy to increase chances of their patient’s recovery and prevent relapses. While there is still a long way to go in understanding the detailed mechanisms of gut microbiota and its effects on mental health, the gut microbiota offers a strong potential target in the future of mental health treatments.