The connection between microbiome and schizophrenia

Journal Pre-proof The connection between microbiome and schizophrenia Bogdana Golofast, Karel Vales

PII:

S0149-7634(19)30777-8

DOI:

https://doi.org/10.1016/j.neubiorev.2019.12.011

Reference:

NBR 3624

To appear in:

Neuroscience and Biobehavioral Reviews

Received Date:

30 August 2019

Revised Date:

1 December 2019

Accepted Date:

6 December 2019

Please cite this article as: Golofast B, Vales K, The connection between microbiome and schizophrenia, Neuroscience and Biobehavioral Reviews (2019), doi: https://doi.org/10.1016/j.neubiorev.2019.12.011

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THE CONNECTION BETWEEN MICROBIOME AND SCHIZOPHRENIA Bogdana Golofast1,2, Karel Vales1

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National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, Czech Republic Third Faculty of Medicine, Charles University, Ruská 87, 100 00 Prague 10, Czech Republic

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The microbiota community transmitted to the offspring may have plasticity. Dynamic changes in the maternal microbiota and the early offspring microbiota would occur due to the prenatal and postnatal environments, respectively, as well as host genetics. Patients with schizophrenia have specific differences in the composition and diversity of bacteria compared with control patients. It is possible to use probiotics for the treatment of inflammatory processes of the gastrointestinal tract, with a positive effect of schizophrenia symptoms.

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ABSTRACT There has been an accumulation of knowledge about the human microbiome, some detailed investigations of the gastrointestinal microbiota and its functions, and the highlighting of complex interactions between the gut, the gut microbiota, and the central nervous system. That assumes the involvement of the microbiome in the pathogenesis of various CNS diseases, including schizophrenia. Given this information and the fact, that the gut microbiota is sensitive to internal and environmental influences, we have speculated that among the factors that influence the formation and composition of gut microbiota during life, possible key elements in the schizophrenia development chain are hidden where gut microbiota is a linking component. This article aims to describe and understand the developmental relationships between intestinal microbiota and the risk of developing schizophrenia. Key words: microbiome; schizophrenia; immune inflammatory response; prenatal environment; postnatal environment; Cesarean section; probiotics; prebiotics

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INTRODUCTION The human microbiota is unequally distributed in the body and includes the aggregate of all microorganisms, that reside on or within human tissues and biofluids along with the corresponding anatomical sites in which they inhabit (Marchesi et al., 2015). The most abundant microbiota in our body is gastrointestinal (gut) microbiota. It may contain hundreds of species of different microorganisms but in adult members, Actinobacteria, Bacteroidetes and Firmicutes predominate (Rajilic-Stojanovic et al., 2009). The gastrointestinal microbiota is better studied than other human bacterial communities. And studies described below have precisely shown that the intestinal microbiota has a great impact on the health of its host.

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The human gastrointestinal tract is a portrait of one of the biggest associations between the host, environments, and antigens within the human body. During the average human lifetime, around 60 tons of food with plenty of microorganisms from the ambient environment transfer through the gastrointestinal tract, which can pose a big threat on the intestinal entirety (Bengmark, 1998). Intestinal microbes play a pivotal part in keeping up the resistance and the metabolic homeostasis effective and are safeguarding against pathogenic microbes. The colony of bacteria, archaea and eukarya populating the gastrointestinal tract is designated by «gut microbiota» and has developed together with the host for an extended period to create a complicated and useful liaison (Bäckhed, 2005, Neish, 2009). Gut microbiota is an important modulator of brain development and subsequent adult behavior (Diaz Heijtz et al., 2011), and pathogens can either be a reason of inflammatory diseases of the central nervous system or protect from them (Ochoa-Reparaz et al., 2011). Epidemiological studies have shown a link between microbial infections early in life and neurodevelopmental disorders, including autism and schizophrenia (Finegold et al., 2002; Mittal et al., 2008). The gut microbiota can affect the immune response by activating the immune system or through mediators that are able to penetrate the blood-brain barrier (BBB) or other chemicals-related substances that have free access to the brain. The mechanisms about how the gut microbiota may affect brain functions will be discussed in detail here later on. The microorganisms count populating the gastrointestinal tract has been evaluated to transcend 1014, that corresponds of ten times more bacterial cells than the number of human cells and over 100 times the number of genomic composition (microbiome) as the human genome (Bäckhed, 2005, Gill et al., 2006). However, a revised assessment has indicated that the ratio of human cells over bacterial cells is closer to equal and their total weight is about 200 grams (Sender et al., 2016). The interrelation with the human host and the bacterial colonizers are that these relationships benefit both parties: the microbiome is granted with an environment to live in and an easy existing nutriments source (Wexler, 2007) and the microbiota offers numerous bonuses to the host, due to physiological capacities such as harvesting energy (den Besten et al., 2013), strengthening gut integrity or shaping the intestinal epithelium (Natividad and Verdu, 2013), protecting against pathogens (Bäumler and Sperandio, 2016) and regulating host immunity (Gensollen, 2016). Microorganisms which live inside our digestive tract are beneficial and essential for the proper development of the central nervous system (CNS), for brain response (Cryan and O'Mahony et al., 2011, Dinan and Cryan et al., 2013, Qin et al., 2010) and the regulation of host physiology. The ecosystem in the human gut is dynamic, there is potential for these processes to be disordered because of a transformed microbial composition, known as dysbiosis. With progressively innovative techniques to characterize ecosystems being developed, a potential role of gut microbiota for intestinal and extraintestinal diseases has become clear (Chang and Lin, 2016, Schroeder and Bäckhed, 2016). This review presents data on the development and configuration of the human gastrointestinal microbiota, its main functions and interaction mechanisms in the microbiota-gutbrain axis. This article has been made through investigations studying the relationship between gut microbiota and neuropsychiatric conditions, behavioral traits in order to detect possible correlations between gut microbiota and schizophrenia. We assume that this review may allow identifying new areas for the study of this severe mental disorder and its treatment. PART 1. MICROBIOME

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Microorganisms have been found throughout the human body, for the most part on the internal and external surfaces, among are the gastrointestinal tract, skin, oral mucosa, saliva, and conjunctiva. According to estimates by Sender et al., the bacterial content of the colon transcends all other organs in the human body by at least two orders of magnitude. In that context, it is important to note, within the gastrointestinal tract, the colon is the only significant donator to the total bacterial population, while the small intestine and stomach are nonessential sources (Sender and Fuchs, 2016). Main functions of the gut microbiota The human being cannot digest all the molecules that make up his diet in his small intestine, he can only produce enzymes to break down proteins, starch, and fatty acids into smaller absorbable molecules, such as acids. amines and monosaccharides. Complex proteins and complex carbohydrates, such as fibers and other plant-derived polysaccharides, cannot be broken down by human enzymes because the human genome does not encode their manufacture. It is, therefore, the intestinal microbiota (Flint et al., 2012) that will digest these almost intact molecules when they reach the colon. In addition, the ability to degrade complex carbohydrates can be dictated by the diet of the human population. The human microbiome plays a major role in the distal intestine because it extracts energy from these otherwise non-digestible food components (Flint et al., 2012). And many metabolic processes of colon lumen are dedicated to this task. The reconstitution of the metabolic pathways of the different body sites sampled in the human microbiome project (HMP) consortium showed site-specific metabolic profiles (Human Microbiome Project Consortium, 2012). Glycosaminoglycan degradation, which was rare or absent in other body site profiles, characterized human intestinal metabolic profiles as determined by metagenomic sequencing. Although significant interindividual variations in microbial species composition can be seen (Lozupone et al., 2012), this functionality was remarkably similar in the intestinal specimens of all HMP individuals. Some studies show population-specific variations, yet the interindividual metabolic capabilities are overall very similar. It is interesting to note, that Bacteroides plebeius strains of Japanese subjects have genetic material encoding porphyranases and agarose (Hehemann et al., 2010). The environment can act as a selection force on the functional potential of the human microbiota, since these genes do not exist in other populations and would come from B. plebeius by horizontal gene transfer from marine bacteria through consumption. seaweed. Some of the important functions of the intestinal microbiota are syntheses of specific lipopolysaccharides and certain vitamins and amino acids (Lloyd-Price et al., 2016), short-chain fatty acids, and of course the degradation of polysaccharides. Genes coding for 3200 unique chemical reactions have been updated through a recent metabolic genome reconstruction of 773 genome members of the human intestinal microbiota, which would mean that this community encodes hundreds or even thousands of metabolic pathways (Magnúsdóttir et al., 2017). Microbiota-gut-brain axis. Ways of interaction. An overview of the gut microbiota in behavior Studies on germ-free (GF) rodents, gastrointestinal tract infections, antibiotics, probiotics, and bacteriotherapy have shown that intestinal microorganisms regulate the brain, behaviors, and stress responses by the creation of the microbiota-gut-brain (MGB) axis (Cryan and Dinan, 2015, Sherwin et al., 2016, Kim and Shin, 2018). Gut microbiota supports two-way communication with major parts of the CNS directly and indirectly. Commensal bacteria (indigenous microbiota) 3

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in the gastrointestinal tract communicate with the CNS and manage brain neurochemistry and behavior in various ways. These pathways include the production of bacterial metabolites, such as short-chain fatty acids (SCFA) and immune mediators, such as cytokines, and also signaling to the brain directly by the longest cranial nerve (vagus nerve) (El Aidy et al., 2014, Dinan et al., 2015, Sherwin et al., 2016a,b). The MGB axis is part of a physiological network containing the immune system (cytokines, chemokines), the endocrine system (hypothalamic-pituitary-adrenal axis), the autonomic nervous system (ANS), and the enteric nervous system (ENS). Gut microbiota is considered to be affecting the hypothalamic-pituitary-adrenal (HPA) axis and the vagus nerve by bacterial metabolites in tryptophan metabolism (Kim and Shin, 2018). The enteric nervous system (ENS) and the central nervous system (CNS) are connected by the vagus nerve. The study by Parashar and Udayabanu has shown that gut microbiota directly in contact with the ENS allows modulating sensory neurons excitability and consequently information relayed to the brain (Parashar and Udayabanu, 2016). Some studies have reported producing some neurotransmitters by gut microorganisms specifically, that Lactobacillus and Bifidobacterium species can produce GABA (Barrett et al., 2012); the species Escherichia coli, Bacillus and Saccharomyces produce norepinephrine; Candida, Streptococcus, Escherichia and Enterococcus produce serotonin, and Bacillus and Serratia synthesize dopamine (Lyte, 2011). Recently evidence has shown that gut microbiota affects the serotonergic system and regulates the synthesis and secretion serotonin (Kelly et al., 2015a, Desbonnet et al., 2015, O’Mahony et al., 2015, Clarke et al., 2013). Microbiota influence this system by altering tryptophan availability in the plasma (Rackers et al., 2018). These neurotransmitters are capable of stimulating enteric cells that can modulate communication between ENS and CNS. Through the gut-brain axis (Rea et al., 2016, Dinan and Cryan, 2017a), the gut microbiota can interact with the central nervous system through communication with the host's immune, neuroendocrine and neural pathways. For example, during infections, inflammation, and autoimmunity on the surface of the intestinal mucosa, modulation of immune responses by the microbiota of the intestinal tract. Besides, the intestinal microbiota may influence microglial cell maturation, morphology, and immune function as evidenced by studies of microglia dysfunction in various preclinical animal models (Rea et al., 2016). The gut microbiota is thought to modulate a psychiatric illness because many psychiatric disorders are related to inflammation and immune dysregulation. By direct communication with the neural and endocrine pathways, the microbiota can also influence brain activity, behavior, and development of mental disorders. Several studies had as a subject of study the relationship between the intestinal microbiota with the neuropsychiatric state, the behavioral traits, and the temperament. Behavioral traits have even been suggested to influence the intestinal microbiota. For example, reduced anxiety phenotypes and a relatively higher amount in the hippocampus of serotonin and its metabolite, 5hydroxyindolacetic acid (5HIAA), were found in germ-free (GF) mice compared to colonized mice. Despite the anxiety phenotypes had been reversible with colonization after weaning, the rise in serotonin levels in the hippocampus was not observed (Clarke et al., 2013). The study by Huo and colleagues (2017) also showed that specific-pathogen-free (SPF) mice with intestinal microorganisms noted increased anxiety-like behavior under the same pressure compare to GF mice. Some research previously reported the opposite that GF F344 rats were more likely to have anxiety-like behavior than SPF rats (Crumeyrolle-Arias et al., 2014; Wong et al., 2016; Zheng et al., 2016, 2017). Desbonnet and colleagues (2014) found significant social behavior impairment in GF mice. These behavior shifts were normalized by following colonization of the gut of GF mice. A later study by Desbonnet et al. (2015) in mice have shown antibiotic-treatment in 4

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adolescence (21 postpartum day onwards) had depleted and reorganized intestinal microbiota composition, which in turn caused reduced anxiety, non-spatial cognition deficits and worse performance in the social transmission of food preference test that had accompanied by modify dynamics of the tryptophan metabolic pathway and significantly decreasing brain-derived neurotrophic factor (BDNF), oxytocin and vasopressin expression in the brain (Desbonnet et al., 2015). The other factors associated with behavior alteration are SCFAs which are produced by gut microbiota through fermentation of polysaccharides (Rea et al., 2016, Dinan and Cryan, 2017b). These SCFAs are known to have neuroactive properties, to induce neuroinflammation, to be associated with behavioral alterations. Dietary fiber-derived SCFAs, such as lactic acid, acetic acid, butyric acid, and propionic acid (PPA), influence intestinal epithelial cells (IECs) and immune cells (Peng et al., 2009, Kelly et al., 2015b, Zheng et al., 2017, Feng et al., 2018). SCFAs that enter the circulation and cross the blood-brain barrier (BBB) can directly influence the central nervous system (Macfarlane et al., 2003, Shi et al., 2006, Flierl et al., 2007, Kim et al., 2012, Maes et al., 2012). It was showed that PPA, that is a common preservative added to dairy products and refined wheat, activates microglia of the hippocampus, white matter, cingulate, and neocortex (MacFabe et al., 2011) and can also modulate the balance between excitation and inhibition in neural circuitry by increased glutamatergic and decreased GABAergic transmission (MacFabe, 2012). PPA seems to be linked with autism spectrum disorder (ASD) symptomatology in humans. Higher autistic symptoms have noticed after consuming food containing propionate, and an improvement has been observed after the elimination of this product (Cenit et al., 2017b). There is now more and more evidence showing a relationship between certain behavioral traits and psychiatric illnesses, with the intestinal microbiota. Also, it seems that the immune and the endocrine system are significant parts of the synergy between microbiota and the brain. Gut commensal can affect the development and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Huo and colleagues noticed significant changes in HPA axis hormone levels with increased corticotrophin-releasing factor (CRF) expression, elevated adrenocorticotropic hormone (ACTH), cortisol, and aldosterone levels in GF stressed mice compared to SPF stressed mice (Huo et al., 2017). Although few human studies have been conducted on the gut microbiota and behavior, there seems to be a twoway relationship between microbial composition and stress. An example is Bailey et al. (2011), who found that stress led to a decrease in the genus Bacteroides and Clostridium (Bailey et al., 2011). Several other studies on the same subject have found that the use of probiotics can reduce stress-related behaviors (Desbonnet et al., 2009) and corticosterone levels due to stress (Gareau et al., 2011). Moya-Pérez et al. (2017b) showed that Bifidobacterium (B. pseudocatenulatum CECT 7765) consumption had beneficially changed the consequences of maternal separation (MS), had induced chronic stress on the HPA axis and had down-regulated intestinal inflammation. These effects had a long-term impact on the central nervous system (CNS) of mice adulthood. Tillisch et al. (2013) have shown in humans that information processing of emotional material can be altered by probiotic treatment. Messaoudi et al. (2011) found that the values of the 24-hour free urinary cortisol test were lower after probiotic treatment. As one study shows, depressed patients would have an increase in the number of Bacteroides, Actinobacteria, Proteobacteria, but a decrease in the number of Firmicutes (Jiang et al., 2015). Contrary to this experience, a study by Naseribafrouei and colleagues (2014) showed that among depressed patients and controls (Naseribafrouei et al., 2014), no difference in microbial composition and 5

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diversity was found. Other pre-clinical studies have involved the reversal of noradrenaline abnormalities in a depressive model in mice (Desbonnet et al., 2009), as well as probiotic treatment in the relief of depressive symptoms. Moreover, bidirectional communication is reported between the central nervous system and the immune system. Received data by Bilbo and Schwarz (2012) confirm the assumption that neonatal immune activation indirectly raises the risk of cognitive deficits, through the programming of neuroimmune responses. Subsequently, that interferes with cognitive functions and emotional behavior. That is consistent with later studies by Filiano et al. (2017) and Freytag et al. (2017). And these data are in good agreement with the “two-hit” hypothesis of schizophrenia, which assumes that the combination of vulnerability (likely instantiated at younger age) and a later-life (typically young adult) precipitating factor (such as, stress, infection) is required for the inducing the illness (Bilbo and Schwarz, 2012, Choy et al., 2009, Pantelis et al., 2003, Maynard et al., 2001, Keshavan, 1999, Keshavan and Hogarty, 1999). Norris and Kipnis (2018) in their review have reported the interesting suggestion that the immune system may be as a “sensory” arm of the brain, recognizing peripheral microorganisms and other menace and informing the brain about them using the cytokines (Kipnis, 2018), as a supplement to the directly interactions through the vagus nerve (Chavan et al., 2017, Pavlov and Tracey, 2017). Neurons of the central nervous system, microglia, and astrocytes can be modulated by cytokine peripheral signaling (Kohman and Rhodes, 2013). This occurs because of regions with leaks in the BBB, such as active transport through transport molecules, HPA axis stimulation at the anterior pituitary HPA axis or hypothalamus, and recruitment of activated cells such as monocytes / macrophages from periphery to brain, activation of cells lining the cerebral vasculature (endothelial cells and perivascular macrophages), binding to cytokine receptors associated with the vagus nerve, and circumventricular organs (Haroon et al., 2012). It has been discovered that immune cells can communicate with the central nervous system through functional lymphatic vessels lining the dural sinuses (Louveau et al., 2015). Therefore, neurogenesis, plasticity, and synapse formation can be modulated by peripheral cytokines (Hodes et al., 2015). There is evidence that cytokines can affect cognition and mood (Dowlati et al., 2010, Udina et al., 2012, Valkanova et al., 2013, Khandaker et al., 2014). Brain regions affected by the administration of inflammatory stimuli include the basal ganglia and the anterior dorsal cortex (anterior cingulate) (DACC), part of the limbic system, involved in cognitive and emotional processing (Harrison et al., 2009, Slavich et al., 2010, Capuron et al.,2012, Felger and Miller, 2012, Felger et al., 2013, Miller et al., 2013). It has been shown that an essential function of the gut microbiota is the priming of the development of the neuroimmune system (Chistiakov et al., 2014, Francino, 2014, Olszak et al., 2012, Round and Mazmanian, 2009). The luminal surface of the intestine (O’Hara and Shanahan, 2006) plays a major role in the process of predisposition to immune disorders, by changes in the signature of the intestinal microbiota at the beginning of immune life (Fujimura et al., 2016, Penders et al., 2007). The hygiene hypothesis first proposed in the late 1980s (Patel and Gruchalla, 2017, Strachan, 1989) and reconceptualized as an "old friends hypothesis" (Williamson et al., 2015, Rook et al., 2003) suggests, that an encounter with less exposure to immunoregulatory microorganisms contributes to the increase in chronic inflammatory disorders, as well as stress-related psychiatric disorders (Klerman and Weissman, 1989, Guarner et al., 2006, Rook and Lowry, 2008, Turnbaugh et al., 2009, Hidaka, 2012, Rook et al., 2013, 2014, Kostic et al., 2015, Reber et al., 2016, Stein et al., 2016, Kelly et al., 2017). Stress leads to 6

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excessive inflammation by disrupting homeostasis between the microbiota and the host. Reber and colleagues showed that repeated immunization of mice with a heat-killed preparation of an immunoregulatory environmental microorganism (Mycobacterium vaccae), averts stress-induced pathology. These data support a strategy of “reintroducing” humans to their old friends to protect against negative stress-related outcomes (Reber et al., 2016). In this part of the review, the concept of gut microbiota and its main functions were considered. It has also been shown that the gut microbiota has been viewed as a crucial regulator of bidirectional communication between the gut and the brain (gut-brain axis), which implies the impact in many neurodevelopmental and neurodegenerative disorders and may affect behavior (De Theije et al., 2011, Cenit et al., 2017b). Several studies have shown that the modifications in the composition of microorganisms inhabiting the GI tract have linked to different neuropsychiatric disorders, including mood disorders, autism spectrum disorder (ASD), Parkinson’s disease (PD), and schizophrenia (Cenit et al., 2017b). Besides, some studies have shown that many patients affected by gastrointestinal problems were more likely to develop mental illness (Mussell et al., 2008, Lee et al., 2015). Thus, dysbiosis of the gut microbiota may facilitate the pathogenesis of mental health disorders, confirming the hypothesis of a pathologic process of bidirectional communication between the gut and the brain (Huang et al., 2019). Many factors can have an impact on microbiota composition in early life, including the mode of birth delivery, antibiotic treatment, nutritional habits, environmental stressors, and host genetics. For a better understanding of this aspect and possible risk factors for the development of mental health disorders, this review has considered the development of microbiota and the elements that influence it throughout life.

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PART 2 Development of the microbiota during the life Gut microbiota: development The confidence that the gut is sterile before birth turned out to be a mistake. That has been proven by the results of several studies looking at bacteria, bacterial DNA, or bacterial products in meconium (Nagpal et al., 2017, Wampach et al., 2017, Jiménez et al., 2008), amniotic fluid (Collado et al., 2016, DiGiulio et al., 2008), and the placenta (Collado et al., 2016, Friedrich et al., 2013). Despite the limited evidence of live bacterial culture from placental and amniotic fluid samples, these discoveries raise the ability that intrauterine human gut development is affected by the development of stage-specific microbiota that begins in utero (Collado et al., 2016). Ensuring the influence of microbiota on the development of the gastrointestinal tract in utero could provide a mechanism that produces the selection and exposure of the conforming microbial population or factors. The environment for such a system is the amniotic fluid that surrounds the developing fetus. The fact that the composition of the amniotic fluid is transformed during pregnancy is noteworthy (Mennella et al., 1998). Amniotic fluid contains mainly fetal urine, with contributions from secreted lung liquid, buccal secretions, and transmembrane flow (Trahair, 2001). And also contains hormones and growth regulators (Bagci et al., 2016), immune modulating proteins, and microbial components (Collado et al., 2016). The pathway for the selection of particular microbes in the amniotic fluid is still unclear. One of the probable way of influencing the developing GI to microbes / microbial products within the amniotic fluid is through swallowing. The human fetus begins to swallow amniotic fluid 10 weeks after conception (Bagci et al., 2016). Which corresponds to the beginning of the innervation of the 7

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esophagus, which usually starts after 13 weeks (Trahair, 2001). In the third trimester of pregnancy, the human fetus swallows up the amniotic fluid to 1 liter per day (Blakelock et al., 1998, Gitlin et al., 1972). This makes it possible to introduce bacteria and bacterial products (e.g., RNA and DNA, glycoproteins) into the developing gut (Chong et al., 2018). Previous studies have ascertained the possibility of the infiltration of maternal microbes to the amniotic fluid (Collado et al., 2016, Jiménez et al., 2008) and the placenta (Epstein et al., 2000). But the transmission of microbes from the mother to the fetus in utero, which leads to active colonization and the effect on developmental, remains unproven (Chong et al., 2018). The developmental trajectory of the gut microbiota is consistent with the concepts of early life psychiatry as a vulnerable phase for the later emergence of psychopathology in adulthood (O’Mahony et al., 2017). At the beginning of life, during the first days, the gut microbiota is not very diversified and unstable, its composition will evolve during the first years of the child to resemble that of an adult when he reaches the age of 3 years (Voreades et al., 2014). It is becoming increasingly popular to study the effect of the mode of delivery and the implications for the development of the central nervous system host (Clarke, 2014, Dominguez-Bello et al., 2010, Adlerberth et al., 2009). There is a difference in bacterial colonization between vaginal and cesarean delivery. In fact, vaginal delivery infants are colonized by the mother's vaginal and faecal bacteria, such as Lactobacilli, while infants born from cesarean delivery are colonized by other bacteria, such as mother's skin and environmental sources such as other newborns, medical equipment, medical staff, or even air (Borre et al., 2014). The trajectory of microbiota acquisition may be due to many other factors, such as exposure to family members and domestic animals (Dominguez-Bello et al., 2010, Marques et al., 2010, Fujimura et al., 2010, Penders et al., 2006), diet (Thum et al., 2012, Koenig et al., 2011), gestational age (Barrett et al., 2013) or the use of antibiotics (Persaud et al., 2014). It is still unclear what relative importance all these factors have in determining the final profile of a stable microbiota. Evidence from recent studies indicates that prenatal stress will influence gut microbiota, with physiological consequences on offspring (Golubeva et al., 2015). Nevertheless, it is still difficult to draw definitive conclusions about the relationship between prenatal stress and intestinal microbiota from clinical studies.

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PART 2.1 Human microbiota during pregnancy Gut microbiota Dynamic changes in the composition that accompany changes in metabolism during pregnancy in the human microbiota (Priyadarshini, et al., 2014, Koren, et al., 2012, Santacruz, et al., 2010, Collado, et al., 2008) are observed. As gestation progresses, the diversity of the gut microbiota, and especially the Actinobacteria and Proteobacteria, increases (Koren et al., 2012). This is why, already at the end of the third trimester, the composition of the intestinal microbiota is significantly different from that at the beginning of pregnancy (Koren et al., 2012). Intestinal microbial diversity has also been shown to increase postpartum in vaginal and vaginal infants (Jakobsson, et al., 2014, Koren, et al., 2012, Kurokawa et al., 2007). Note that germ-free mice that received a human microbiota transplant in the third trimester had the following metabolic syndrome symptoms: inflammation and decreased glucose tolerance, and increased adiposity (Koren et al., 2012, Santacruz et al., 2010, Collado et al., 2008). Short-chain fatty acids, which are essential intestinal microbial metabolites, have been shown to be associated with metabolic changes during pregnancy and may be partly responsible for the effects mentioned above 8

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(Priyadarshini et al., 2014). It is important to note that neurodevelopment may be affected by microbiota modulation during the second and third trimesters, as most changes in the gut microbiota occur at these times. Vaginal microbiota The human vaginal microbiome is composed of several types of stable community states that become destabilized during pregnancy (Romero et al., 2014, Ravel et al., 2011). It is most abundant in Lactobacillus spp. before pregnancy, but this species may be reduced during pregnancy (DiGiulio et al., 2015, MacIntyre et al., 2015). But there are only studies that show a simultaneous reduction in overall bacterial diversity during pregnancy (Aagaard et al., 2012), while others indicate the opposite (DiGiulio et al., 2015, MacIntyre et al., 2015). In addition, it was observed that postpartum bacterial diversity has increased (MacIntyre et al., 2015). Among different ethnic groups, there are differences in the composition of the vaginal microbiome during pregnancy and postpartum, indicating that host genetics, the environment, and bacterial colonization interact together (MacIntyre et al., 2015). The mother's vaginal microbiome, which initially colonizes the infant, is extremely similar to the infant's microbiome, this corresponds to patterns of vertical transmission across the animal kingdom (Funkhouser et al., 2013, Dominguez-Bello et al., 2010, Ley et al., 2006). Oral microbiota An important part of human microbiota is oral microbiota, which performs an important protective function against the colonization of external bacteria that can hit systematic health. At the same time, the most extended oral health disease, caries, gingivitis, and periodontitis are microorganisms based (Arweiler NB and Netuschil L, 2016). In the study by Dasanayake et al. (2005) noted that throughout pregnancy elevated levels of Actinomyces naeslundii genospecies (gsp) 2 and Lactobacillus casei in saliva are respectively negatively and positively associated with gestational age at delivery and birth weight. This conclusion matches with the hypothesis that oral organisms influence the delivery process via the orogenital contact or through opportunity penetration the uterine environment from the bloodborne route. The paradigm that most intra-uterine infections, which are associated with preterm birth, originate in the lower genital tract and ascend into an otherwise sterile uterus is outdated and may need to be reconsidered (Wassenaar and Panigrahi, 2014). Actinomyces naeslundii gsp 2 is not considered part of the periodontitis pathogenic complex (Socransky et al., 1998). Despite this, A. naeslundii gsp 2 may also be regarded as pathogenic through they have been caused periodontal infections in gnotobiotic rodents and have been related with actinomycosis and gingivitis (Ellen, 1982, Slack et al., 1975, Jordan and Hammond, 1972). It has been observed that the reason why infants were born with low weight or prematurely would be periodontal disease (as an independent risk). It has been observed that in the homogenized cord (Wright et al., 1994) and the amniotic fluid of this case of preterm delivery (PTD) with chorioamnionitis (Dixon et al., 1994), periodontal pathogens are found. In the oral cavity of some women who have given birth prematurely to low weight infants, high levels of pathogens have been observed (Offenbacher et al., 2001, 1998). In some studies preterm low birth weight (PLBW) has been associated with periodontal disease (Lopez et al., 2002, Jeffcoat et al., 2001, Offenbacher et al., 2001, Dasanayake et al., 1998, Offenbacher et al., 1996), however, some other studies have not reached the same conclusions (Davenport et al., 2002, Mitchell-Lewis et al., 2001, Offenbacher et al., 1998). Ambiguous data on the relationship between PLBW and Ig level are specific for the serum periodontal pathogen. According to 9

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Dasanayake et al. (2001) this relationship is positive, while Madianos et al. (2001) claim negative association with PLBW. Recent studies analyzing the relationship between maternal periodontal disease and the risk of preterm delivery have shown that patients with a high risk of preterm delivery had higher levels of inflammatory cytokines (Escobar-Arregoces, et al., 2018, Latorre Uriza, 2018). These results are consistent with Offenbacher et al. (1998), who first reported the association between maternal periodontal disease and preterm birth (Escobar-Arregoces, et al., 2018). A study of the effect of periodontal treatment on the reduction of pro-inflammatory markers and its association with preterm labor report conflicting data. Offenbacher et al. (2006) report that periodontal treatment showed a 3.8-fold reduction in preterm birth rates and a decrease in IL1β and IL6. Penova-Veselinovic, found that in the periodontal treatment group there was a significant decrease in the levels of IL1β, IL10, IL-12p70 and IL6 compared to the control group. Da Silva et al. (2017) reported a decrease in inflammatory biomarkers in gingival crevicular fluid and serum after non-surgical periodontal therapy in pregnant women. Despite this, the treatment did not affect the level of inflammatory biomarkers in umbilical cord blood and without reducing the incidence of adverse gestational outcomes. However, studies such as Michalowicz et al. (2009), Fiorini et al. (2013) and Pirie et al. (2013) report that non-surgical periodontal therapy during pregnancy did not lead to a decrease in markers of systemic inflammation. It is worth nothing that, thanks to the development of newer epidemiological methods to assess bias caused by the truncated outcome, Merchant et al. (2018) re-analyzed data from a study by Michalowicz et al., reporting that treatment of periodontitis during pregnancy does not significantly change stakes of low birth weight or preterm birth (Michalowicz et al., 2006). Through the use of Merchant and al. the survivor average causal effect (SACE), also called the principal strata effect, to correct potential bias resulting from unequal survival of fetuses in the treatment and control group of the Obstetrics and Periodontal Therapy (OPT) study, differences in risk for preterm birth reached statistical significance and showed a beneficial effect of periodontal treatment.

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PART 2.2 Prenatal environment impacts on microbiota A real serious contact with the world of microorganisms occurs after birth, and in many respects the future health of a person depends on how this meeting will happen. There is evidence that the first colonizers are inhabiting the human body even before his birth. Although controversial, some evidence exists to support the hypothesis of a prenatal microbiome, contrary to what is generally thought, namely that initial intestinal colonization occurs at birth during vaginal delivery (Perez-Muñoz et al., 2017, Willyard, 2018). A microbiome of the placenta close to the microbiome of the mouth has been demonstrated morphologically and by sequencing, from bacteria isolated in human meconium, feces that form in the fetus before birth, and others (Jiménez et al., 2008, Stout et al., 2013, Ardissone et al., 2014, Aagaard et al., 2014). The development of the fetus may be influenced by a placental microbiome, even if it is not necessarily transferred to the fetus in utero. But placental colonization can occur during delivery due to breaks in the placental barrier (Willyard, 2018). Although bacteria have been isolated from the umbilical cord of neonates born from cesarean umbilicals (Jiménez et al., 2005), many of these studies have been criticized for lack of adequate controls for contamination, for evidence of the presence of bacteria viable rather than searching for bacterial genes by sequencing or inappropriate molecular approaches to detect the bacterium (Perez-Muñoz et al., 2017). 10

Moreover, there is additional evidence against the prenatal microbiome, and it comes from the existence of germ-free mouse models (Perez-Muñoz et al., 2017).

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2.2.1 Maternal diet and the microbiota Maternal nutritional status before and during pregnancy will influence the outcomes for the mother and the baby. The importance of an adequate diet during fetal life for long-term physical health is well described (Barker, 1998, Harding, 2001). Recent studies of diet in humans, in addition to poor cardiovascular health or obesity, have an impact on neurocognitive development in humans and rodents (Monk et al., 2013). However, some of these studies have been criticized because inappropriate controls are often selected and may introduce confounding factors that complicate the interpretation of truly intriguing results (Pellizzon, Ricci, 2018, Almeida-Suhett et al., 2017). If the mouse was fed a high-fat maternal diet, then there could be a greater increase in the number of bacteria in the mother's gut microbiome during pregnancy, but also differences in the composition's change from animals receiving a control regime (Gohir et al., 2015). The composition of the intestinal metabolome and microbiota in the macaque, mouse, and rat has been altered by prenatal exposure and adolescence to a high-fat diet (Oberbach et al., 2017, Buffington et al., 2016, Gohir et al., 2015, Ma et al., 2014). It has also been shown that the composition of the gut microbiota can be modified by a western prenatal diet, which results in an increase in the Firmicutes / Bacteroides ratio as well as gender differences in the expression of the genes of the colon (Steegenga et al., 2017). In addition, unhealthy diets in mice also lead to social deficits (Buffington et al., 2016, Graf et al., 2016), change in hypothalamic stress response (Grissom et al., 2017), inflammation (Grissom et al., 2017, Du et al., 2012) in offspring, and differences in expression sex ratio (Edlow et al., 2016, Graf et al., 2016). Researches about nutrients that affect microbiota have shown that some of them can have a positive influence. In particular, the study in mice by Patterson and colleagues, have revealed that a high-fat diet supplemented with omega-3 polyunsaturated fatty acids increased the diversity of the microbiota and significantly raised Bifidobacterium at the genus level (Patterson et al., 2014). Gibson et al. have noted that prebiotics help the growth of beneficial gut bacteria and that they include nondigestible fibers that are fermented by bacteria in the colon which produce short-chain fatty acids and play an important role in the body's functions (Gibson et al., 2017). Concerning the probiotics that are beneficial strains of bacteria, they bring health benefits to the host and their administration during pregnancy in humans may reduce the risk of atopy but not other immune-related diseases such as asthma (Elazab et al., 2013, Azad et al., 2013a). A study in rats by Hsu and colleagues, reports that maternal gut microbiota-targeted therapies (with probiotic Lactobacillus casei or prebiotic inulin) could be reprogramming strategies to protect from the development of hypertension caused by maternal fructose-rich diet (Hsu et al., 2018). Drugs and the microbiota Some medications can have a direct effect on the composition of the microbiota. The most evident class of medicine to affect the microbiota, are antibiotics that have a well-described impact on the gut microbiota with long-standing consequences for the host (Davey et al., 2013, de Theije et al., 2014, Keeney et al., 2014, Degroote et al., 2016, Langdon et al., 2016, Le Bastard et al., 2018). But non-antibiotic prescription drugs have a significant influence on the overall structure of the gut microbiota too (Le Bastard et al., 2018). Despite all this, only a few studies describe a correlation between the microbiota and the prenatal effect of drugs, and below are given some examples. For example, data by Kuperman and Koren have revealed that 11

antibiotics (which are the most commonly prescribed drugs during pregnancy) reduce the diversity and bacterial burden of the microbiome (Kuperman and Koren, 2016). Besides, negative effects of different classes of antidepressants, including selective serotonin (MunozBellido et al., 2000) inhibitors, ketamine (Yang et al., 2017), and tricyclic antidepressants (Csiszar and Molnar, 1992), can be seen in the growth of bacteria. That may matter, given that the depression is common during pregnancy, about 14 to 23% of pregnant women have symptoms of depression (Yonkers et al., 2009, Jimenez-Solem, 2014), and the antidepressants use during pregnancy has increased over the past 20 years (Cooper et al., 2007, Wichman et al., 2008).

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2.2.2 Maternal stress. Maternal immune activation model It has been proven that maternal stress is modulated by the HPA axis and that it affects this axis in the offspring. Maternal stress has resulted in children's altered resilience of different strains of rodents (Hiroi et al., 2016, Lee et al., 2016, Golubeva et al., 2015, Rana et al., 2015, Bale, 2015), increased anxiety, increased serum corticosterone levels, and increased social unrest. Maternal stress can also alter the intestinal and vaginal microbiota during pregnancy, disrupt glucose metabolism in mice (Jašarević et al., 2017), and reduce the diversity of maternal intestinal microbiota. The vaginal microbiota-related changes in pregnancy-related mice were interrupted by a variety of prenatal stress, and this stress also had an impact on the protein content of the vaginal mucosa, which could possibly have contributed to an alteration of the vaginal mucosa. the abundance of Firmicutes and Bacteroidetes in the intestinal microbiota of their offspring (Jašarević et al., 2015). In the case of humans, persistent maternal stress (including prenatal and postnatal stress) would lead to mental health problems in adult offspring (Betts et al., 2015) and influence the development of the offspring microbiota during the first 110 days after birth (Zijlmans et al., 2015). The maternal immune activation (MIA) model is a controversial model in which maternal infections during pregnancy could alter psychiatric outcomes in children (Estes and McAllister, 2016). MIA modeling in mice commonly administers a polyinosinic mimetic viral polycytidylic acid or bacterial lipopolysaccharide to produce psychiatric endophenotypes in offspring. Specifically, viral mimetic polyinosinic polycytidylic acid administered in embryonic day 12.5 mice changed the composition of the gut microbiota and increased intestinal loss by reducing claudin expression while also increasing intestinal cytokine levels, including including interleukin 6, in offspring (Hsiao et al., 2013). This model also improved bacterial production of 4-ethylphenylsulfate, resulting in anxiety-like symptoms in wild-type mice (Hsiao et al., 2013). But there is a heterogeneity in the time of administration of polyinosinic viral mimetic polycytidylic acid, which can lead to the development of different biomarkers or behaviors common to different disorders, including schizophrenia (Juckel et al., 2011, Li et al., 2009) and spectrum disorders of autism (Malkova et al., 2012). Bacterial mimetic lipopolysaccharide can also induce behavioral phenotypes for depression, for anxiety, for alterations in hippocampal development and neurogenesis (Escobar et al., 2011, Romero et al., 2007), for an increase in postnatal inflammation (Oskvig et al., 2012), and for autism spectrum disorders in offspring (Depino, 2015, Oskvig et al., 2012) although there is currently no study on its impact on the microbiota. In mice, persistent fetal intestinal lesions in adulthood, as well as placental lesions, are the result of maternal inflammation induced by lipopolysaccharide (Fricke et al., 2018). PART 2.3 12

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Cesarean section, neurodevelopment, and health Now we will consider in more detail how the processes of colonization and the formation of the immune response occur during and after birth. We will focus on the C-section since it has been shown that delivery by cesarean section can have an immediate impact on psychological health in future life. There are now a large number of studies showing a marked effect of mode of delivery on the gut microbiome (Jakobsson et al., 2014, Dominguez-Bello et al., 2010, Mueller et al., 2015, Biasucci et al., 2008, Bäckhed et al., 2015, Madan et al., 2010, Azad et al., 2013b, Salminen et al., 2004, Brumbaugh DE et al., 2016, Dogra S et al., 2015, Grześkowiak et al., 2015, Martin et al., 2016, Hill et al., 2017, Tun et al., 2018), although some studies have found less of an influence than others (Chu et al., 2017). Infants born via cesarean section (CS) had a gut microbiota more similar to the maternal skin microbiota than the vagina (Jakobsson et al., 2014, Dominguez-Bello et al., 2010, Mueller et al., 2015, Biasucci et al., 2008), delayed Bacteroides colonization (Mueller et al., 2015, Biasucci et al., 2008), delayed Lactobacillus colonization (Dominguez-Bello et al., 2010), lower circulating chemokines (Jakobsson et al., 2014), and a higher risk of vertical obesity transmission from their mother (Tun et al., 2018). Despite the fact that recovery of the microbiota in C-section infants using a vaginal swab has been tested, the long-term consequences of such an intervention have yet to be studied (Dominguez-Bello et al., 2016). The relative contribution of such disorders to brain health is less clear, although epidemiology and animal researches are beginning to reveal some clear links (O’Neill et al., 2016, Fond et al., 2017, Moya-Pérez et al., 2017, Martinez et al., 2017, Curran et al., 2017). The biochemical landscape in the maternal body can be completely different if mothers give birth by cesarean section and if there is no labor. In fact, the labor is responsible for a change in contractile and endocrine inflammatory factors. The creation of the neonatal microbiome and the change of maternal microbiome could be affected by these modifications. In most cases, fetal membranes break during labor, exposing the fetus to maternal vaginal bacteria (Stinson et al., 2018). The initial environment is shaped by the pioneer species present in the gut of the newborn. This influences the immune cascades and the dynamic succession of microbes. In the intestine, the microbial community is modulated by the pH gradient, digestive processes, gases, and nutrients. These attributes also see their characteristics influenced (McKeen et al., 2019). So, in utero, a microbiota resembling an oral microbiota present in the mother will then begin to colonize the intestine of the newborn, for example, low-abundance commensal bacteria such as Escherichia Coli, Prevotella, and Neisseria (Aagaard et al., 2014). However, the delivery mode is considered to be the first confirmed major event that allows the microbiome to be seeded in infants with sustainable colonizers (Backhed et al., 2015). The bacteria delivered vaginally are mainly colonized by Bacteroides, Escherichia/Shigella, Parabacteroides, and Bifidobacterium, among which several are obligatory anaerobes. C-section infants are fortified with Staphylococcus, Streptococcus, Veilonella, Haemophilus, and Enterobacter, which are associated with environmental, oral and cutaneous species (Backhed et al., 2015), with much of it being aerobic. In the first year of life in infants, differences in gene content (i.e., the metagenome), and the structure of the microbial community decrease between those delivered vaginally and those delivered by C-section. However, observing until the age of 2, differences in innate and adaptive immunity remain detectable. If these infants were delivered by C-section, lower levels of IgM, IgA, and IgG secreting cells were found, indicating a reduced adaptive immune response, a lower CD4+ T lymphocyte response, and lower levels of chemokines supporting Th1, IFNy and IL-8 (Amenyogbe et al., 2017). 13

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The pioneer facultative anaerobic species with metabolic flexibility in the presence of oxygen, modify the environment in the first weeks of life in favor of obligate anaerobic species through the use of oxygen to create a more anaerobic environment (Penders et al., 2006), and by reducing the substrates of light by redox-dependent (oxygen)-dependent genetic pathways that produce metabolites, such as acetate, which may be obligatory and stimulate anaerobes (Appleman et al., 2005). The meconium of newborns is rich in facultative anaerobes such as E. coli, but the fecal microbiota becomes more diversified with the appearance of obligate anaerobic such as Bifidobacterium and Clostridium from the first week (Jiménez et al., 2008). For infants born from a C-section, recent research shows that if there was a period of work before the operation, then the microbiota of infants resembles that of infants born in the vagina, and if not, the microbiota resembles that of the maternal skin (Chu et al., 2017). Early microbial disruption is due in part to cesarean section, and during infancy this disruption of microbial colonization affects the microbial-host interaction, leading to long-term metabolic consequences in the host (Dominguez-Bello et al. 2016, Cox et al., 2014, Dominguez-Bello et al., 2010). Besides, it has been shown that during the first two years after birth, neonates of cesareans will be more likely to contract atopic disease than naturally born newborns, conforming to the data from LISA study by Negele et al. (2004). As reported by the conclusions drawn from a systematic review, Rutayisire et al. (2016), cesarean section is associated with a lower abundance of Actinobacteria and Bacteroidetes phyla, Bifidobacterium and Bacteroides, the most affected genera, and lower microbial diversity. A recent study (Liu et al., 2019) noticed that the compared with the vaginally delivered and cesarean delivered infants was characterized by a decrease in phylum Actinobacteria, class Actinobacteria, order Bifidobacteria, and family Bifidobacteriaceae, as well as an increase in phylum Firmicutes, classes Negativicutes and Clostridia, orders Selenomonadales and Clostridiales, and family Lactobacillaceae. Four genera were significantly different: Bifidobacterium was enriched in the group vaginally delivered, and Lactobacillus, Veillonella, and Klebsiella were enriched in the group cesarean delivered. It was concluded by a systematic review of Rutayisire et al. (2016) that cesarean section was associated with a lower abundance of Actinobacteria and Bacteroidetes phyla, Bifidobacterium and Bacteroides (being the most affected genera), as well as lower microbial diversity. Moreover, these authors, in good agreement with Milani et al. (2017), reported that the Firmicutes phylum, mainly represented by Clostridium and Lactobacillus, was increased more in CS infants than in neonates with vaginally delivered (VD) from birth to the third month of life. It is observed that Lactobacillus is very abundant in the vagina of the mother and specific to it (Chu et al., 2017). The extent of infant acquisition of Lactobacillus in the gastrointestinal tract is a good example of the effect of birth mode on the gut microbiota. As reported by Nagpal et al. (2016), unlike infants born in the vagina, who had higher detection rates of Lactobacilli in the intestinal tract throughout the first six months, cesarean infants persisted during this period to have a low detection rate in Lactobacilli. However, by the age of three, this difference in Lactobacilli detection rates has disappeared. These data prove that colonization of the gut microbiota can begin already before birth, that is to say in utero. Besides, relatively different proportions of facultative and obligatory anaerobes in the meconium of CS babies and delayed/inferior colonization of Lactobacilli indicate that from the first day of life, the elements of intestinal dysbiosis associated with the mode of delivery can begin to accumulate (Nagpal et al., 2016). Birth mode also affects bacterial levels in the Bacteroides and Clostridium genera in the individual's microbiota (Jakobsson et al., 2014, Penders et al., 2006, Wampach et al., 2017, Martin et al., 2016, Bäckhed et al., 2015, 14

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Fallani et al., 2010, Biasucci et al., 2010). As reported by a study of 24 infants in south-east Sweden, at the phylum, if neonates are born by cesarean section and not born vaginally, then we find that low abundance of Bacteroidetes (Jakobsson, et al., 2014). It has been observed that this phenomenon persists even after the first 2 years of birth (Jakobsson et al., 2014). This is consistent with previous reports that report late establishment in the first six months of Bacteroides group members in cesarean infants (Martin et al., 2016) and one year of life (Adlerberth et al., 2006). The link between development, gastrointestinal microbiota transmission and birth mode (vaginal or cesarean section) has not been demonstrated by all studies. For example, according to one study, during the first 3 months after birth, 21 births were not affected by the birth mode (Arboleya et al., 2012). In this study, this could be explained by the incorporation of premature infants (gestational age 30-35 weeks), since another study of premature infants also revealed that the mode of delivery was not associated with significantly to the composition of the microbiome (Stewart et al., 2017). In summary, studies indicate that if infants are born by cesarean section, then they tend to have: a less diverse microbiota (Martin et al. 2016, Jakobsson et al., 2014, Biasucci et al., 2008), a lower number of anaerobes (e.g., Bacteroidetes), that they contract atopic diseases (Biasucci et al. 2008) and metabolic disorders (Dominguez-Bello et al., 2016) more often than children born from unassisted vaginal delivery, and there is delayed colonization of the microbial population. However, these studies are complicated by the differences in analytical methodology and ethnic and geographical diversity (Chong et al., 2018). Chu et al. studied the potential metabolic function of neonatal and early infant microbiota and taxonomic composition in several body sites (vaginal introitus, oral cavity, nostrils, skin, posterior fornix, stool) and concluded that the infant microbiota undergoes significant reorganization the first 6 weeks of life, mainly motivated by the body site and not by the mode of delivery (Chu et al., 2017). At the age of 6 and 12 months, Rutayisire et al. (2016) found no differences in the microbiota because of the mode of delivery, this was also observed by other authors, even up to the age of 7 years (However differences at this age were less pronounced than in neonates) (Milani et al., 2017, Salminen et al., 2004). Different confounding factors could be the partial cause of the differences in the results obtained by different authors, but also these divergences can be explained by confusions that are not always correctly identified, for example, factors related to experimental techniques used (dependent and independent culture techniques, DNA extraction methods, etc.), neonatal exposures (such as intrapartum antibiotic prophylaxis), or racial or geographical differences (Arboleya et al., 2018). It is important to know that in terms of the risk of childhood and maternal illness, the abuse of C-section is not without risk. It has been shown that, unlike women who give birth by VD, women with CS are more likely to develop a urinary tract infection (Gundersen et al., 2018). Subcutaneous delivery is the main risk factor for maternal postpartum infection (Smaill et al., 2014). Because of antibiotics introducing antimicrobial agents during the perinatal period to reduce the risk of infection for these women, this poses an additional risk for the development of the infant and maternal microbiota. Besides, the differences between CS and VD babies are not limited to the gut microbiota; Infants born after CS have been found to have reduced levels of immune mediators such as cytokines (Malamitsi-Puchner et al., 2005). As a result, there were unsurprising reports that CS had both short- and long-term consequences for infants, and that in comparison with VD it was associated with a very poor health outcome. As can be seen in the Apgar scores (measuring neonatal health), the differences between CS and VD babies are already observable from the first moments of life (Costa-Ramón et al., 2018). Subsequently, a higher risk 15

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of developing celiac disease (Decker et al., 2010), allergic diseases (Wopereis et al., 2014, Bager et al., 2008, Thavagnanam et al., 2008), obesity (Mueller et al., 2017, Pei et al., 2014), hypertension in young adults (Horta et al., 2013), and type 1 diabetes (Cardwell et al., 2008), was observed in subjects delivered by CS. Some epidemiological studies show that cesarean delivery results in a slight increase in some neuropsychiatric disorders, such as autism spectrum disorders (ASD), attention deficit hyperactivity disorder and bipolar disorder (Curran et al., 2015, Chudal et al., 2014). But other definitive studies have not found links with attention deficit/ hyperactivity disorder, autism or psychosis (Curran et al., 2016, O’Neill et al., 2016). Recently, even after controlling for common family confounders and measured covariates, a higher risk of obsessive-compulsive disorder was associated with a variety of perinatal risk factors, including the mode of delivery for birth (Brander et al., 2016). Regarding psychological development, there are several hypotheses showing a potential connection with CS childbirth (Curran et al., 2015). With cesarean section, brain disorders later in life, as well as neurodevelopmental disorders could appear due to changes in the normal developmental trajectories of the microbiota-brain-gut axis as well as the disruption of its normal maturing (McVey Neufeld et al. al., 2016, Sampson et al., 2015, Borre et al., 2014, Foster et al., 2013, Collins et al., 2012, Cryan and Dinan, 2012, Dinan and Cryan, 2012, Rhee et al., 2009). Exposure to a bacterium at birth is a critical event in establishing a stable intestinal microbiota, which is altered when infants are delivered by cesarean section (Moya-Pérez et al., 2017). We understand more and more that the immune system and the hypothalamic-pituitary-adrenal (HPA) axis will be better prepared to face future insults if there has been birth stress due to vaginal birth (Cho and Norman, 2013). The fact that the elective CS is normally programmed between 37 and 39 weeks of gestation (as opposed to complete 40-week gestation to avoid spontaneous labor) may be another possible explanation for the impact of childbirth on psychological development (Tita et al., 2009). The last few weeks may be important for brain development. Therefore, not being born at term may lead to an increased risk of psychological problems (Curran et al., 2015). A study done in 2010 shows that a birth between 37 and 39 weeks or early-term birth implied a need for special education (Mackay et al., 2013). In addition, the gut microbiota affects brain physiology through regulation of microglia development, maturation and function of microglia, synaptogenesis, neurotransmitters regulation and regulation of neurotrophic factors such as BDNF (Abdel-Haq et al., 2019, Erny et al., 2015, Stilling et al., 2015, Clarke et al., 2013, McVey Neufeld et al., 2011, Heijtz et al., 2011, Sudo et al., 2004). In spite of everything, any association may be motivated by factors independently associated with both psychological development and CS and not only CS itself. Cerebral physiology could be affected, according to researches on the main mechanisms of neuropsychiatric disorders, by the gut microbiota (Zhuang et al., 2019). Brain physiology affects behavior through the pathways of gut–brain connection (neural and humoral), thus showing that the microbial community in the intestine is an important element (Cryan and Dinan, 2015). Also, other studies have shown that gene expression associated with learning, memory, neuronal plasticity, neurogenesis and disorders such as schizophrenia, cognitive dysfunction, depression, could be influenced by changes at the level of the host epigenome because of gut microbiota activity (Majnik et al., 2015, Stilling et al., 2014). Conforming to recent studies for the prevention of neurodevelopmental and neurodegenerative disorders, the intestinal microbiota is essential for maintaining the healthy functional condition of microglia (Erny et al., 2015, Harry 16

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et al., 2013). As reported by some studies, the intestinal microbiota of children with ASD presents different shares of Firmicutes and Bacteroidetes (Tomova et al., 2015, Finegold et al., 2010). Besides, attention-deficit /hyperactivity disorder (ADHD) and schizophrenia have also been evaluated to be related to gut microbes (Cenit et al., 2017a, Dinan et al., 2014). With a study by Rutayisire et al. (2017), it was shown that cesarean section had a real impact on the total scores of the Strengths and Difficulty Questionnaire (SDQ), which corroborates previous studies reporting CS associations with ASD (Curran et al., 2015) and ADHD (Silva et al., 2014). However, no such association had been shown by two previous studies. Al Khalaf et al. (2015) noted no significant association between total SDQ scores and CS in three-year-old children and Curran et al. (2016) detected no association between abnormal SDQ scores and CS in sevenyear-old children. The results of Rutayisire et al. (2017) for the SDQ subscales indicate that cesarean delivery is not associated with hyperactivity, emotional problems or conduct problems, but with behavioral problems in childhood. Exposure to microbiota at early-life is one of the alleged biological mechanism that links the development of behavioral problems and CS. It has been suggested that the child development and risk of unfavorable behavior may be due to postpartum complications in his mother after cesarean section. Concerning psychological impact factors, the appearance of negative attitude and behavior in the mother could have effects on peer and behavior problems of the child. And for children born via cesarean section, this could be the explanation for the increase in the rate of neurobehavioral problems (Rutayisire et al., 2017). The study by Polidano et al. (2017) suggested that obesity, attention deficit disorder (ADD), and breastfeeding were important mediators for the relationship between child cognitive outcomes and of cesarean delivery. By the 1st stage of the mediating analysis of this study, it was also shown that higher rates of obesity, lower rates of breastfeeding, and higher rates of ADD are associated with a cesarean birth. According to the 2nd stage, higher cognitive performance is significantly associated with breastfeeding, whereas ASD, ADD and obesity are significantly associated with lower cognitive performance (Polidano et al., 2017).

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PART 2.4 Postnatal environment impacts on microbiota The microbiome and metabolic reactions of the human infant gut are distinct from those of the adult gut. Colonization of the baby’s intestine begins immediately after birth, in a process that is believed to include the initial seeding with vaginal and skin microbes obtained from the mother, which are gradually replaced during the first months of life with strains obtained from other sources with large shifts compositions during weaning or antibiotic treatment (Mueller et al., 2015). Exposure to antibiotics within the first 3 years of life in humans decreased microbiome stability and diversity while it transiently increased transcription of antibioticresistant genes (Yassour et al., 2016) and increased adiposity in male individuals during childhood (Azad et al., 2014).

2.4.1 Postnatal diet and the microbiota Multiple investigations have determined that nutrition and medication use are the main factors affecting gut microbiota diversity (Zeevi et al., 2015, Falony et al., 2016, Goodrich et al., 2016, Turpin et al., 2016, Wang et al., 2016, Zhernakova et al., 2016, Jackson et al., 2018, Rothschild et al., 2018). The important factor in the establishment of commensal microbiota of the newborn is the nature of nutrition. Breast milk is an optimally suited nutrition for infants, 17

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ensuring its optimal development (Butte et al., 2002). Human milk is very rich in lactose, fatty acids and hundreds of different types of oligosaccharides consisting of different combinations of sugar moieties bonded through a variety of glycosidic bonds, some of which are sialylated (Smilowitz et al., 2014). Oligosaccharide glycoside of milk and other bonds cannot be lysed by enzymes that encode the human genome, like dietary fiber in the gastrointestinal tract of an adult, and the infant relies on bacteria to digest these compounds. It is believed that the microbes necessary for their digestion are transmitted from mother to baby vertically through milk (Mueller et al., 2015). These bacteria, in particular Bifidobacterium infantis, Bacteroides thetaiotaomicron, and Bacteroides fragilis, are present in the intestinal microbiota of most children who are exclusively breastfed in the first months of life (Yatsunenko et al., 2012, Bäckhed et al., 2015). The genomes of these species are well equipped for cleavage of oligosaccharides present in human milk, encoding several receptors, intracellular and extracellular enzymes that can digest many of the sugar components of human milk oligosaccharides (Sela et al., 2011). Under the postnatal period, many women suffer from acute and chronic health conditions like cough/colds, infections, mastitis, intestines problems, headache, migraine, back pain, hypertension, depression (Glazener et al., 1995, Brown and Lumley, 1998, Yokoe et al., 2001, Amir et al., 2007, Declercq et al., 2008, Ahnfeldt-Mollerup et al., 2012, Woolhouse et al., 2012), and need medications. Most of the commonly used drugs are compatible with breastfeeding and relatively safe for nursing infants. The dose obtained by babies through drug excretion into breast milk, is mostly small and much less than the known medication safe doses used in newborns and infants (Hotham et al., 2015). Nevertheless, in humans, antidepressants have been detected to transfer through breast milk, and some can reach a clinically significant concentration in the infant’s serum (Sachs and CO Drugs, 2013), although their effects on the infant have not yet been established (Glover and Clinton, 2016). Some pharmaceutical drugs may cause side effects in breastfed babies (Chaves and Lamounier, 2004) or can interfere with the let-down reflex and reduce milk supply (Chaves and Lamounier, 2004, U.S. Department of Health & Human Services, 2018). Dysbiosis of the neonatal intestine makes a significant contribution to developing colic in the term infant, to the disease processes which concern premature infants, and to the impacts of newborns’ health future. Treatment with enteral probiotics, prebiotics, and synbiotics during postnatal life seems to be a possible way of transforming the infant's microbiome. Intestinal colonization by beneficial bacteria is important for the establishment and maintenance of the mucosal barrier, therefore protecting the newborn from enteric pathogens and inflammation (Sohn and Underwood, 2017). Studies of the use of compositions for bottle-feeding, with the addition of oligosaccharides, indicate the achievement of a prebiotic effect (Fanaro et al., 2005, Rao et al., 2009, Srinivasjois et al., 2013), which confirms their effectiveness comparable to that of breastfeeding. The international study including 440 healthy on time born babies had shown that the formula with a combination of neutral oligosaccharides and pectin-derived acidic oligosaccharides is effective as prime prevention in low developing atopic dermatitis risk infants (Grüber et al., 2010). As for probiotics, oral introduced probiotic strains are not able to stay in the intestines for a long time, since the composition of the indigenous (constant) microbiota is largely determined genetically and is based on subtle immune interactions with a host (Methé et al., 2012, Huttenhower et al., 2012). However, the positive effects of probiotics have been proven (Rijkers et al., 2010), including mental health. Studies by Huang et al. (2016) report a

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reduced risk of depression and studies by Pärtty et al. (2015) and Gilbert et al. (2013) indicate a reduction in the risk of autism. When breastfeeding is stopped and solid foods are introduced, the infant's intestinal microbiota begins to change in the direction of a more adult composition characterized by an increase in the number of Bacteroides, Clostridium, Faecalibacterium and Ruminococcus (Bäckhed et al., 2015, Mueller et al., 2015), the composition of the intestinal microbiota in children continues to resemble more and more the composition of adults until it reaches maturity at the age of 3-4 years (Yatsunenko et al., 2012). Besides nutrition, lifestyle may also affect the intestinal microbiota composition and diversity. A recent investigation by Mitchell and colleagues has described that doing exercise was linked with modifications in gut microbial composition and with an increase in butyrate producing bacteria regardless of dietary in rodents and humans. However, the overall quality of evidence in the studies in humans was low (Mitchell et al., 2019).

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2.4.2 Postnatal stress and the microbiota Events in early childhood, both positive and negative, have a programming effect on the subsequent development of the individual, on its behavior, physiological and neurobiological functions (Ladd et al., 2000, Bondar and Merkulova, 2016, Silberman et al., 2016). Clinical studies have shown that stress in early childhood in humans leads to a decrease in cognitive functions and emotional disturbances that can persist throughout life (Gershon et al., 2013, Pesonen et al., 2013). Studies in rodents also show that stress in early life is associated with behavioral and cognitive abnormalities in adulthood (Sánchez et al., 2001, Pryce and Feldon, 2003, Kosten et al., 2012). Early postnatal stress affects the hypothalamic-pituitary-adrenal axis and promotes to the programming of brain health later in life (Heim and Nemeroff, 2001). Different types of early postnatal stress (social isolation and maternal separation) change the intestinal microbiota composition and metabolism in rats (Farshim et al.,2016, Doherty et al., 2018, O’Mahony et al., 2009) and their inflammatory profiles (Doherty et al., 2018, O’Mahony et al., 2009). Social isolation also impaired memory and learning in rats (Doherty et al., 2018). Studies with germfree mice noticed that were more vulnerable to restraint stress-resulting in higher corticosterone and adrenocorticotropic hormone in plasma (Sudo et al., 2004, Clarke et al., 2013), a reduction in glucocorticoid receptor messenger RNA, and an increased stress response (Sudo et al., 2004). Notably, these effects were rescued with microbiota transplantation during adolescence but not during adulthood (Sudo et al., 2004).

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2.4.3 Host genetics Diet and medications only explain small part variations of the microbiome in the human populace (Scepanovic et al., 2019). Host genetics has also been suggested, as a member of affecting relative gut microbiota abundance (Khachatryan et al., 2008, Goodrich et al., 2014). Even so, variations in the microbiome between individuals can be considerable, the microbiome of each individuals can not stay stable (David et al., 2014, Ding and Schloss, 2014, Oh et al., 2016). That suggests that the host genetic is one factor maintaining the human microbial communities' composition (Kolde et al., 2018). Host genetics plays a critical role in human diseases, but just recently has science come to understand how the microbiota cooperates with host genetics. For example, metabolic disorders that have a genetic component (Herbert et al., 2006, Frayling et al., 2007) are also associated 19

with a specific gut microbiota structure (Turnbaugh et al., 2009, Qin et al., 2012, Karlsson et al., 2013), suggesting that impaired host bacterial regulation is a possible mechanism for origination and development of a disease. On the way to the understanding of possible interactions between the risks of developing schizophrenia and the composition of the host microbiota, it is important to note that genetics form a strong risk factor for schizophrenia (Henriksen et al., 2017) with heritability between 64 and 81% (Sullivan et al., 2003, Lichtenstein et al., 2009).

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PART 3 The microbiome in schizophrenia Schizophrenia is a destructive illness, it is one of the top 15 leading causes of disability worldwide in 2016 (GBD 2016 Disease and Injury Incidence and Prevalence Collaborators, 2017). Previous investigations have focused on the analysis of the human genome to determine the pathogenesis of SCZ (The Schizophrenia Psychiatric GWAS Consortium, 2011). Still, the known interactions are probably estimate just for about 4% of the variance in schizophrenia. Consequently, for a better understanding of this disease, affecting approximately 0.3 to 0.7% of the general population global (Saha et al., 2005, Moreno-Küstner et al., 2018), there should be researches also to recognize the role of non-human genetic factors in the inception of schizophrenia (Zheng et al., 2019). An epidemiological study has shown that prenatal microbial infection in the early stages of pregnancy, has increased the risk of developing schizophrenia and other schizophrenia spectrum disorders by 10-20 times in offspring (Babulas et al., 2006). Several studies have investigated the intestinal microbiota in association to schizophrenia (Clarke et al., 2013, Sudo et al., 2004, Christian et al., 2015, Hsiao et al., 2013, Desbonnet et al., 2010, Castro-Nallar et al., 2015, Desbonnet et al., 2015, Bercik et al., 2011, Bailey et al., 2011, Desbonnet et al., 2009, Gareau et al., 2011, Tillisch et al., 2013, Messaoudi et al., 2011, Jiang et al., 2015, Naseribafrouei et al., 2014, Severance et al., 2013, Dickerson et al., 2014, Davey et al., 2012, Davey et al., 2013, Morgan et al., 2014, Bahr et al., 2015). It is difficult to determine the mechanism by which intestinal microbiota can contribute to the development of schizophrenia, given the limitations associated with the current lack of an animal model of schizophrenia, which would cover all the complexities of the disease. (Al-Asmari and Khan, 2014, Powell and Miyakawa, 2006). However, as described earlier, the gut microbiota could modulate brain function and behaviors through the “microbiota-gut-brain” (MGB) axis. Recent evidence has shown that the gut microbiota have been reported to be associated with alterations in anxiety (Diaz Heijtz et al., 2011), memory (Gareau et al., 2011), cognition (Desbonnet et al., 2014), and locomotor activity (Sampson et al., 2016). Nonetheless, some studies have evaded to the role of the gut microbiome in schizophrenia behaviors. In animal studies, intestinal microbiota have played a key role in postnatal development and maturation of neural, immune, and endocrine systems (Clarke et al., 2013), and these behavioral and physiological processes are often disturbed in schizophrenia patients (Miller et al., 2011). These studies suggest that the disruption of the “microbiota-gut-brain” (MGB) axis may promote the development of schizophrenia (Zheng et al., 2019). Studies in mice by Desbonnet and colleagues have shown the microbiota modulates the programming of social behavior and cognition, attributes that are known to be violated in schizophrenia (Desbonnet et al., 2015). A recent study has found that unmedicated and medicated patients with schizophrenia had a decreased microbiome α-diversity index and have noticed alterations of gut microbial composition compare to healthy controls. Some unique bacterial taxa (such as Veillonellaceae 20

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and Lachnospiraceae) were related to the severity of schizophrenia (Zheng et al., 2019). Clinical studies have allowed for the role of change in the digestive and digestive microbiota in schizophrenia. For example, non-compliance with the regulation of inflammatory processes is involved in schizophrenia (Al-Asmari and Khan, 2014, Chase et al., 2015) and it is expected that the intestinal microbiota modulates immune processes (Lopetuso et al., 2014), it is expected that the microbiome-intestine-brain axis has the ability to act on schizophrenia using immunological devices. When the oropharyngeal microbiome was compared to patients with schizophrenia and healthy people, Castro-Nallar and his colleagues found that certain types of bacteria significantly predominate in patients suffering from this mental state. In addition, differences in the number of species and their distribution were recorded, and they also observed completely different metabolic pathways. In patients with schizophrenia, lactic acid bacteria and the system of metabolite transport prevailed (Castro-Nallar et al., 2015). But this study provides early confirmations of differences in the oral microbiota between patients with schizophrenia and the control group; there are no confirmations regarding the connection of the oropharyngeal component with the digestive microbiome, encompassing effects of the former on the gut-brain axis. Yuan et al. (2018) studied microbiota changes in 41 patients with schizophrenia in the first episode after 24 weeks of treatment with risperidone. In patients with schizophrenia compared with healthy controls, there was significantly less fecal Bifidobacterium, Escherichia coli and Lactobacillus. Conversely, a significantly high amount of feces of Clostridium coccoides. After 24 weeks of treatment with risperidone, there was a significant increase in the amount of fecal Bifidobacterium and E. Coli, and there was a significant decrease in the amount of feces of Clostridium coccoides and Lactobacillus. The authors concluded that patients with schizophrenia in the first episode of the disease, suffering from schizophrenia, have anomalies in the composition of the microbiota, and noted that significant changes in fecal bacteria were due to treatment with risperidone. In addition, they suggested that these changes were associated with metabolic changes caused by risperidone. The differences in fecal microbiota investigated by Schwarz et al. (2018) between 28 individuals diagnosed with first-episode psychosis (half of whom received a diagnosis of schizophrenia by the study 1-year follow up appraisal) and 16 health controls. They found an increased amount of Lactobacillus bacteria in psychotic patients. Interesting to note that, after up to 12 months of treatment, the subgroup of patients that showed the strongest differences in microbiota coincided with the subjects who had a lower response (Schwarz et al., 2018). Shen et al. (2018) evaluated the distinction in gut microbiota between 64 patients with schizophrenia and 53 healthy controls and found in patients with schizophrenia a higher number of Proteobacteria, Succinivibrio, Megasphaera, Collinsella, Clostridium, Klebsiella and Methanbrevibacter and a lower number of Blautia, Coprococcus, Roseburia compared to healthy controls. Interestingly, the authors noted the possibility of using 12 microbiotas as diagnostic factors for distinguishing patients with schizophrenia from the control group. Yolken et al. (2015) tested the association between genomes schizophrenia and bacteriophage. 41 persons with schizophrenia and 33 healthy controls have participated in this study. Patients with schizophrenia had in the oropharynx significantly more common Lactobacillus phage phiadh. The existence of this microorganism also correlated with immune disorders and valproate administration in the study group. Severance et al. (2013) evaluated serological surrogate markers of bacterial translocation soluble CD14 (sCD14) and lipopolysaccharide binding proten (LBP). LBP and sCD14 levels 21

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were significantly interconnected, as accord with their coordinated roles in activating the innate immunity. Both these markers in persons with schizophrenia had significantly correlated with Creactive protein (CRP), indicating a common pathway of inflammation. Although coherence these markers, the study had detected notably elevated sCD14 level in schizophrenia compared to controls, which was not matched by raise LBP. Considering bacterial translocation might partially promote to inflammation psychiatric disorder-associated, other forms of innate immunity dysregulation proper to the disease may also explain these results. Critchley and Harrison (2013) tested the impact of visceral homeostasis on both physiological and mental capacities of the brain and added to the studies showing that microbiota might influence gutbrain axis at any age, leading to neurodevelopmental or neurodegenerative conditions (Dinan and Cryan, 2017b). Investigations of the fungal composition of the human gut-the Mycobiome are also rising (Suhr and Hallen-Adams, 2015). A case-control cohort study with 261 individuals with schizophrenia, 270 with bipolar disorder, and 277 non-psychiatric controls has been done. No differences were found when analyzing Candida albicans exposure at the group level. However, there has been an increase in the likelihood of schizophrenia in men when conducting statistical distribution by gender (Severance et al., 2016a). The same group conducted a randomized, double-blind, placebo-controlled, 14-week period probiotic trial, and demonstrated that probiotic treatment significantly reduced C. albicans antibodies in males only, and a trend toward improvement in positive psychiatric symptoms in seronegative males (Severance et al., 2017). Both groups had antipsychotic treatment, but antipsychotic medication regimes were not different between probiotic and placebo groups.

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PART 3.1 The association between schizophrenia and immune inflammatory response Several clinical studies have investigated blood-based biomarkers of microbial translocation (Castro-Nallar et al., 2015, Yolken et al., 2015), Severance et al. (2012, 2013, 2016, 2017)). Patients with schizophrenia exhibited higher serum antibody levels to fungal pathogens Saccharomyces cerevisiae and Candida albicans (Severance et al., 2012, 2016) and soluble CD14 (Severance et al., 2013), a protein marker of bacterial translocation. Studies of the effects of psychotropic drugs on these biomarkers showed that levels of antibodies to Saccharomyces cerevisiae were higher in patients with psychosis of the first episode who did not receive antipsychotic treatment, compared with patients receiving antipsychotics (Severance et al., 2012). Otherwise, antibodies to C. albicans, sCD14, and LBP did not differ in patients who take various types of psychiatric medicines (including lithium, valproate or antipsychotics) (Severance et al., 2016, 2013). The increased level of these serological biomarkers suggests increased permeability of the intestinal lumen or “leaky gut” through the process of microbial translocation, and denotes inflammation of the intestine (Dickerson et al., 2017). Hsiao et al. (2013) in a preclinical model of autism detected that microbial dysbiosis led to intestinal permeability and elevated cytokine levels. Thereby, the gut may become a cause of autointoxication. Emaciation or dysbiosis of microbes that promote development of the immune system may be at the reason of a chronic inflammatory state in severe mental illnesses (SMI), which can affect the function of the central nervous system (Dickerson et al., 2007, Frodl and Amico, 2014, Pedersen et al., 2008). Actually, the memory performance was significantly reduced in women with schizophrenia who were seropositive for C. albicans, compared to their respective seronegative counterparts (Severance et 22

al., 2016). The outcomes by Severance et al. (2017) had shown biological improvement attributable to probiotic treatment and proposed that manipulation of the intestinal microbiota with probiotics may regulate immune responses and leads us to the conclusion that microbial therapy could be a potential strategy to improve psychiatric symptoms and relieve gastrointestinal comorbidities.

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PART 3.2 Studies about probiotic and prebiotics use, with reference to schizophrenia Considering the latest data on the relationship between intestinal microbiota and schizophrenia and the role of environmental factors in the development of this disease, it is possible to use probiotics for the treatment of inflammatory processes of the gastrointestinal tract, with a positive effect of schizophrenia symptoms. Such treatment with “psychobiotics” (live bacteria, which when ingested in adequate amounts, confer mental health benefits) could become a breakthrough in the management of mental illnesses (Saulnier et al., 2013, Sarkar et al., 2016, Deans, 2017). Severance and colleagues explored the possible relationship between food antigen-associated immune activation in patients with schizophrenia and gastrointestinal inflammation. They recorded 193 subjects with non-recent and 67 with recent beginning of schizophrenia, while there were 207 persons in the control group. They uncovered food antigen antibodies and gastrointestinal inflammation in both schizophrenia groups (Severance et al., 2012). In a study published in 2015, the same authors explored the link between dietary agents (wheat gluten and bovine milk casein) and immune response in blood and sample of cerebrospinal fluid (CSF) in 105 patients with first episode of schizophrenia and 61 persons in the control group. In the experimental group of schizophrenic patients, the levels of IgG response to dietary proteins were significantly higher in both serum and CSF (Severance et al., 2015). Preliminary yet interesting information is emerging from clinical trials with probiotics in the treatment of schizophrenia (Bruce-Keller et al., 2018). Microbiome transplants from donor mice fed with high-fat diet showed that high fat-shaped microbiota disrupted cognitive, exploratory, and stereotypical/impulsive behaviors (Bruce-Keller et al., 2015). Other studies involving animal models demonstrated that probiotics may improve cognition, mood, anxiety, while improving neural activity and signaling (Sudo et al., 2004, Desbonnet et al., 2010, Bravo et al., 2011, Smith et al., 2014, Bruce-Keller et al., 2018). Also, mice studies have shown the ability of probiotics to promote hypothalamic synaptic plasticity and prevent decreases in hippocampal neurogenesis induced by stress (Ait-Belgnaoui et al., 2014). Dietary trans and saturated fats, may increase intestinal inflammation (Deopurkar et al., 2010, Okada et al., 2013), which results in a decrease of commensal Bacteroidetes and increase of pathogenic Enterobacteriaceae and Proteobacteria (Lupp et al., 2007, Stecher et al., 2007, Pédron and Sansonetti, 2008). Karakuła-Juchnowicz et al. (2016) reviewed the role of the food antigens in schizophrenia, the use of diet modification, as well as antibiotics and probiotics as the possible treatment solutions. Probiotics are microorganisms, usually Lactobacilli and/or Bifidobacteria (Messaoudi, 2011, Tillisch et al., 2013, Steenbergen, 2015, Sarkar et al., 2016). Prebiotics are nondigestible carbohydrates that increase beneficial microbiota. Prebiotics may improve emotional affect and modulate stress responses (Schmidt et al., 2015). Randomized trials have shown the efficacy of probiotics on mood (Messaoudi, 2011, Steenbergen, 2015) as well as the ability to reduce responses to stress (Kato-Kataoka, 2016). However, other studies have produced controversial results and therefore more trials are needed to completely demonstrate 23

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efficacy, to identify the specific strains that are most beneficial, as well as the correct dose and treatment duration (Doron and Snydman, 2015, Bruce-Keller et al., 2018). Similarly, large, controlled and well-powered studies about the efficacy of prebiotics are warranted (Bruce-Keller et al., 2018). Tomasik et al. studied probiotic in schizophrenia and found their significant impact in reducing von Willebrand factor (VWF) and increasing BDNF, monocyte chemotactic protein-1 (MCP-1), T-cell-specific protein RANTES (regulated on activation, normal T cell expressed and secreted), and macrophage inflammatory protein-1 beta (MIP-1) beta. Also, they found that probiotics were related to the regulation of intestinal immune and epithelial cells and suggested that supplementation of probiotics may improve control of gastrointestinal leakage in patients with schizophrenia (Tomasik et al., 2015). Dickerson et al. (2014) performed a randomized, double-blind, placebo-controlled study and enrolled 65 patients with schizophrenia who were first treated with double-blind probiotic or placebo for 14 weeks. Although no significant differences between probiotics and placebo groups were found in terms of changing schizophrenia symptoms severity, probiotics reduced the likelihood to develop severe bowel difficulty throughout the trial. Afterward, Severance et al. (2017) conducted a randomized, placebo-controlled, longitudinal pilot study and explored the use of probiotics in the treatment of both yeast gut infection and psychiatric symptoms 56 patients with schizophrenia. Probiotics were associated with a decrease of Candida albicans antibody levels as well as a decrease in gastrointestinal symptoms in male subjects and trends for improvement in positive schizophrenia symptoms in males who received probiotics and were seronegative for C. albicans.

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CONCLUSIONS Trough the knowledge we already have, the studies and the analysis being done recently, we can draw some conclusions. The microbiota community transmitted to the offspring may have plasticity. Dynamic changes in the maternal microbiota and the early offspring microbiota would occur due to the prenatal and postnatal environments, respectively, as well as host genetics. Although these changes may be beneficial for immediate survival, they may result in immediate and later physiological and behavioral consequences. This field has the potential for the development of new bioactive and dietary/lifestyle interventions, that would modulate the microbiota during pregnancy to reduce the risk of disease later in life. However, there are few studies directly assessing the impact of changes to the microbiota composition early in life on brain health outcomes during adulthood. Further research should focus on studying the microbiota modulation to support early neurodevelopment and brain health later in life. Additional studies of the relationship between schizophrenia and changes in the immune system, as well as the intestinal microbiota have great potential. In addition, exploring the possibility that resource such as probiotics may contribute to the treatment of inflammatory processes in the gastrointestinal system, and have a positive influence on the symptoms of schizophrenia, may promote the development of new therapies to help the human with this disease and potentially reducing the adverse metabolic side effects of current treatments. It will also be significant to research the effect of antibiotic treatment on neuropsychiatric conditions through the modification of the intestinal microbiota. In addition, the study of this area can lead to the creation of special dietary regimes, lifestyle interventions, which would contribute to the modulation of the microbiota during pregnancy, diminishing the risk of developing the disease at a later age. 24

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ACKNOWLEDGMENTS This work was supported by the GACR 304/18-09296S, AZV CR 17-31852A, Institutional support for NIMH-CZ was provided by the project "Sustainability for the National Institute of Mental Health" number LO161, "PharmaBrain" CZ.02.1.01/0.0/0.0/16_025/0007444 and Third Faculty of Medicine, Charles University in Prague. We would like to thank DanielBermejoRodriguez for language proofreading.

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