Neuroscience and Biobehavioral Reviews 108 (2020) 712–731

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

The connection between microbiome and schizophrenia T

a,b, a
Bogdana Golofast *, Karel Vales
a
National Institute of Mental Health, Topolova 748, 250 67 Klecany, Prague East, Czech Republic
b
Third Faculty of Medicine, Charles University, Ruská 87, 100 00 Prague 10, Czech Republic

A R T I C LE I N FO A B S T R A C T

Keywords: There has been an accumulation of knowledge about the human microbiome, some detailed investigations of the
Microbiome gastrointestinal microbiota and its functions, and the highlighting of complex interactions between the gut, the
Schizophrenia gut microbiota, and the central nervous system. That assumes the involvement of the microbiome in the pa-
Immune inflammatory response thogenesis of various CNS diseases, including schizophrenia. Given this information and the fact, that the gut
Prenatal environment
microbiota is sensitive to internal and environmental influences, we have speculated that among the factors that
Postnatal environment
Cesarean section
influence the formation and composition of gut microbiota during life, possible key elements in the schizo-
Probiotics phrenia development chain are hidden where gut microbiota is a linking component. This article aims to de-
Prebiotics scribe and understand the developmental relationships between intestinal microbiota and the risk of developing
schizophrenia.

1. Introduction et al., 2011), and pathogens can either be a reason of inflammatory

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., 2016). 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
(Rajilić-Stojanović 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.
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 mod-
ulator of brain development and subsequent adult behavior (Diaz Heijtz
diseases of the central nervous system or protect from them (Ochoa-
Repáraz et al., 2011). Epidemiological studies have shown a link be-
tween microbial infections early in life and neurodevelopmental dis-
orders, 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 g (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 epi-
thelium (Natividad and Verdu, 2013), protecting against pathogens
(Bäumler and Sperandio, 2016) and regulating host immunity

⁎
Corresponding author.
E-mail address: bogdana.golofast@nudz.cz (B. Golofast).

https://doi.org/10.1016/j.neubiorev.2019.12.011
Received 30 August 2019; Received in revised form 1 December 2019; Accepted 6 December 2019
Available online 09 December 2019
0149-7634/ © 2019 Elsevier Ltd. All rights reserved.
B. Golofast and K. Vales
(Gensollen et al., 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,
2011; Dinan and Cryan, 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 in-
novative techniques to characterize ecosystems being developed, a
potential role of gut microbiota for intestinal and extraintestinal dis-
eases 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 interac-
tion mechanisms in the microbiota-gut-brain 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 schizo-
phrenia. We assume that this review may allow identifying new areas
for the study of this severe mental disorder and its treatment.
2. Microbiome
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).
2.1. 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 mi-
crobiota (Flint et al., 2012) that will digest these almost intact mole-
cules when they reach the colon. In addition, the ability to degrade
complex carbohydrates can be dictated by the diet of the human po-
pulation.
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 varia-
tions in microbial species composition can be seen (Lozupone et al.,
2012), this functionality was remarkably similar in the intestinal spe-
cimens 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 selec-
tion 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.
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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 un-
ique 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).
2.2. 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., 2016a, 2016b; Kim and Shin, 2018). Gut micro-
biota supports two-way communication with major parts of the CNS
directly and indirectly. Commensal bacteria (indigenous microbiota) 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 (cy-
tokines, 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 evi-
dence 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, mor-
phology, 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
B. Golofast and K. Vales
to influence the intestinal microbiota. For example, reduced anxiety
phenotypes and a relatively higher amount in the hippocampus of
serotonin and its metabolite, 5-hydroxyindolacetic 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 ob-
served (Clarke et al., 2013). The study by Huo et al. (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,
2017a, 2017b). Desbonnet et al. (2014) found significant social beha-
vior 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 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 trans-
mission of food preference test that had accompanied by modify dy-
namics of the tryptophan metabolic pathway and significantly de-
creasing 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 poly-
saccharides (Rea et al., 2016; Dinan and Cryan, 2017b). These SCFAs
are known to have neuroactive properties, to induce neuroinflamma-
tion, 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., 2017a, 2017b; Feng
et al., 2018). SCFAs that enter the circulation and cross the blood-brain
barrier (BBB) can directly influence the central nervous system
(Macfarlane and Macfarlane, 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, ac-
tivates 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) sympto-
matology 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 sig-
nificant parts of the synergy between microbiota and the brain. Gut
commensal can affect the development and regulation of the hypotha-
lamic-pituitary-adrenal (HPA) axis. Huo and colleagues noticed sig-
nificant changes in HPA axis hormone levels with increased cortico-
trophin-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 two-way 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. pseudocatenu-
latum CECT 7765) consumption had beneficially changed the con-
sequences of maternal separation (MS), had induced chronic stress on
the HPA axis and had down-regulated intestinal inflammation. These
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Neuroscience and Biobehavioral Reviews 108 (2020) 712–731
effects had a long-term impact on the central nervous system (CNS) of
mice adulthood. Tillisch et al. (2013) have shown in humans that in-
formation processing of emotional material can be altered by probiotic
treatment. Messaoudi et al. (2011) found that the values of the 24 -h
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 et al. (2014) showed that among depressed
patients and controls (Naseribafrouei et al., 2014), no difference in
microbial composition and diversity was found. Other pre-clinical stu-
dies 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
et al. (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
et al., 2012; Choy et al., 2009; Pantelis et al., 2003; Maynard et al.,
2001; Keshavan, 1999; Keshavan and Hogarty, 1999).
Norris and Kipnis (2019) in their review have reported the inter-
esting 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 stimu-
lation at the anterior pituitary HPA axis or hypothalamus, and re-
cruitment 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 or-
gans (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 evi-
dence 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 mi-
crobiota at the beginning of immune life (Fujimura et al., 2016; Penders
et al., 2007). The hygiene hypothesis first proposed in the late 1980s
(Patel et al., 2017; Strachan, 1989) and reconceptualized as an "old
friends hypothesis" (Williamson et al., 2015; Rook et al., 2003) sug-
gests, that an encounter with less exposure to immunoregulatory
B. Golofast and K. Vales
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 excessive inflammation by disrupting homeostasis be-
tween 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 ne-
gative 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 micro-
biota has been viewed as a crucial regulator of bidirectional commu-
nication between the gut and the brain (gut-brain axis), which implies
the impact in many neurodevelopmental and neurodegenerative dis-
orders 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 pa-
tients affected by gastrointestinal problems were more likely to develop
mental illness (Mussell et al., 2008; Lee et al., 2016). Thus, dysbiosis of
the gut microbiota may facilitate the pathogenesis of mental health
disorders, confirming the hypothesis of a pathologic process of bidir-
ectional 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.
3. Development of the microbiota during the life
3.1. 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, 2013). Despite the limited evidence of live
bacterial culture from placental and amniotic fluid samples, these dis-
coveries 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 and Beauchamp, 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 pro-
teins, 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
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Neuroscience and Biobehavioral Reviews 108 (2020) 712–731
the innervation of the 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 L 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 devel-
oping 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 et al.,
2014; Dominguez-Bello et al., 2010; Adlerberth and Wold, 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 de-
termining the final profile of a stable microbiota.
Evidence from recent studies indicates that prenatal stress will in-
fluence gut microbiota, with physiological consequences on offspring
(Golubeva et al., 2015). Nevertheless, it is still difficult to draw defi-
nitive conclusions about the relationship between prenatal stress and
intestinal microbiota from clinical studies.
4. Human microbiota during pregnancy
4.1. 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, in-
creases (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 post-
partum 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 (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.
B. Golofast and K. Vales
4.2. 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 Lac-
tobacillus 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 colo-
nizes the infant, is extremely similar to the infant's microbiome, this
corresponds to patterns of vertical transmission across the animal
kingdom (Funkhouser and Bordenstein, 2013; Dominguez-Bello et al.,
2010; Ley et al., 2006).
4.3. 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 and Netuschil, 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 po-
sitively associated with gestational age at delivery and birth weight.
This conclusion matches with the hypothesis that oral organisms in-
fluence the delivery process via the orogenital contact or through op-
portunity penetration the uterine environment from the bloodborne
route. The paradigm that most intra-uterine infections, which are as-
sociated 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 period-
ontitis 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 and
Gerencser, 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,
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 re-
lationship between PLBW and Ig level are specific for the serum peri-
odontal pathogen. According to Dasanayake et al. (2001) this re-
lationship is positive, while Madianos et al. (2001) claim negative
association with PLBW.
Recent studies analyzing the relationship between maternal peri-
odontal disease and the risk of preterm delivery have shown that pa-
tients with a high risk of preterm delivery had higher levels of in-
flammatory cytokines (Escobar-Arregoces et al., 2018; Latorre Uriza
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et al., 2018). These results are consistent with Offenbacher et al.
(1998), who first reported the association between maternal period-
ontal 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 peri-
odontal 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 gin-
gival 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 re-
ducing 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 devel-
opment 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 un-
equal 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.
5. 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 con-
troversial, 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 morphologi-
cally 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 mi-
crobiome, 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 um-
bilicals (Jiménez et al., 2005), many of these studies have been criti-
cized 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). Moreover, there is additional
evidence against the prenatal microbiome, and it comes from the ex-
istence of germ-free mouse models (Perez-Muñoz et al., 2017).
5.1. Maternal diet and the microbiota
Maternal nutritional status before and during pregnancy will in-
fluence 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 hu-
mans, in addition to poor cardiovascular health or obesity, have an
impact on neurocognitive development in humans and rodents (Monk
B. Golofast and K. Vales
et al., 2013). However, some of these studies have been criticized be-
cause inappropriate controls are often selected and may introduce
confounding factors that complicate the interpretation of truly intri-
guing 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 composi-
tion 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 compo-
sition 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 in-
clude 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 repro-
gramming strategies to protect from the development of hypertension
caused by maternal fructose-rich diet (Hsu et al., 2018).
5.2. 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 antibiotics (which are the
most commonly prescribed drugs during pregnancy) reduce the di-
versity and bacterial burden of the microbiome (Kuperman and Koren,
2016). Besides, negative effects of different classes of antidepressants,
including selective serotonin (Munoz-Bellido 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 14–23%
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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5.3. 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 preg-
nancy-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 off-
spring (Betts et al., 2015) and influence the development of the off-
spring 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 psy-
chiatric outcomes in children (Estes and McAllister, 2016). MIA mod-
eling in mice commonly administers a polyinosinic mimetic viral
polycytidylic acid or bacterial lipopolysaccharide to produce psychia-
tric endophenotypes in offspring. Specifically, viral mimetic poly-
inosinic 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 in-
duced by lipopolysaccharide (Fricke et al., 2018).
6. Cesarean section, neurodevelopment, and health
Now we will consider in more detail how the processes of coloni-
zation 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 psy-
chological 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., 2016;
Azad et al., 2013b; Salminen et al., 2004; Brumbaugh et al., 2016;
Dogra 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 Bac-
teroides colonization (Mueller et al., 2015; Biasucci et al., 2008),
B. Golofast and K. Vales
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 micro-
biome 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 dy-
namic succession of microbes. In the intestine, the microbial commu-
nity 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 in-
testine of the newborn, for example, low-abundance commensal bac-
teria such as Escherichia Coli, Prevotella, and Neisseria (Aagaard et al.,
2014). However, the delivery mode is considered to be the first con-
firmed major event that allows the microbiome to be seeded in infants
with sustainable colonizers (Bäckhed 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 (Bäckhed 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 de-
livered 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).
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)-depen-
dent genetic pathways that produce metabolites, such as acetate, which
may be obligatory and stimulate anaerobes (Appleman and Wormser,
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 Clos-
tridium 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 in-
fants resembles that of infants born in the vagina, and if not, the mi-
crobiota resembles that of the maternal skin (Chu et al., 2017). Early
microbial disruption is due in part to cesarean section, and during in-
fancy 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
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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 di-
versity. A recent study (Liu et al., 2019) noticed that the compared with
the vaginally delivered and cesarean delivered infants was character-
ized 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 Sele-
nomonadales 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 Firmi-
cutes phylum, mainly represented by Clostridium and Lactobacillus,
was increased more in CS infants than in neonates with vaginally de-
livered (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 in-
fants 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. Be-
sides, relatively different proportions of facultative and obligatory
anaerobes in the meconium of CS babies and delayed/inferior coloni-
zation of Lactobacilli indicate that from the first day of life, the ele-
ments 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 in-
dividual's microbiota (Jakobsson et al., 2014; Penders et al., 2006;
Wampach et al., 2017; Martin et al., 2016; Bäckhed et al., 2015; 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 trans-
mission 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 compo-
sition 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., Bac-
teroidetes), 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
B. Golofast and K. Vales
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 re-
organization 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 micro-
biota 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 tech-
niques used (dependent and independent culture techniques, DNA ex-
traction methods, etc.), neonatal exposures (such as intrapartum anti-
biotic 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 and Grivell, 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 mi-
crobiota; 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 mo-
ments of life (Costa-Ramón et al., 2018). Subsequently, a higher risk 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/ hyper-
activity 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 neuro-
developmental 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., 2016;
Sampson and Mazmanian, 2015; Borre et al., 2014; Foster and McVey
Neufeld, 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
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prepared to face future insults if there has been birth stress due to va-
ginal 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, ma-
turation 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 micro-
biota (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 dysfunc-
tion, depression, could be influenced by changes at the level of the host
epigenome because of gut microbiota activity (Majnik and Lane, 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, 2013). As reported by some
studies, the intestinal microbiota of children with ASD presents dif-
ferent 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 seven-year-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 pro-
blems 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 chil-
dren 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, at-
tention deficit disorder (ADD), and breastfeeding were important
mediators for the relationship between child cognitive outcomes and of
cesarean delivery. By the 1 st 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
B. Golofast and K. Vales
obesity are significantly associated with lower cognitive performance
(Polidano et al., 2017).
7. 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 in-
testine 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 com-
positions during weaning or antibiotic treatment (Mueller et al., 2015).
Exposure to antibiotics within the first 3 years of life in humans de-
creased microbiome stability and diversity while it transiently in-
creased transcription of antibiotic-resistant genes (Yassour et al., 2016)
and increased adiposity in male individuals during childhood (Azad
et al., 2014).
7.1. Postnatal diet and the microbiota
Multiple investigations have determined that nutrition and medi-
cation 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, ensuring its optimal
development (Butte et al., 2002). Human milk is very rich in lactose,
fatty acids and hundreds of different types of oligosaccharides con-
sisting 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 Bifido-
bacterium infantis, Bacteroides thetaiotaomicron, and Bacteroides fra-
gilis, 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 sev-
eral 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, in-
testines problems, headache, migraine, back pain, hypertension, de-
pression (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
and Hotham, 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
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
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Neuroscience and Biobehavioral Reviews 108 (2020) 712–731
concern premature infants, and to the impacts of newborns’ health fu-
ture. 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 bar-
rier, therefore protecting the newborn from enteric pathogens and in-
flammation (Sohn and Underwood, 2017). Studies of the use of com-
positions 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 oli-
gosaccharides is effective as prime prevention in low developing atopic
dermatitis risk infants (Grüber et al., 2010). As for probiotics, oral in-
troduced 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 inter-
actions 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 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 col-
leagues has described that doing exercise was linked with modifications
in gut microbial composition and with an increase in butyrate produ-
cing 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).
7.2. Postnatal stress and the microbiota
Events in early childhood, both positive and negative, have a pro-
gramming 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 micro-
biota 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 germ-free mice noticed that were more vulnerable to re-
straint 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 re-
sponse (Sudo et al., 2004). Notably, these effects were rescued with
microbiota transplantation during adolescence but not during adult-
hood (Sudo et al., 2004).
B. Golofast and K. Vales
7.3. Host genetics
Diet and medications only explain small part variations of the mi-
crobiome in the human populace (Scepanovic et al., 2019). Host ge-
netics 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 re-
cently 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 asso-
ciated 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 de-
velopment 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).
8. 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 un-
derstanding of this disease, affecting approximately 0.3–0.7 % 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 asso-
ciation 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,
2013; Morgan et al., 2014; Bahr et al., 2015a, 2015b). It is difficult to
determine the mechanism by which intestinal microbiota can con-
tribute to the development of schizophrenia, given the limitations as-
sociated 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 stu-
dies, intestinal microbiota have played a key role in postnatal devel-
opment 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
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Neuroscience and Biobehavioral Reviews 108 (2020) 712–731
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 cogni-
tion, 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
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 in-
volved 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 im-
munological devices.
When the oropharyngeal microbiome was compared to patients
with schizophrenia and healthy people, Castro-Nallar and his collea-
gues 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 trans-
port 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 micro-
biota, 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 be-
tween 64 patients with schizophrenia and 53 healthy controls and
found in patients with schizophrenia a higher number of Proteo-
bacteria, Succinivibrio, Megasphaera, Collinsella, Clostridium, Kleb-
siella and Methanbrevibacter and a lower number of Blautia, Copro-
coccus, 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 Lac-
tobacillus phage phiadh. The existence of this microorganism also
B. Golofast and K. Vales
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 were significantly inter-
connected, as accord with their coordinated roles in activating the in-
nate immunity. Both these markers in persons with schizophrenia had
significantly correlated with C-reactive 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. Con-
sidering bacterial translocation might partially promote to inflamma-
tion 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 gut-brain axis at
any age, leading to neurodevelopmental or neurodegenerative condi-
tions (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 rando-
mized, double-blind, placebo-controlled, 14-week period probiotic trial,
and demonstrated that probiotic treatment significantly reduced C. al-
bicans 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.
9. 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 Sacchar-
omyces 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 cerevi-
siae 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. al-
bicans, sCD14, and LBP did not differ in patients who take various types
of psychiatric medicines (including lithium, valproate or anti-
psychotics) (Severance et al., 2016, 2013).
The increased level of these serological biomarkers suggests in-
creased 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 be-
come 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 schi-
zophrenia who were seropositive for C. albicans, compared to their
respective seronegative counterparts (Severance et al., 2016). The
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Neuroscience and Biobehavioral Reviews 108 (2020) 712–731
outcomes by Severance et al. (2017) had shown biological improve-
ment attributable to probiotic treatment and proposed that manipula-
tion 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.
10. 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 “psy-
chobiotics” (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 inter-
esting 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 an-
tibiotics 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 bene-
ficial microbiota. Prebiotics may improve emotional affect and mod-
ulate 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 con-
troversial results and therefore more trials are needed to completely
demonstrate 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, con-
trolled 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
B. Golofast and K. Vales
significant impact in reducing von Willebrand factor (VWF) and in-
creasing BDNF, monocyte chemotactic protein-1 (MCP-1), T-cell-spe-
cific 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 supple-
mentation 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 symp-
toms 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 anti-
body levels as well as a decrease in gastrointestinal symptoms in male
subjects and trends for improvement in positive schizophrenia symp-
toms in males who received probiotics and were seronegative for C.
albicans.
11. 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, respec-
tively, as well as host genetics. Although these changes may be bene-
ficial 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 interven-
tions, 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 treat-
ment 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, di-
minishing the risk of developing the disease at a later age.
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 DanielBermejo-Rodriguez for language proofreading.
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Neuroscience and Biobehavioral Reviews 108 (2020) 712–731
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