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The current state of knowledge on the link between the human microbiome and some neuropsychiatric disorders.

INTRODUCTION

Neuropsychiatric disorders are considered multifactorial disorders that can be caused by developmental processes influenced by the complex interaction of genetics with individual experience. The bacterial organisms that live on Earth overcome all of the others together. Microbes do not just dominate the planet, but human body too, being around 100 million microorganisms in the gastrointestinal tract (1) and exceeding 150 times the human genome (2).

Microbiome varies from birth, as babies born naturally are covered with microbes such as bifidobacteria and lactobacilli, Bacteroides, Proteobacteria or Actinobacteria, while those which come to the world through caesarean surgery are covered by microbes that normally exist on the skin of adults like E.coli, Clostridium difficile to the detriment of those mentioned above (3).

It is estimated that the thousands of billions of microbes living in adult human body weighing almost 1 kilogram in total (4). Most of them live in the intestines, about 99%, with the highest density up to 10 12per ml (5) and their destruction can have unpleasant consequences, such as obesity, diabetes, anxiety, autommune- diseases or the development of bowel deficits (6).

THE DYNAMICS BETWEEN MICROBIOME AND THE HUMAN BODY

The intestinal microbiota reconfigures the boundaries of knowledge. The interaction between the organism and the intestinal microbiota is bidirectional. Based on a millenary evolution, the microbiota functions as an independent ecosystem that constantly interacts with the digestive, immune and nervous system of the human body. (7) The guts of the intestinal microbiota are diverse, most commonly mentioned being the mechanically and biologically active barrier designed to protect the body from infectious aggression at this level, especially through the production of short chain fat acids and stimulation of epithelial regeneration (8).

Microbiota also interferes in the maturation of the immune system, helping to develop the lymphoid tissue associated with the intestine. Continuous stimulation of the immune system maintains a physiological level of inflammation at a low level, which helps to better protect against other microorganisms (9). Protection against various pathogens can also be accomplished by consuming microorganisms that form the microbiota of compounds that pathogens could use for multiplication (10).

Another important role of intestinal microbiota is the production of different substances and vitamins, being the main source of vitamins in complex K of the human body, and vitamin B (11). By producing substances such as dopamine, serotonin or other neurotransmitters, the intestinal microbiota can also act remotely. For these reasons, studies suggested a possible link between intestinal dysbiosis and autism-like disorders (12). At the same time, the intestinal microbiota interferes with the metabolism of bilirubin and bile acids, the enterohepatic circuit of all these products being closely related to the normal functioning of the saprophytes involved in the intestinal metabolism of the respective products (13).

The intestinal microbiota also interferes with the metabolism of certain substances, such as drugs. In this regard, a study was carried out comparing the level of certain liver enzymes involved in drug metabolism in laboratory mice grown in germ-free medium and those grown under normal conditions, with results indicating lower values for those in the first group. In another stage of the study, mice grown in microorganism-free environment were bacterially colonized and 20 days later it has been observed that even in them the level of liver enzymes has increased (14). At the intestinal microbiota level, some drugs are activated, such as sulfasalazine, some are reactivated after inactivation by the liver, such as irinotecan, while others are inactivated, such as digoxin. The consistency of the microbiota may be influenced by the consumption of various xenobiotics, antibiotics or proton pump inhibitors (13) for which there are studies that indicate association with irritable bowel syndrome or Clostridium difficile infections.

The modification of the microbiota, alteration of the intestinal mucosal structure, aging (15) could lead to a progressive leakiness of the blood-brain-barrier (16), which, corroborated with parietal intestinal inflammation and excessive stimulation of the immune response, determine the initiation of pathological processes with multiple local and systemic repercussions: intestinal, hepatic diseases, metabolic disorders, type 2 diabetes complications such as pigmentary retinopathy, kidney toxicity, hypertension, diabetic foot (17). Stress also increases the permeability of gut allowing bacteria intigens to cross the bowel barrier causing inflammation (18).

INFLUENCERS OF THE MICROBIOME AND GUT-BRAIN REGULATION

Studies have shown that various factors controlled by the body more or less, can in some way influence the microbioma. People who are still exposed to childhood food imbalances or environmental stressors can lead to bad gene changes (19). Also, factors like culture or ethnicity can influence microbiome (20).

Based on metagenomic assays, Prevotella, Bacteroides and Ruminococcus spp. are predominant in the healthy human intestinal community. In animal and human studies that looked at the correlation between microbiome and obesity, it was found that obese individuals had a low microbial diversity, a high percentage of Firmicute and Actinobacteria, and a low percentage of Bacteriodes, Verrucomicrobia and Faecalibacterium prausnitzii.

Studies have also shown that food intake significantly influences the composition of the microbe. Thus, it has been found that people whose faeces contain more Prevotella tend to consume more fiber, (21) whereas those predominantly Bacteroides tend to consume more protein and fat. (22)

At the same time, studies have shown that there is less change in vegetarians in terms of the abundance of bacterial species in the intestines than in those who have a diet based on protein and animal fats. This could be justified by the fact that people produce bile acids in response to the consumption of animal products and bile acids, in turn, affecting the development of bacteria. (23) It has been observed that the composition of the microbiome suffers seasonal fluctuations. Thus, during the summer, the ratio of Bacteroidetes increased and the ratio of Actinobacteria and Firmicute decreased, which can be attributed to the consumption of fresh fruits and vegetables. (24)

These results demonstrate that intestinal microbiome can respond rapidly to dietary changes and that a understanding the mechanisms that influence the bacterial balance can lead to the use of individualized diets as a means of modulating bacterial microflora for prophylaxis or treatment for a wide range of conditions.

A study published in 2015 in the journal Nature found another mechanism by which intestinal microbes could influence human physiology. That study has shown that ingredients in the food industry known as emulsifiers cause changes in the intestinal microbiome that lead to more inflammation associated with inflammatory bowel disease and metabolic syndrome.

Although the genetic baggage can not be altered, the microbiome can be modified through diet, probiotics and prebiotics. Besides the positive effects of probiotics such as fermentation and absorption of carbohydrates, the important source of vitamin K and B, the elimination of carcinogenic elements, they filter and eliminate harmful organisms like bacteria, toxins, chemicals and other residues (25).

There are also studies that have favorable outcomes related to the effects of probiotics on certain psychiatric disorders such as anxiety, autism, depression and schizophrenia (26), neurogastroenterological studies (27), as well as directions indicating possible favorable prognoses in multiple sclerosis (28).

GUT MICROBIOME AND NEUROPSYCHIATRIC DISORDERS

The intestine contains a dense network of neurons called the enteric nervous system controlling the physiological function of the gastrointestinal tract. The enteric nervous system is connected to the central nervous system (brain and spinal cord) through the intestinal--brain axis. Hormonal, neuronal and inflammatory signals are transmitted between the intestine and the brain through the blood. The enteric nervous system is directly connected to the cerebral trunk through the vagus nerve. Endocrine, neuroendocrine and inflammatory signals generated by intestinal microbiome and specialized cells can influence the brain. In turn, the brain can influence microbial composition and its function through endocrine and neuroendocrine mechanisms (29).

As mentioned before, an unbalanced micro biota can have a particular impact on the body, especially in terms of neuropsychiatric disorders. (30) Some studies have revealed the idea that the intestinal microbiota may interfere with the expression of certain genes by modifying the host epigenoma. (31) From here, the fact that epigenetic mechanisms are implicated in some neural processes, one can conclude that by manipulating the microbiota, we can also modify the epigenome, and can control and prevent certain neuropsychiatric diseases. It is also known that microbiota acts in microglia activation, in neurogenesis and in myelination and can also intervene in processes such as cognition and mood (32).

Aspects that come to reinforce the idea of a close relationship between the microbiome and the nervous system are the numerous studies on mice. For example, a test on mice kept under germ free conditions, after which the microbes were introduced according to what was needed. Behavioral, learning, appetite, and memory changes have been observed. (33) Mice kept separate from mothers from birth, mature, have an increased level of Adrenocorticotropic hormone (ACTH) and Corticotropin-releasing hormone (CRH). Increased levels of hormones dosed at the age of maturity are inversely proportional to the age at which they were separated (34), so the development of the hypothalamic pituitary adrenal axis can be influenced and regulated by the intestinal microbiota. With the bacterial colonization, a number of intestinal transformations have been observed, such as increased levels of neurotransmitters (serotonin, gamma-Aminobutyric acid), HPA-directed transformations (e.g. axis that plays a particularly important role in stress re sponses) (35).

Also, recent studies on mice have shown that non-microbiological animals have different behaviors than those with intestinal microbiota, and those kept in germ free conditions have anxiety, high levels of stress (36). These findings have led to the following idea, namely that fecal microbiota transplantation can be used to modify some behavioral patterns, some changes of the microbiota can be considered a cause rather than a consequence of behavioral transformations.

AUTISM

Treatment with Lactobacillus reuteri may increase the level of oxytocin, which further regulates the regions in the brain responsible for the deficits observed in children with autism. (42) Studies on mice have also shown that oxytocin variations are controlled by the microbiome. (43) Moreover, Lactobacillus reuteri can reverse the behavioral aspect associated with autism, once again demonstrating that microbial gut can influence social behavior. Another study conducted on mice, revealed that the treatment with Bacteroides fragilis on subjects with autism restored the intestine permeability (40).

Studies have shown that microbial disorders since childhood have generated diseases such as autism. Thus, a group of children with autism compared with a control group indicate that the first category presents disorders of amino acid metabolism and a high level of oxidative stress (37). Also, the group of children with autism shows an impaired microbiota compared to the control group and associated gastrointestinal comorbidities. Children with autism also usually have a higher level of Proteobacteria and Bacteroidetes at the expense of Bifidobacteria and Firmicutes (38) and in this category Clostridia in particular is found in higher amounts than the control group. (39) It has been demonstrated that maternal obesity and diabetes increases the risk of the future children being diagnosed with autism (40). Indeed, studies have shown that obesity of future mothers have a negative impact on fetus development and its long-term health. This latest study shows that obesity and diabetes also have an effect on the development of the baby's nervous system (41).

ATTENTION DEFICIT HIPERACTIVITY DISORDER (ADHD)

Although there are some hypotheses about the genetic and environmental determinations of this disorder (44), this is not yet clearly proven, and further research is needed to determine what triggers this disorder. ADHD may occur as a result of damage to the baby's brain during fetal development, at birth or after birth injury, infection, due to temporary lack of oxygen or other congenital illness. (45) Also, stress, smoking, drug use, alcohol and medications banned during pregnancy, or other maternal medical conditions during pregnancy, microbial aspects and dietary variations that may influence the microbiome (46) can cause the child's ADHD disorder.

SCHIZOPHRENIA

Also, disorders of certain neurotransmitters such as dopamine and glutamate may contribute to the occurrence of schizophrenia. There are theories that indicate that dopamine is produced by the microbiome, and increased inflammation of the gastrointestinal tract associated with schizophrenia has a close connection with the microbiome. (47) The link between schizophrenia and the microbiota is still being studied.

STRESS RESPONSE AND DEPRESSION

The hypothalamic-pituitary-adrenal axis (HPA) is stimulated during stress reactions. Adrenocorticotropin Hormone (ACTH) is involved in regulating the secretion of corticoid hormones through the adrenocortical glands. Production of ACTH is itself controlled by the central nervous system. A subcortical, hypothalamic muscular structure secretes in its basal part a hormone called Corticotropine Releasing Factor (CRF), which stimulates the production of ACTH via the pituitary gland. ACTH stimulates the secretion of adrenal cortical hormones. If natural or synthetic corticoids are injected in the hypothalamus, decreases the secretion of ACTH, but also the production of adrenal cortical hormones in response to stressful stimuli.

Studies that have been developed on mice in germ-free situations have indicated that the microbiota may influence HPA activity by high levels of ACTH and corticosteroids in response to certain stress factors (48), and when the mice's microbiome has been colonized with commensal species from the control mice, HPA activity normalized. Here is another aspect that links the microbial influence of neurological functions (49).

Several strains of Bifidobacteria and Lactobacilli have been shown to improve behavior with anxiety and depression tendencies, often generating eating disorders. In a randomized study, women who ate fermented milk products (sana, kefir) containing probiotics showed reduced activity in brain areas corresponding to anxiety and depression. (50) Also, studies on rodents that were separated from the mother showed that treatment with Bifidobacterium infantis improved the symptoms of depression when they were subjected to a forced swim test (51).

Another recent study has shown a link between severe depressive syndrome and Faecalibacterium spp (52). Moreover, the study indicated that when the microbiota of depressed subjects was transferred to those born in germ free conditions the symptoms of depression were also transferred (53). Also, differences in food styles can have different effects in depression. A western diet increases the risk of depression, while a Mediterranean diet could reduce the risk (54).

PARKINSON'S DISEASE

The cause of the progressive loss of neurons in Parkinson's disease is unknown. Studies indicate a combination of environmental and genetic factors. (56) Environmental factors such as exposure to certain heavy metals, pesticides, fungicides, increases the risk of cellular apoptosis due to oxidative stress are also representing an increased risk factor for Parkinson's disease. (57)

In addition, a study of 72 patients and as many controls revealed a decrease in the level of Prevotellaceae bacteria in patients with Parkinson's disease and a link between the level of Enterobacteriaceae and some symptoms of the disease, underlining the role of the microbiome in Parkinson's disease. (58) Also, the species Blautia, Coprococcus and Roseburia are much less represented in the feces of Parkinson's patients compared to Faecalibacterium genus and Ralstonia than in controls.

Another study indicates that in animals kept in germ-free conditions or under antibiotic treatment whose alpha synuclein human activity is overexpressed, they have specific manifestations of Parkinson's disease compared to animals with normal microbiota. Moreover, by introducing the microbiota from Parkinsonian patients in susceptible mice, the characteristic Parkinsonian symptoms are exacerbated compared to the microbiota from healthy patients (59).

ALZHEIMER'S DISEASE

Regarding the association of the microbiome and Alzheimer's disease, it was shown for example that the metabolic syndrome, which in fact represents the association of several diseases that increase the risk of diabetes and cardiovascular disease (stroke, myocardial infarction) and obesity are factors that can increase the risk of Alzheimer's disease. (60) Certain mechanisms can explain the link between microbial imbalances, obesity, type 2 diabetes and Alzheimer's. (61) Imbalances of the microbiota may be a triggering factor of obesity and its vascular effects, increase intestinal permeability and may lead to systemic inflammation, which will generate insulin resistance and type 2 diabetes that also pose risk factors for Alzheimer's .(62) The beta-amyloid precursor protein (APP) is a type I transmembrane protein that plays a central role in the pathogenesis of the disease. Sequential cleavage of APP by protease generates (Pamyloid which is deposited in the brain of patients affected as senile plaques and is one of the main pathological signs. This mechanism is regulated by the inflammatory process, also related to the microbiome. In addition, brain derived neurotrophic factor is a growth factor, a protein resulting from BDNF gene expression, with a role in neuronal growth and survival, cell differentiation, synapse formation and cognitive function (63).

Decreased BDNF serum levels are associated with several neuropsychiatric disorders including Alzheimer's. (64) In experimental testing on mice in free germ-free conditions, low levels of BDNF were found along with specific mental impairment (65). Also, NMDA (N-methyl-D-aspartate) receptors are neurotransmitter receptors that are located in the post-synaptic membrane of a neuron, involved in signal transduction. They play an important role in learning and memory formation. Increased levels of NMDA and BMAA (P-Methylamino-L-alanine) which is a neurotoxin and could have a potential role in various neurodegenerative disorders, were found in the brains of people with Parkinson's, complex of Guam, amyotrophic-lateral sclerosis and Alzheimer's, and are thought to be generated by cyanobacteria present in the microbiome. Stress, poor nutrition, food deficiencies, and bowel dysbiosis can also result in increased BMAA levels, which may contribute to neurological dysfunction (66).

In addition, saxitoxin (STX) which is a potent neurotoxin and anatoxin-a, also known as Very Fast Death Factor (VFDF), which is a secondary, bicyclic aminealkaloid and cyanotoxin with acute neurotoxicity, they are related to cyanobacteria and they may be present especially when the barrier of the intestinal tract becomes more permeable with age (67). Both the intestinal epithelium and the blood brain barrier become more permeable with age, which makes the nervous sys tem more vulnerable to neurotoxins adapted to microbiota or different pathogens. Also, food imbalances, repeated infections or other aggressions, constantly assault the nervous system due to the progressive destruction of the blood brain barrier.

CONCLUSIONS

Studies on the role of microbiota in the proper functioning of the body are increasingly every day. Studies in mice and humans showed clear changes in autistic behavior depending on microbial variations. As well as in depression, variations in the microbiome have led to the improvement of the depressive state. Research requires in-depth studies to establish a more precise connection between schizophrenia, ADHD and the microbiota. Also, regarding Alzheimer's disease, there are certain connections between the microbiome and the disease itself, indicating that certain risk factors of the disease can be determined by the microbiota imbalances. Certain neurotoxins that can cross the intestinal barrier have been found in Alzheimer's patients, these being linked to cyanobacteria. Other studies have revealed the presence of certain bacterial species in Parkinson's patients as compared to controls. Besides these links, it can be concluded that the microbe is highly influenced by diet, environmental factors, age. Also, it is absolutely necessary to continue the studies linking gut microbiome to neuropsychiatric diseases, given that there are already established links, and especially for the need to approach new therapeutic perspectives and also prevention.

ACKNOWLEDGEMENTS AND DISCLOSURES

C.A. is supported by an UEFISCDI grant called "Complex study regarding the interactions between oxidative stress, inflammation and neurological manifestations in the pathophysiology of Irritable bowel syndrome (animal models and human patients)" code PNIII-P1-1.1-TE-2016-1210, no. 58 din 02/05/2018.

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Cojocariu Roxana Oana--Biochimist, "Sf.Dimitrie" Hospital, Targu Neamt, Romania

Alin Ciobica--Researcher II, Department of Research, Faculty of Biology, Alexandru Ioan Cuza University, B dul Carol I, no 11, Iasi, Romania, Academy of Romanian Scientists, Splaiul Independentei nr. 54, sector 5, 050094 Bucuresti, Romania, Center of Biomedical Research, Romanian Academy, Iasi, B dul Carol I, no 8, Romania

Daniel Timofte--Associate Professor "Gr. T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115, Iasi, Romania

Correspondence:

Daniel Timofte,

MD, PhD, "Gr.T.Popa" University of Medicine and Pharmacy, "Sf. Spiridon" University Hospital, Iasi, 700111, Iasi, ROMANIA, e-mail: dantimofte@yahoo.com Tel. + 40 731 46 00 00

Submission: 15 apr 2018

Acceptance: 01 jun 2018
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Author:Oana, Cojocariu Roxana; Ciobica, Alin; Timofte, Daniel
Publication:Bulletin of Integrative Psychiatry
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Date:Jun 1, 2018
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