# The Role of Microbiome in Psychiatric Diseases (Insomnia and Anxiety/Depression) with Microbiological Mechanisms

Authors: Madiha Khan Niazi; Farooq Hassan; Tabussam Tufail; Muhammad Amjed ismail; Khadija Riaz
Journal: Advanced Gut & Microbiome Research
 (2023)

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## Abstract

More focus is being paid to the relationship between gastrointestinal microbiota and human health. The microbiota-gut-brain axis was created as a result of the intricate networks and connections between the gastrointestinal bacteria and the host, highlighting the significant impact that this environment may have on brain health and central nervous system problems. To communicate with the central nervous system, the gastrointestinal, autonomic, immune, neuroendocrine, and neuroendocrine systems engage in a bidirectional interaction with the microbiota. Through a number of neurological processes, including stimulation of the altered neurotransmitter function, hypothalamic-pituitary-adrenal axis, and immune system activity, changes in this network may have an impact on both health and sickness. Anxiety and sadness are two neuropsychiatric conditions that may be impacted by the microbiota-gut-brain axis, according to a recent study. Numerous host disorders, including obesity, diabetes, and inflammation, have already been related to alterations in the gut microbiota’s makeup. In this article, the effects of the gut microbiota on the functioning of the central nervous system are examined, with a focus on the symptoms of anxiety and depression. After examining how stress affects the autonomic, neuroendocrine, immunological, and neurotransmitter systems, modern gastrointestinal-based therapies stress the importance of the microbiome in the prevention and treatment of brain-based diseases including anxiety and depression.


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## Body

## 1. Introduction

Given that over 60 million Americans suffer from insomnia and that an estimated 8.5 million Americans use sleeping aids annually, it is clear that this medical condition necessitates a slightly different approach to therapy. As chronic illnesses become more prevalent, the gut microbiota is becoming more important in the onset and/or course of numerous diseases. Numerous studies on circadian rhythms and the sleep-wake cycle in relation to sleep have been conducted. Recent studies have concentrated on how our bodies’ 100 trillion-strong microbiomes regulate our circadian cycles, including sleep [1].


## 2. The Gut Microbiota

The human GI tract contains approximately 1014 bacteria or more than ten times as numerous as somatic and germ cells [2]. Growing data suggests that the microbiota may have an effect on human health, despite more recent projections casting doubt on the American Academy of Microbiology’s previous predictions that the ratio of bacteria to human cells will approach 3 : 1. The large intestine contains the majority of the microbiota, which changes during the course of the host’s life cycle, with infancy being the period of highest dynamic change. The gut microbiota of most people is shared by around one-third of them, while the remaining two-thirds are known to be individually unique [3]. Consequently, the microbiota of a person can be utilized to identify them. Due to its individuality, a “healthy” microbiome can be challenging to define and establish. Even though it may be challenging to recognize microbiota biosignatures, it is generally accepted that stable communities and a variety of species are signs of a healthy microbiome. Although the host-microbiome connection is still being slowly researched, it is currently believed to be symbiotic and complementary [4]. In other words, the microbiota continuously affects a variety of host systems over the course of an individual’s lifetime, including the development and operation of innate and adaptive immune responses and the maintenance of homeostasis [5]. In addition, bacteria control a number of metabolic processes carried out by the host [6]. The host and its five related bacteria normally coexist in symbiosis, as was previously indicated. Dysbiosis, which has been linked to a range of illnesses, can arise when specific events or conditions change this dynamic [7].


## 3. Microbiota-Gut-Brain Axis

The connection between the brain and the gut has already been well established [8]. The neuroendocrine, immunological, autonomic (ANS), and enteric nervous (ENS) systems, among others, facilitate the interchange of afferent and efferent signals in both directions across a range of physiological regions [9]. For instance, interactions between these systems frequently occur in the GI tract, which has the body’s highest concentration of immune cells and 500 million nerve endings [10]. Twenty percent of these nerves, which together make up the ENS, have primary afferent intrinsic neurons. Through the vagus nerve, these ENS afferent neurons transmit minor alterations in the GI tract to the brain [10]. Through established connections between the GI tract and the CNS, this neuronal and metabolic communication process also takes place throughout the rest of the body. The “gut-brain axis,” a dynamic communication channel encompassing several tissues and organs, has been named by researchers. Due to the relevance of these axis’ components for digestion and satiety, they have so far been the subject of intensive research [11]. This gut-brain axis dysfunction number six is associated with inflammation, persistent stomach pain, eating disorders, nausea, and stress, among other pathophysiological effects [12]. The gut’s millions of bacteria play an important role in the gut-brain axis and may have a big impact on someone’s health. Integrative therapies for GI and CNS illnesses may be created by better understanding the molecular mechanisms and pathways that link the gut and brain as shown in Figure 1 [13].Figure 1
Gut-brain axis.


## 4. Key Communication Pathways and Neurobiological Mechanisms

Gut bacteria are thought to affect a multitude of metabolic, gastrointestinal, and neurological problems, according to research from the domains of neurology, gastroenterology, and microbiology [14]. These microbes may also have an impact on brain chemistry and behavior because of the intricate information transfer through the gut-brain axis and the network of communication between the gut bacteria and the brain. The neuroendocrine and neuroimmune systems linked to stress and stress-related illnesses, as well as the sympathetic and parasympathetic branches of the autonomic nervous system (ANS), are just a few examples of the mechanisms and channels by which the CNS and microorganisms interact and influence host behavior [15]. The following discussion will center on important neurobiological and communication pathways, such as those that cross cell walls, metabolites, neurotransmitters, and brain neurotrophic factors. These pathways taken together might provide insight into the function of the microbiome in complicated CNS disorders and homeostasis [15].


### 4.1. Vagus Nerve

The vagus or tenth (X) cranial nerve, which transmits sensory data between the central nervous system and the peripheral nervous system, serves as a direct conduit from the gut to the brain [16]. The central nervous system and gut bacteria communicate via the primary afferent channels that pass through the vagus nerve, according to the results of numerous research [17]. These findings suggest that one potential neurological mechanism behind these correlations is the activation of c-FOS in vagal sensory neurons and following vagotomies. Increased neuronal c-FOS mRNA and c-FOS expression have been proposed as markers of recent brain activation. It is interesting to note that visceral sensory nuclei in particular autonomic and brain regions had higher levels of c-FOS in pathogenic animals with Campylobacter jejuni and Citrobacter rodentium infections than noninfected animals did [9]. The vagal nerve pathway is thought to be involved in the transfer of gut immunological signals to the central nervous system, according to investigations on vagotomy performed on rats infected with Salmonella typhimurium to simulate the situation of a real bacterial infection. After cutting the vagal nerve pathway, there were fewer immune cells and reduced c-FOS expression in those neurons [18]. To create behavioral problem-solving therapy strategies, it may be helpful to understand the role of the vagal afferent pathways in mediating communication between the brain and gut bacteria.


### 4.2. Cell Wall Components and Immune Responses

Innate and adaptive immune systems in the host mucosa are stimulated by the peptidoglycan cell wall of bacteria. These pathogen-associated molecular patterns or these proinflammatory microbial components essentially cause the innate immune response to occur (PAMPs). When PAMPs interact with the pattern-recognition receptors (PRRs) on defense cells, inflammatory cytokines are produced. These cytokines can either directly or indirectly impact the brain via the permeable blood-brain barrier or peripheral vagal pathways [19]. The brain can be impacted by proinflammatory cytokines such as interleukin 6 (IL-6) and chemokine ligand 2 (CCL2), either through the humoral pathway, where PAMPs act on toll-like receptors (TLRs) in particular brain regions, or the neural pathway, where afferent nerves are involved. PAMPs linked to Gram-positive bacteria include lipoteichoic acids and peptidoglycan monomers. Intestinal epithelial cells may produce additional neural signaling molecules as a result of many of these cell wall constituents [20]. However, the gut microbiota has potent immunomodulatory effects on the mucosal and systemic immune systems, raising the possibility that it may do the same for cognition and behavior. Additional research is needed to verify these results.


### 4.3. Metabolites

The digestion and microbial fermentation of food and nutritional components produce metabolites, which can significantly affect immune responses and cognitive processes [21]. For instance, it has been shown that changing the composition of the gut microbiota may affect the availability and regulation of tryptophan and fatty acids. The immune system may interact with tryptophan and fatty acids to modify cellular immunological responses. These metabolites serve as important regulators of the gut-brain axis and prospective therapeutic targets, which considerably aid in maintaining human health [22].


### 4.4. Fatty Acids

High levels of fatty acids in the brain assist in controlling a number of activities, including neurotransmission, cell survival, and neuroinflammation [23]. Chemical messengers known as eicosanoids control immunological and inflammatory responses by influencing genes, producing cytokines, and altering membrane structure and function. Eicosanoids are also produced in part by dietary fatty acids [24]. Peroxisome proliferator-activated receptors are a subfamily of nuclear receptors, which have an impact on cellular development and functionality, and can bind to and be activated by fatty acids. Nuclear receptors called PPARs are involved in the transcription of genes. Different immune cells may bind to fatty acids in order to induce inflammation. Short-chain fatty acids, the main metabolic byproducts of gut bacteria, have strong anti-inflammatory capabilities. Acetate, isobutyrate, butyrate, hexonate, and propionate are produced by specific species of the microbiota’s Eubacterium, Faecalibacterium, Roseburia, Lactobacillus, Bifidobacterium, and Enterobacter [25]. It has been demonstrated that these fatty acids affect intestinal permeability, improve immune system performance, change lipoprotein profiles, and lower colonic pH. Additionally, short-chain fatty acids enhance the release of neuropeptides like glucagon-like peptide (GLP-1) and peptide YY (PYY), which have a special function in enteroendocrine signaling, by interacting with a matching receptor (such as GPR43 or GPR41) [26]. When these peptides are produced, the enteric and primary afferent vagal pathways, which regulate how energy balance is handled, are engaged. Notably, characteristics of propionate and N-neuroactive butyrate have also been found. This implies yet another potential method by which the gut microbiota affects human behavior [27]. Insomnia is a disorder characterized by difficulty falling asleep and poor sleep continuity and is associated with increased risks for physical and cognitive decline. Insomnia with short sleep duration is considered the most biologically severe phenotype of the disorder. Evidence suggests that short-chain fatty acids (SCFAs), the main byproducts of fiber fermentation in the gut, may affect sleep via gut–brain communications [23].


### 4.5. Tryptophan

Tryptophan is a necessary amino acid that the brain uses to make serotonin and other biologically active substances [28]. The majority of serotonin, which has been linked to depression, is made in the gut by the enterochromaffin cells of the GI tract. Serotonin biosynthesis depends on tryptophan availability and the tryptophan hydroxylase enzyme, which controls serotonin synthesis. Immune system changes have been linked to low plasma tryptophan levels [29]. The CNS may be significantly affected by the effects of tryptophan when paired with immune system activity, which could lead to the onset of mood disorders. Some probiotics may have the ability to alter the metabolism of tryptophan and lessen the severity of stress-induced sadness. Kynurenine is preferentially converted to kynurenic acid [30].


## 4.1. Vagus Nerve

The vagus or tenth (X) cranial nerve, which transmits sensory data between the central nervous system and the peripheral nervous system, serves as a direct conduit from the gut to the brain [16]. The central nervous system and gut bacteria communicate via the primary afferent channels that pass through the vagus nerve, according to the results of numerous research [17]. These findings suggest that one potential neurological mechanism behind these correlations is the activation of c-FOS in vagal sensory neurons and following vagotomies. Increased neuronal c-FOS mRNA and c-FOS expression have been proposed as markers of recent brain activation. It is interesting to note that visceral sensory nuclei in particular autonomic and brain regions had higher levels of c-FOS in pathogenic animals with Campylobacter jejuni and Citrobacter rodentium infections than noninfected animals did [9]. The vagal nerve pathway is thought to be involved in the transfer of gut immunological signals to the central nervous system, according to investigations on vagotomy performed on rats infected with Salmonella typhimurium to simulate the situation of a real bacterial infection. After cutting the vagal nerve pathway, there were fewer immune cells and reduced c-FOS expression in those neurons [18]. To create behavioral problem-solving therapy strategies, it may be helpful to understand the role of the vagal afferent pathways in mediating communication between the brain and gut bacteria.


## 4.2. Cell Wall Components and Immune Responses

Innate and adaptive immune systems in the host mucosa are stimulated by the peptidoglycan cell wall of bacteria. These pathogen-associated molecular patterns or these proinflammatory microbial components essentially cause the innate immune response to occur (PAMPs). When PAMPs interact with the pattern-recognition receptors (PRRs) on defense cells, inflammatory cytokines are produced. These cytokines can either directly or indirectly impact the brain via the permeable blood-brain barrier or peripheral vagal pathways [19]. The brain can be impacted by proinflammatory cytokines such as interleukin 6 (IL-6) and chemokine ligand 2 (CCL2), either through the humoral pathway, where PAMPs act on toll-like receptors (TLRs) in particular brain regions, or the neural pathway, where afferent nerves are involved. PAMPs linked to Gram-positive bacteria include lipoteichoic acids and peptidoglycan monomers. Intestinal epithelial cells may produce additional neural signaling molecules as a result of many of these cell wall constituents [20]. However, the gut microbiota has potent immunomodulatory effects on the mucosal and systemic immune systems, raising the possibility that it may do the same for cognition and behavior. Additional research is needed to verify these results.


## 4.3. Metabolites

The digestion and microbial fermentation of food and nutritional components produce metabolites, which can significantly affect immune responses and cognitive processes [21]. For instance, it has been shown that changing the composition of the gut microbiota may affect the availability and regulation of tryptophan and fatty acids. The immune system may interact with tryptophan and fatty acids to modify cellular immunological responses. These metabolites serve as important regulators of the gut-brain axis and prospective therapeutic targets, which considerably aid in maintaining human health [22].


## 4.4. Fatty Acids

High levels of fatty acids in the brain assist in controlling a number of activities, including neurotransmission, cell survival, and neuroinflammation [23]. Chemical messengers known as eicosanoids control immunological and inflammatory responses by influencing genes, producing cytokines, and altering membrane structure and function. Eicosanoids are also produced in part by dietary fatty acids [24]. Peroxisome proliferator-activated receptors are a subfamily of nuclear receptors, which have an impact on cellular development and functionality, and can bind to and be activated by fatty acids. Nuclear receptors called PPARs are involved in the transcription of genes. Different immune cells may bind to fatty acids in order to induce inflammation. Short-chain fatty acids, the main metabolic byproducts of gut bacteria, have strong anti-inflammatory capabilities. Acetate, isobutyrate, butyrate, hexonate, and propionate are produced by specific species of the microbiota’s Eubacterium, Faecalibacterium, Roseburia, Lactobacillus, Bifidobacterium, and Enterobacter [25]. It has been demonstrated that these fatty acids affect intestinal permeability, improve immune system performance, change lipoprotein profiles, and lower colonic pH. Additionally, short-chain fatty acids enhance the release of neuropeptides like glucagon-like peptide (GLP-1) and peptide YY (PYY), which have a special function in enteroendocrine signaling, by interacting with a matching receptor (such as GPR43 or GPR41) [26]. When these peptides are produced, the enteric and primary afferent vagal pathways, which regulate how energy balance is handled, are engaged. Notably, characteristics of propionate and N-neuroactive butyrate have also been found. This implies yet another potential method by which the gut microbiota affects human behavior [27]. Insomnia is a disorder characterized by difficulty falling asleep and poor sleep continuity and is associated with increased risks for physical and cognitive decline. Insomnia with short sleep duration is considered the most biologically severe phenotype of the disorder. Evidence suggests that short-chain fatty acids (SCFAs), the main byproducts of fiber fermentation in the gut, may affect sleep via gut–brain communications [23].


## 4.5. Tryptophan

Tryptophan is a necessary amino acid that the brain uses to make serotonin and other biologically active substances [28]. The majority of serotonin, which has been linked to depression, is made in the gut by the enterochromaffin cells of the GI tract. Serotonin biosynthesis depends on tryptophan availability and the tryptophan hydroxylase enzyme, which controls serotonin synthesis. Immune system changes have been linked to low plasma tryptophan levels [29]. The CNS may be significantly affected by the effects of tryptophan when paired with immune system activity, which could lead to the onset of mood disorders. Some probiotics may have the ability to alter the metabolism of tryptophan and lessen the severity of stress-induced sadness. Kynurenine is preferentially converted to kynurenic acid [30].


## 5. Neurotransmitters and Neuropeptides

Numerous bacteria produce neurotransmitters and neuropeptides, includingLactobacillus, Bifidobacterium, Escherichia, Enterococcus, and Trichuris [9]. Some of these include serotonin, brain-derived neurotrophic factor, and gamma-aminobutyric acid (GABA) (BDNF). Neurotransmitters, which are chemical messengers that communicate from one neuron to a target neuron, muscle cell, or gland cell, employ chemical synapses to do so [31]. Neurons can communicate with one another when neuropeptides are released into the brain, where they activate a number of unique receptors. One way in which neuropeptides differ from neurotransmitters is the fact that some of them seem to be connected to particular behaviors. The brain and behavior can be significantly impacted by changes to these two neural signaling molecules as depicted in Table 1.Table 1
Neurotransmitters and its mechanisms.
NeurotransmittersMechanismReferencesGABAThe primary inhibitory neurotransmitter of the central nervous system (CNS), GABA, is generated during the breakdown of glutamate. GABA is essential for controlling neuronal excitability. Anxiety and depression are two of the many chronic disorders whose pathogenesis has been linked to GABA system dysfunction. In culture, bacteria such asLactobacillus and Bifidobacterium species can convert glutamate to GABA. The capacity of L. rhamnosus to alter the central expression of GABA receptors in significant CNS brain regions in mice provides additional proof that it may be useful in the treatment of anxiety and depression. The fact that some of the behavioral and physiological changes brought on by L. rhamnosus require the vagus nerve has led to the revelation that there is a functional communication link between bacteria, the stomach, and the brain. According to certain theories, bacteria may alter the GABA system and so affect the chemistry of the brain.[32, 33]Brain-derived neurotrophic factor (BDNF)The central nervous system is supported by the neurotrophin (protein) BDNF, which also encourages the creation and differentiation of new neurons and synapses (CNS). It is generally known that BDNF plays a role in neuronal differentiation, survival, and the growth and plasticity of synapses. It has been demonstrated that a number of antidepressants, among other treatments, can increase BDNF expression in the brain. Chronic depression has been linked to low levels of BDNF. It is crucial to emphasize that BDNF mRNA and protein levels have been linked to the gut-brain axis. Pathogen-free mice have demonstrated that intestinal microbiota increases levels of hippocampal BDNF after receiving antibiotics and fecal transplants.Trichurismuris infection was observed to reduce the amounts of BDNF mRNA in the hippocampus in mice; however, treatment with B. longum caused the levels of BDNF to be restored to normal. It has been shown that oral antibiotic treatment of specific pathogen-free animals, colonization of GF BALB/c mice with NIH Swiss mice, promotes exploratory behavior and BDNF expression. Conflicting conclusions about BDNF and connections between BDNF levels and anxiety-like behaviors have been drawn from studies using GF mice. Researchers discovered a link between the drop in BDNF levels and the decrease in anxiety in Swiss Webster, NMRI, and BALB/c male mice. However, two additional studies utilizing Swiss Webster female mice showed that BDNF levels varied, exhibiting both increases and declines. In addition to strain and sex, it is probable that other hormonal and/or experimental factors will change how the gut flora affects BDNF. For instance, the hypothesis that a mouse’s reaction to stress is impacted by its estrous cycle may help to explain the observed differences in BDNF expression between male and female mice. The timing and order of behavioral tests, the housing conditions for GF mice, and other variables might have had an impact on the BDNF findings. In view of the function BDNF plays in neuroplasticity and neurological illnesses, additional research is required to examine the interactions between BDNF and other neurotrophins as well as the circumstances in which these growth factors are impacted by the microbiome.[34, 35]SerotoninSerotonin is a unique monoamine neurotransmitter and plays a critical role in controlling nearly all brain functions. Anxiety and depression are two neuropsychiatric illnesses that have links to serotonergic system disorders. A few of the causes of dysfunction include insufficient serotonin production, a deficiency in serotonin receptor sites, or a barrier that prevents serotonin from reaching the receptor sites. It is noteworthy that enterochromaffin cells in the GI tract create about 90% of serotonin. Escherichia and Enterococcus species, which are typically found in the gut, can also create serotonin. Additionally, gut microorganisms can encourage the creation of serotonin by interacting with enterochromaffin cells via short-chain fatty acids. The ability of the CNS to operate may be directly impacted by the gut microorganisms that regulate serotonin production. For instance, compared to control animals that had naturally colonized the area, male germ-free (GF) mice displayed increased levels of serotonin and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in the hippocampus. Furthermore, the plasma tryptophan concentrations were higher in the male GF mice, pointing to a putative humoral mechanism by which the gut microbiota may affect CNS serotonergic neurotransmission. Additionally, serotonin and 5-HIAA levels in adult GF mice were not increased by introducing bacteria from previously colonized animals into their microbiome.[36, 37]


## 6. Influence of the Microbiota-Gut-Brain Axis on Anxiety and Depression

Two of the most common mental illnesses are anxiety, which is defined as apprehension or fear, and depression, which affects more than 350 million individuals worldwide [38]. Due to their significant functional restrictions, people with certain mental health conditions are less able to work, which raises their annual health care costs and places financial strain on the public health care system. It is alarming how frequently people with these mental health issues either choose not to seek treatment or find that it is ineffective. Although the exact etiology of many illnesses is still unknown, there have been several postulated neurological reasons put forth. These reasons cover anything from infections, inflammation, and stress to anomalies in brain chemistry. As an illustration, research has connected anxiety and depression to changes in vital neurotransmitters, adjustments in neuroendocrine pathways and hormones (like cortisol), an increase in inflammatory cytokines (like IL-6), and circulating leukocytes in response to illness and inflammation. These dynamic and interrelated physiological processes can all be referred to as stress. The hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nerve system are two crucial biological responses to stress [39]. The programming and reaction of the stress system and commensal microbes in the gut are crucial to the current inquiry. Through autonomic, stress-related neuroendocrine and immunological pathways, the gut microbiota may aid in the treatment and prevention of anxiety and depression.


### 6.1. Microbes and Stress

Stopping stress reactions has substantial psychobiological impacts on the brain and behavior, even if mental stress is a vital component of existence. One example of a microbe that can benefit from host stress is the bacteriumE. coli. We call microbes like these as “stress microbes,” and the microbes that can provide resilience against stress, like some species of Lactobacillus, as “resilience microbes” because there is evidence that they affect our physiology in these ways, possibly for their own evolutionary benefit. According to research from a range of disciplines, including neurology and microbiology, psychological stressors can impair the body’s natural barrier defenses, including those given by commensal microorganisms. An innovative study showed, for instance, that putting mice in a cage without bedding, food, or water reduced the quantity of Lactobacilli that could be cultivated from the gastrointestinal system. Despite a number of experimental shortcomings, the negative impacts of creative housing were proposed as a plausible explanation (such as the paucity of food and water) [40]. This discovery, however, stimulated more investigation into the effects of psychological stressors on microbiological health. For instance, adolescent rhesus monkeys drastically reduced their levels of cultured Lactobacilli when given full access to food and water as well as the stressor of mother separation [41]. The monkeys with the most behavioral stress also had the fewest Lactobacilli that had grown, which is an interesting observation. The gut flora of adults who undergo chronic stress may change. Mice were subjected to a social disruption stressor [42] which increased innate immune reactivity and circulating cytokines. They discovered that mice exposed to the stressor had a microbiome that was different from control animals under no stress, with notable decreases in Bacteroides spp. and Clostridium spp. Additionally, as evidenced by increased blood levels of IL-6 and splenic macrophage susceptibility to microbial activation, mice exposed to the social stressor demonstrated heightened immunological and inflammatory responses. Mice given antibiotics or those modified through genetic engineering (GF) did not show an increase in circulating IL-6 and splenic responsiveness when exposed to the social disruption stressor, suggesting that the microbiota may be required for stressor-induced immune activation. According to an important work, where exposure to a mild restraint stressor led to an elevated synthesis of adrenocorticotropic hormone and corticosterone, GF mice exhibit a hyperactive HPA-axis response to stress [43]. This response could be somewhat reversed by colonizing with bacteria from control mice, and it could be fully reversed by colonizing with B. infantis. It was interestingly found that the elevated stress hormone response could be reversed by recolonization during a “critical window” of time [44]. This idea was reinforced by the fact that mature mice (9 weeks old) were unable to alter the heightened HPA-axis response (9 weeks of age). This critical window has received attention from research on GF mice and behavior, which also shows that microbiota regeneration should start early in life. When a specific pathogen-free microbiota was given to GF female mice after week 10, anxiety-like behaviors did not return, in contrast to when specific bacterial strains were given at birth and three weeks later [45]. Additionally, Hooks et al. showed that giving GF mothers a vaccine prior to childbirth completely reversed the stress response in adult offspring. Similar results were shown in mice that were exposed to a particular strain of bacteria within the first 100 days of life, which resulted in the reversal of asthmatic symptoms [46]. Further study is required to completely comprehend these crucial inoculation windows, which may also result in the creation of cutting-edge treatments for diseases brought on by stress.


### 6.2. Microbes and Human Behavior

Significant alterations in behaviors related to mood, pain, and cognition have been linked to changes in gut microbial makeup. In order to examine potential links between different gut microbial communities and IBDs and mental health problems, Collins et al. used GF animals. These findings show the major behavioral influence of the gut microbiome. In the elevated plus maze or light-dark box tests, GF rats no longer exhibit anxiety-like reactions [47]. These anomalies’ causes are not currently known. Anxiety levels have been associated to modifications in the pathogenic bacteria T. muris, C. rodentium, and C. jejuni.


## 6.1. Microbes and Stress

Stopping stress reactions has substantial psychobiological impacts on the brain and behavior, even if mental stress is a vital component of existence. One example of a microbe that can benefit from host stress is the bacteriumE. coli. We call microbes like these as “stress microbes,” and the microbes that can provide resilience against stress, like some species of Lactobacillus, as “resilience microbes” because there is evidence that they affect our physiology in these ways, possibly for their own evolutionary benefit. According to research from a range of disciplines, including neurology and microbiology, psychological stressors can impair the body’s natural barrier defenses, including those given by commensal microorganisms. An innovative study showed, for instance, that putting mice in a cage without bedding, food, or water reduced the quantity of Lactobacilli that could be cultivated from the gastrointestinal system. Despite a number of experimental shortcomings, the negative impacts of creative housing were proposed as a plausible explanation (such as the paucity of food and water) [40]. This discovery, however, stimulated more investigation into the effects of psychological stressors on microbiological health. For instance, adolescent rhesus monkeys drastically reduced their levels of cultured Lactobacilli when given full access to food and water as well as the stressor of mother separation [41]. The monkeys with the most behavioral stress also had the fewest Lactobacilli that had grown, which is an interesting observation. The gut flora of adults who undergo chronic stress may change. Mice were subjected to a social disruption stressor [42] which increased innate immune reactivity and circulating cytokines. They discovered that mice exposed to the stressor had a microbiome that was different from control animals under no stress, with notable decreases in Bacteroides spp. and Clostridium spp. Additionally, as evidenced by increased blood levels of IL-6 and splenic macrophage susceptibility to microbial activation, mice exposed to the social stressor demonstrated heightened immunological and inflammatory responses. Mice given antibiotics or those modified through genetic engineering (GF) did not show an increase in circulating IL-6 and splenic responsiveness when exposed to the social disruption stressor, suggesting that the microbiota may be required for stressor-induced immune activation. According to an important work, where exposure to a mild restraint stressor led to an elevated synthesis of adrenocorticotropic hormone and corticosterone, GF mice exhibit a hyperactive HPA-axis response to stress [43]. This response could be somewhat reversed by colonizing with bacteria from control mice, and it could be fully reversed by colonizing with B. infantis. It was interestingly found that the elevated stress hormone response could be reversed by recolonization during a “critical window” of time [44]. This idea was reinforced by the fact that mature mice (9 weeks old) were unable to alter the heightened HPA-axis response (9 weeks of age). This critical window has received attention from research on GF mice and behavior, which also shows that microbiota regeneration should start early in life. When a specific pathogen-free microbiota was given to GF female mice after week 10, anxiety-like behaviors did not return, in contrast to when specific bacterial strains were given at birth and three weeks later [45]. Additionally, Hooks et al. showed that giving GF mothers a vaccine prior to childbirth completely reversed the stress response in adult offspring. Similar results were shown in mice that were exposed to a particular strain of bacteria within the first 100 days of life, which resulted in the reversal of asthmatic symptoms [46]. Further study is required to completely comprehend these crucial inoculation windows, which may also result in the creation of cutting-edge treatments for diseases brought on by stress.


## 6.2. Microbes and Human Behavior

Significant alterations in behaviors related to mood, pain, and cognition have been linked to changes in gut microbial makeup. In order to examine potential links between different gut microbial communities and IBDs and mental health problems, Collins et al. used GF animals. These findings show the major behavioral influence of the gut microbiome. In the elevated plus maze or light-dark box tests, GF rats no longer exhibit anxiety-like reactions [47]. These anomalies’ causes are not currently known. Anxiety levels have been associated to modifications in the pathogenic bacteria T. muris, C. rodentium, and C. jejuni.


## 7. The Gut Microbiota, Clock Genes, and Sleep

The gut microbial population changes throughout time in terms of both composition and function. People with depression, for instance, often experience milder symptoms at night and severe ones in the morning. Shift workers exhibit depressive symptoms far more frequently than other workers. Depressive episodes are commonly associated with sleep issues [48].Microbes and circadian genes are closely related [49]. The disruption of the host circadian cycle has an immediate effect on the balance of gut bacteria. These changes resemble those that come after real-shift employment. The body’s biological clock and the microbial clock also work together. According to Thaiss et al., the gut microbiota population and functions in Per1/2/mice lost their circadian regularity [50]. Brooks et al.’s study found that due to the deletion of the clock gene Bmal1, mice’s fecal microbiota significantly changed in rhythmicity with regard to the total load and taxonomic abundance [51]. These results suggest that variations in host clock genes like Bmal1, Per1, and Per2 are directly associated to changes in intestinal microbiological cycles. The host’s metabolism may be profoundly impacted by the interaction between the circadian clock and the microbiota. The host microbiota influences the circadian transcription factor NFIL3, which boosts host metabolism, according to recent research. This finding might help to explain why those who work shifts and frequently suffer jet lag have a greater frequency of metabolic syndrome [52]. The microbiota may also have an effect on the suprachiasmatic nucleus (SCN), which regulates the expression of the host clock genes. As an animal model for the lack of microbiota, germ-free (GF) mice are used. There are differences in the microbiological basis, anatomical and morphological traits, metabolic metabolism, immune system, and biological cycles between GF animals and conventional experimental animals. GF mice are therefore superior study models for examining the impact of gut flora on host brain function [53]. The expression of circadian clock genes oscillates less in GF mice, according to Frazier et al. [54]. Intestinal dysbiosis might be facilitated by clock gene mutations. According to results by Song et al., intestinal stimulation from food increased the gut microbiome dysbiosis that caused the core clock gene mutations in mice [55]. The facts described above reveal that, in addition to controlling the host clock gene regulation network, gut bacteria can also induce a variety of pathogenic metabolic illnesses, highlighting the critical function gut bacteria play in guaranteeing the consistent expression of host clock genes [56].Numerous studies have demonstrated that hyperactivation of the HPA axis, which can interfere with sleep and is also a key factor in the development of depression, has an impact on clock gene polymorphisms in depressive patients. There is considerable doubt that the circadian clock genes greatly influence the development of sleep issues including insomnia. Preclinical studies have also shown that clock gene mutations may be the source of the irregular sleep patterns experienced by people with affective disorders. Patients with depression have abnormal expression of the clock gene, which results in clinical symptoms that mirror jet lag [57]. Dopamine is a key neurotransmitter with genes associated with the circadian clock that has been linked to depression. For example, dopamine release in the striatum was increased when the CLOCK protein was inactive and the dopamine-related gene expression in the ventral tegmental region drastically modified in CLOCK knockout animals. Additionally, the clock gene’s expression in specific brain regions may be altered by environmental factors and epigenetic control [58].


## 8. Clinical Application

In conclusion, the human circadian cycle and the rhythm of the microbiome interact in a reciprocal manner. A balanced gut flora is necessary for regulating the circadian cycle, controlling cortisol levels, and producing vital neurotransmitters for sleep. Circadian rhythm disruption may cause intestinal dysbiosis. The treatment of insomnia requires an all-encompassing strategy that includes dietary and mineral supplementation as well as lifestyle modifications [59]. In addition, studies have shown that herbal and homeopathic remedies can successfully change how the nervous system functions.
(i)
Getting the best sleep: techniques that recognize and address issues with intestinal permeability and dysbiosis(ii)
Eat foods that are high in probiotics and prebiotics. Supplement your diet with prebiotic and probiotic products(iii)
Utilize vitamins to target the nervous and digestive systems in particular(iv)
Sleeping well: a room should be completely dark, with the temperature adjusted between 60 and 68 degrees Fahrenheit, for sleeping.(v)
Before going to bed, turn off the Wi-Fi or place your phone on airplane mode. At night, lower the lighting in your house(vi)
Exercise can increase serotonin levels and the variety of gut bacteria. Create dependable routines. Unpredictable schedules can cause both emotional and physical problems. You should begin your day with a self-care routine in the morning and unwind quietly in the evening with prayer, meditation, or soothing music(vii)
Establish a regular thinking schedule, heal any emotional scars from the past, and employ practical strategies to manage distracted ideas all day(viii)
Be thankful and positive at all times


## 9. Conclusion and Future Directions

Research on the effects of sleep deprivation and circadian misalignment on rodent and human health has increased during the past 20 years. A growing amount of research suggests that good, sufficient sleep; having positive emotions; and maintaining gut-microbiota balance are all important components of a bidirectional system. This is because high-throughput sequencing technologies for analyzing microbiota are now more widely available.In conclusion, changing gut microbiomes has a major impact on the development of mental illnesses including depression and sleeplessness. It is crucial to identify cutting-edge research techniques that can be applied to better comprehend the mechanism underlying this link. The issues listed below need to be resolved [60]. We should think about how probiotics affect the balance of the gut microbiota and look into how different probiotics work alone and together to provide different therapeutic benefits [61]. Given recent research showing that some gut bacteria have circadian rhythms and are susceptible to melatonin, the frequency and timing of stool sample collection are very essential. In order to find the ideal times and frequencies for sample collection, a future study should ascertain how samples collected at various times of the day differ from one another. These studies ought to clarify the progression of alterations in the composition and organization of the gut microbiota after the commencement of a circadian rhythm disruption [62]. We need to look at how much disturbed sleep habits can affect the equilibrium of the flora in the gut. It is crucial to comprehend the differences in gut microbial activity and composition between acute and chronic insomnia [63]. It is crucial to understand the complex relationships between insufficient sleep, irregular circadian rhythms, mood disorders, food energy intake, and gut flora. Given these factors, it will be crucial to distinguish between restricted intake and ad libitum feeding, particularly when shift employment affects sleep and waking opportunities. Controlled environments that closely resemble shift work could be employed for human studies to begin examining these connections. Because they provide the higher sample sizes necessary to detect changes when lifestyle parameters like calorie intake and sleep patterns are not held constant, cohort studies will be critical in evaluating the consequences of continued shift employment in real-world situations [64]. It is crucial to look into how changes in the gut’s microbial population affect the cycles of depression and sleep. These results will aid in making rational decisions about when to administer drugs for the treatment of mental diseases including depression and insomnia. It will also assist in reducing negative drug reactions while enhancing the medicinal advantages of pharmaceuticals [65]. An individual-level randomized, double-blind clinical trial may be employed to reduce the interference and perplexing bias that human subjective elements contribute to test outcomes. This investigation will allow for the evaluation of the efficiency of intestinal flora-targeted insomnia treatments.



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