**7. Role of microbiota-gut-brain axis in neurological and psychiatric diseases**

Changes in the microbial environment, as a result of different stressors, are linked with alterations of barrier, motility and activation of the immune system. Perturbation of this axis lead to changes in the stress-response and behavior, which are thought to be involved in several CNS diseases, such as anxiety, depression autism, Parkinson's disease and Alzheimer's disease [97].

Neuropsychiatric comorbidity, including depression and anxiety, is common finding in patients with a functional GI disorder such as the IBS and it reaches 60% of this somatic pathology. On the other hand, IBS has also been related with changes in the gut microbiota including reduced diversity and temporal instability at the genus level. It is interesting to note that behavioral and psychological changes are often present in patients with active celiac disease, which are associated with findings of regional cerebral hypoperfusion in their brains [25, 98].

Some recent works reported for changed expression of GABA A receptor and its B subunits, responsible for the primary inhibitory brain mediation [73, 99, 100], subunits of NMDA receptors, realizing excitatory neurotransmission [101], concentration of serotonin 1A and tryptophan. Some of the above mentioned alterations corresponded with disturbed emotional behavior, which supports the interaction between microbial composition and behavior [1, 8].

In recent years evidence has emerged that neurodegenerative diseases (NDs) are strongly associated with the microbiome composition in the gut [101, 102].

## **7.1 Role of microbiota-gut-brain axis in mood disorder**

A "leaky gut" is suggested to play a pathogenic role in depression. There are evidences for altered intestinal permeability in patients with mood disorder and their first degree relatives [18]. For most of the depressed patients the brain-gut axis function is impaired, including imbalance in brain neurotransmitters, decline of brain neuroplasticity, dysfunction of hypothalamic-pituitary-adrenal axis, chronic periphery inflammation and neuroinflammation, as well as gastrointestinal diseases and gut microbiota dysbiosis [103]. However, the impact of depression on the microbiota has not yet been studied [25].

Wong et al. proposed that suppression of caspase-1 plays a protective role in modulation of the interaction between representatives of the intestinal microbiota and the state of stress. They reported the importance of signals from inflammasome along the gut microbiota-inflammasome-brain axis which attribute to modification of cerebral processes, especially for manifestation of anxiety-depressive symptoms [3, 87].

Acute tryptophan depletion (ATD) in subjects suffering from depression, was preceded by bimodal emotional processing, corresponding with bimodal manifestation of the clinical symptom. It was proved in a small patient's cohort where the alleviation of depressive symptoms occurred 24 h after ATD and the mood processing was at the better level about 5 h after depletion. The opposite processes were registered in patients who experienced worsening of the depressive symptoms [2, 104].

Serotonin is a key element of this axis, acting as a neurotransmitter in the CNS and in the ENS, located in the gut wall. This transmitter is formed in neuroendocrine cells and plays a role of paracrine hormone in the intestine. Serotonin is also an endocrine hormone which passes into the blood and bind to the platelets. Besides its system effects like maintaining the bone density and participation in metabolite processes, it performs a key connection between both ends of the gut-brain axis [105]. It is interesting that most of the serotonin is produced at the periphery predominantly in the tGI epithelium, but also in bones, breast and pancreas. Only 5% of its synthesis is realized at central level. The only difference in ways of serotonin synthesis is the use of tryptophan hydroxylase type 1 in peripheral mechanism and instead of it-type 2-in the central one [105]. The reversal process of serotonin degradation is performed with the help of monoamine oxidase and aldehyde dehydrogenase to 5HIAA both in the periphery and in the CNS [2, 96, 106].

#### *7.1.1 Microbiota-gut-brain axis in major depression*

Major depression disorder (MDD) is an incapacitating multifactorial psychiatric disease, which is characterized by a range of symptoms affecting both emotional and cognitive domains [107]. The hypothesis of activated peripheral blood monocytes and T lymphocytes is well known [18]. Another supposed mechanism is impaired excitation/inhibition balance that is potentially mediated by the reduced amount of GABA. The low concentration of brain-derived neurotrophic factor has been proposed as a unifying hypothesis for reduced cell numbers in frontal cortex and amygdala and also for reduced hippocampal volume. Despite the great advances in the knowledge of this disease, its etiology and pathophysiology are still not fully understood [108].

It is important that metabolites as hippurate, dimethylamine and dimethylglycine derived from the blood of patients with MDD are actually products of their intestinal microbiota [109]. Similar to findings in animal experiments in depression, limited number of studies in humans with small cohorts found changes of the gut microbiota strains [25, 110]. All this trials proposed the potential relationship between the alteration of gut microbiota composition and MDD manifestation [18].

Significant difference in the isolated bacteria from stool samples of 58 Chinese subjects, diagnosed with major depression compared to 63 healthy individuals was found. Y.

The following three main bacterial phyla are specific for the gut microbiota of depressed subjects: Firmicutes, Actinobacteria and Bacteroidetes. Depression behavior models were created through transplantation of stool samples taken from five subjects with depression into germfree mice. And vice versa, transplantation of feces from five healthy individuals did not lead to behavioral effect. Mice receiving microbiota from patients with depression showed disturbances in hippocampal gene activation and also in carbohydrate and amino-acid metabolism [16, 109]. This study provided convincing evidence that the depressive phenotype could be transferred by transplantation of the microbiota.

Kelly et al. recruited 34 patients with major depression and 33 healthy individuals with similar demographics. Plasma levels of cytokines, C-reactive protein, salivary cortisol and plasma lipopolysaccharide-binding protein were determined by ELISA, and showed alterations supporting a proinflammatory phenotype linked with depression. Depression was associated with decreased gut-microbiota richness and diversity. A fecal microbiota transplant was prepared from a subgroup of patients with depression or from healthy individuals and transferred by oral gavage to a microbiota-deficient rat model [114].

But further research in larger samples and unified MDD populations is required to confirm whether disturbances in gut microbiota have a causative role for the onset of MDD.

### **7.2 Microbiota-gut-brain axis in autistic spectrum disorders (ASD)**

During the early onset of this developmental disorder an autistic enterocolitis and changes in intestinal permeability occur [111]. Moreover, urinary metabolic phenotyping has determined biochemical changes that were consistent with abnormalities in the composition of the gut microbiota, found in autistic children.

Recent studies suggest that changes in antigenic load due to the impairment of gut barrier function is triggering factor for clinical manifestation of autism [112]. Desbonnet et al. are the first scientists who found that microbiota are crucial for the programming and presentation of distinct normal social behaviors, including social motivation and preference for social novelty, while also being important regulators of repetitive behaviors. Taking into account that these aspects of behavior are impaired in neurodevelopmental disorders such as schizophrenia and autism [5] and with a male preponderance, these data extend our knowledge regarding the genesis of neurodevelopmental disorders of altered sociability. A better understanding of the underlying mechanisms of these social deficits, which may include modulation of immune cell cytokines release, changes in vagal nerve activity and neuroendocrine function, can help for developing of innovative and more effective strategies in managing of these social disturbances [76].

A study of Kang et al. revealed less abundance of Bifidobacteria species and the mucolytic bacterium *Akkermansia muciniphila* in children with autism [114–116]. Other experiment showed less diverse gut microbial composition with lower levels of *Prevotella*, *Coprococcus*, and unclassified *Veillonellaceae* in ASD [117]. Another study showed a significant increase in several mucosa-associated Clostridiales, whereas a decrease in Dorea, Blautia and Sutterella was seen in AUTISM-FGID [118].

#### **7.3 Microbiota-gut-brain axis in Alzheimer disease**

Alzheimer disease is a progressive neurodegenerative illness associated with accumulation of proteinaceous misfolded amyloid-b (Ab) fibrils and oligomers,

#### *Behavioral Neuroscience*

together with neurofibrillary tangles consisting of hyperphosphorylated tau protein in the cerebral cortex and other brain regions [118]. Recent research indicates that alterations of the gut microbiome could activate proinflammatory cytokines and increase intestinal permeability, leading to insulin resistance, which has also been found in AD [119].

Bacterial representatives of the gut microbiome excrete lipopolysaccharides (LPSs) and amyloids. These products lead to forceful pro-inflammatory and innateimmune effects, activate the system Following enhanced amyloid aggregation, as well secondary degeneration occur, which are typical signs of AD, together with impaired cleansing mechanisms of Aβ peptide [17, 120, 121]. It has been suggested that diet and specific nutrients could alert the composition of the intestinal microbiota and might influence the production or aggregation of amyloid proteins [29, 114, 122].
