**4. Microbiome and human mental health**

The metabolism of tryptophan via the kynurenine pathway leads to the formation of kynurenine and its neuroactive metabolites, such as 3-hydroxykynurenine, kynurenic acid, quinolic acid, and xanthurenic acid. The involvement of kynurenine and its metabolites in the pathogenesis of depressive disorders and schizophrenia is being studied [43]. For example, in patients with schizophrenia, an increased concentration of 3-hydroxykynurenine in the blood was measured. It is important to note that after targeted treatment, the level of this metabolite was normalized. This fact indirectly confirms the initial violation of tryptophan metabolism along the kynurenine pathway in schizophrenia [44].

According to the 2016 report, "The Five Year Forward View for Mental Health," from the independent Mental Health Taskforce to the NHS in England, mental disorders in the modern world affect every fourth person on the planet [45], which is a serious justification for the search for new mechanisms of the influence on mental status, including by studying and correcting the microbiome.

A clinical study examined how the gut microbiota and its associated metabolites were changed in sleep disorders in children with autism spectrum disorders (ASD). There was a decrease in the abundance of *Faecalibacterium* and *Agatobacterium*, a decrease in 3-hydroxybutyric acid and melatonin, and an increase in serotonin levels. These changes can worsen sleep problems and major symptoms in children with ASD [46].

Some studies have reported interesting correlations between severity of behavioral and gastrointestinal symptoms; others have demonstrated potential benefits of probiotics in correcting dysbiosis and reducing the severity of ASD symptoms. The general conclusion of these studies is that future research based on more randomized controlled studies with larger population sizes and standardized use of strains, concentration of probiotics, duration of treatments, and methods of DNA extraction is needed in this area, which may lead to more robust results [47].

According to the World Health Organization, mental disorders are quite common even in people who lead a seemingly normal lifestyle [48]. At the same time, new evidence suggests that less than 10 percent of mental and neurodegenerative diseases have a strict genetic etiology. Other predisposing and concomitant factors, such as stress, environmental exposures to potentially toxic elements, and other factors may influence neurometabolism, which may increase the risk for depression, autism, sclerosis, PD, and AD [49, 50]. Among these factors, an important place is occupied by the gut–brain microbiome relationship at the level of metabolomic connections, which allow us to conceptually rethink the causes and mechanisms of mental health disorders. Possibly in some categories of people with predisposition, the metabolic activity of the gut microbiome may affect not only the development, but also the severity of depressive disorder [51].

## **5. Microbiome and inflammatory events after stroke**

The gut inflammatory and immune response can play a key role in the pathophysiology of severe course and development of complications after stroke. This can be judged by studying the mechanisms that occur in the brain when damaged. Proinflammatory T cells are often associated with increased inflammatory damage, but research of the gut inflammatory and immune response after stroke is still in its initial stage [52]. It would be crucial to understand which metabolites from the gut

microbiome may affect the degree of brain damage, stroke outcome, and concomitant post-stroke diseases.

An experimental stroke model of GF mice clearly demonstrated the role of microbiota. When the mice were recolonized using a dysbiotic post-stroke microbiota, an increase in the volume of brain damage and functional deficit was observed [53]. In another experimental study, after the use of a cocktail of antibiotics in animals, a significant decrease in the volume of the heart attack in the acute phase of stroke was observed. The neuroprotective effect was varied depending on the type of antibiotic and correlated with the specific microbial population, rather than with the overall bacterial density. In particular, a link was found between the large and small size of a brain infarction and the enzymatic pathway of the aromatic metabolism in certain strains of *Bacteroidetes* [54].

In clinical pilot research, which included patients with severity of neurologic deficit, the taxonomic composition of the gut microbiota using real-time polymerase chain reaction (PCR) was studied. Correlation analysis revealed some connection between microbiology and clinical and laboratory indicators, for example, strong negative correlations between Glasgow coma scale scores and the abundance of *Enterococcus* spp. (r = −0.77, p < 0.05). It is interestin that statistically significant negative correlations between cortisol levels and the abundance of *B. thetaiotaomicron* or *F. prausnitzii* (*r* = − 0.57, *r* = − 0.62, respectively) were detected only in patients in a vegetative state [55].

Many authors report dysbiosis in stroke patients [56–58]. Some authors associate the dominance of SCFA producers, such as *Akkermansia*, *Odoribacter*, *Ruminococcaceae*, and *Victivallis*, with positive clinical outcomes, while the genus *Enterobacter* had significantly negative correlation with the dynamics of neurological status [56]. At the same time, in another study, *Akkermansia* was reduced in patients with cerebral infarction compared with a group of healthy people (p < 0.05) [57].

Pluta et al. [58] presented taxonomic findings in stroke patients. The authors launched an active discussion and tried to find explanations for the metabolic features of various genera and types of microbes, which, according to various data, dominated in the gut of stroke patients. For example, *A. muciniphila* uses mucin to produce acetate, which can be used by other bacteria, such as bacteria from the Ruminococcaceae and Odoribacter families, to produce butyrate [59]. However, despite many studies in this direction, significant differences and even sometimes contradictions of taxonomic findings lead us to conclude that the available information is not enough to form a coherent hypothesis.

It should be noted that the data on the taxonomic composition of the gut microbiota in most studies were obtained by examining samples from patients in the early stages (first and second day) after a stroke. The study of the composition of the gut microbiota in patients with a complicated course after stroke is even more relevant. These patients need intensive care for a long time due to the development of socalled chronic critical illness (CCI) [60]. Loss of microbial diversity and pathogen domination of the gut microbiota has been noted in such patients [61]. Significant differences were found for four genera: *Prevotella*, *Klebsiella*, *Streptococcus*, and *Clostridium XI* [62], which were previously mentioned in connection with some neuropsychiatric disorders [63, 64].

The interrelation of factors influencing the development of a CCI as a result of long-term violation of the functions of the brain and the gut microbiota has been studied [15]. The results confirm the association of taxonomic composition and profile of certain aromatic metabolites of the gut microbiota with the progression or reversibility of neurological disorders in CCI patients. A gross imbalance of microbial metabolism contributes to the formation of general metabolic dysfunction of the human body (**Figure 2**).

**35**

**6. Conclusion**

**Figure 2.**

*"Dialogue" between the Human Microbiome and the Brain*

It is important to remember that microbial diversity and composition of the microbiota can be influenced by many personal and environmental factors (diet, infection, concomitant diseases, use of antibiotics and other medications, social stress, etc.), which can significantly affect the microbiota–gut–brain axis at all stages of life [65]. This fact should be considered in the future when developing

*Post-stroke complications and mechanisms of chronic critical illness are closely related to taxonomy disorders* 

Due to growing interest in the human microbiome and rapid development of diagnostic technologies, the taxonomy of the gut microbiota in various diseases and disorders of the brain is quickly accumulating. Most researchers are coming to a common understanding of the importance of the communication between the human microbiome and the brain and are investigating binding small molecules as biomarkers and pathophysiological effects. Soon, the significance of particular microbial metabolites in the human metabolome will be evaluated in more detail. Figuratively speaking, this will allow us to master the "language" of the "dialogue" between the microbiome and the brain. Already, many researchers would like to consider the gut microbiota as a new therapeutic target, including for the treatment of brain diseases, stroke prevention, reduction of neuroinflammation and more

methods to correct the dysfunction of the microbiota.

*and metabolic dysfunction in the gut microbiota.*

successful neurorehabilitation of patients.

*DOI: http://dx.doi.org/10.5772/intechopen.94431*

*"Dialogue" between the Human Microbiome and the Brain DOI: http://dx.doi.org/10.5772/intechopen.94431*

**Figure 2.**

*Human Microbiome*

tant post-stroke diseases.

metabolism in certain strains of *Bacteroidetes* [54].

tion is not enough to form a coherent hypothesis.

neuropsychiatric disorders [63, 64].

the human body (**Figure 2**).

patients in a vegetative state [55].

microbiome may affect the degree of brain damage, stroke outcome, and concomi-

In clinical pilot research, which included patients with severity of neurologic deficit, the taxonomic composition of the gut microbiota using real-time polymerase chain reaction (PCR) was studied. Correlation analysis revealed some connection between microbiology and clinical and laboratory indicators, for example, strong negative correlations between Glasgow coma scale scores and the abundance of *Enterococcus* spp. (r = −0.77, p < 0.05). It is interestin that statistically significant negative correlations between cortisol levels and the abundance of *B. thetaiotaomicron* or *F. prausnitzii* (*r* = − 0.57, *r* = − 0.62, respectively) were detected only in

Many authors report dysbiosis in stroke patients [56–58]. Some authors associate the dominance of SCFA producers, such as *Akkermansia*, *Odoribacter*, *Ruminococcaceae*, and *Victivallis*, with positive clinical outcomes, while the genus *Enterobacter* had significantly negative correlation with the dynamics of neurological status [56]. At the same time, in another study, *Akkermansia* was reduced in patients with cerebral infarction compared with a group of healthy people (p < 0.05) [57]. Pluta et al. [58] presented taxonomic findings in stroke patients. The authors launched an active discussion and tried to find explanations for the metabolic features of various genera and types of microbes, which, according to various data, dominated in the gut of stroke patients. For example, *A. muciniphila* uses mucin to produce acetate, which can be used by other bacteria, such as bacteria from the Ruminococcaceae and Odoribacter families, to produce butyrate [59]. However, despite many studies in this direction, significant differences and even sometimes contradictions of taxonomic findings lead us to conclude that the available informa-

It should be noted that the data on the taxonomic composition of the gut microbiota in most studies were obtained by examining samples from patients in the early stages (first and second day) after a stroke. The study of the composition of the gut microbiota in patients with a complicated course after stroke is even more relevant. These patients need intensive care for a long time due to the development of socalled chronic critical illness (CCI) [60]. Loss of microbial diversity and pathogen domination of the gut microbiota has been noted in such patients [61]. Significant differences were found for four genera: *Prevotella*, *Klebsiella*, *Streptococcus*, and *Clostridium XI* [62], which were previously mentioned in connection with some

The interrelation of factors influencing the development of a CCI as a result of long-term violation of the functions of the brain and the gut microbiota has been studied [15]. The results confirm the association of taxonomic composition and profile of certain aromatic metabolites of the gut microbiota with the progression or reversibility of neurological disorders in CCI patients. A gross imbalance of microbial metabolism contributes to the formation of general metabolic dysfunction of

An experimental stroke model of GF mice clearly demonstrated the role of microbiota. When the mice were recolonized using a dysbiotic post-stroke microbiota, an increase in the volume of brain damage and functional deficit was observed [53]. In another experimental study, after the use of a cocktail of antibiotics in animals, a significant decrease in the volume of the heart attack in the acute phase of stroke was observed. The neuroprotective effect was varied depending on the type of antibiotic and correlated with the specific microbial population, rather than with the overall bacterial density. In particular, a link was found between the large and small size of a brain infarction and the enzymatic pathway of the aromatic

**34**

*Post-stroke complications and mechanisms of chronic critical illness are closely related to taxonomy disorders and metabolic dysfunction in the gut microbiota.*

It is important to remember that microbial diversity and composition of the microbiota can be influenced by many personal and environmental factors (diet, infection, concomitant diseases, use of antibiotics and other medications, social stress, etc.), which can significantly affect the microbiota–gut–brain axis at all stages of life [65]. This fact should be considered in the future when developing methods to correct the dysfunction of the microbiota.
