Ijms 22 10028

International Journal of
Molecular Sciences
Review
The Role of Gut Microbiota and Gut–Brain Interplay in
Selected Diseases of the Central Nervous System
Julia Doroszkiewicz 1, * , Magdalena Groblewska 2 and Barbara Mroczko 1,3
1 Department of Neurodegeneration Diagnostics, Medical University of Białystok, 15-269 Białystok, Poland;

[email protected]
2 Department of Biochemical Diagnostics, University Hospital in Białystok, 15-269 Białystok, Poland;
[email protected]
3 Department of Biochemical Diagnostics, Medical University of Białystok, 15-269 Białystok, Poland
* Correspondence: [email protected]; Tel.: +48-85-686-51-68
Abstract: The gut microbiome has attracted increasing attention from researchers in recent years.
The microbiota can have a specific and complex cross-talk with the host, particularly with the central
nervous system (CNS), creating the so-called “gut–brain axis”. Communication between the gut,
intestinal microbiota, and the brain involves the secretion of various metabolites such as short-chain
fatty acids (SCFAs), structural components of bacteria, and signaling molecules. Moreover, an
imbalance in the gut microbiota composition modulates the immune system and function of tissue
barriers such as the blood–brain barrier (BBB). Therefore, the aim of this literature review is to describe
how the gut–brain interplay may contribute to the development of various neurological disorders,
combining the fields of gastroenterology and neuroscience. We present recent findings concerning the

effect of the altered microbiota on neurodegeneration and neuroinflammation, including Alzheimer’s
Citation: Doroszkiewicz, J.;
and Parkinson’s diseases, as well as multiple sclerosis. Moreover, the impact of the pathological shift
Groblewska, M.; Mroczko, B. The in the microbiome on selected neuropsychological disorders, i.e., major depressive disorders (MDD)
Role of Gut Microbiota and Gut–Brain and autism spectrum disorder (ASD), is also discussed. Future research on the effect of balanced gut
Interplay in Selected Diseases of the microbiota composition on the gut–brain axis would help to identify new potential opportunities for
Central Nervous System. Int. J. Mol. therapeutic interventions in the presented diseases.
Sci. 2021, 22, 10028. https://doi.org/
10.3390/ijms221810028 Keywords: gut microbiota; dysbiosis; gut–brain axis; central nervous system; enteric nervous system;
neuroinflammation; neurodegeneration; neuropsychiatric disorders
Academic Editor:
Antonella Scorziello
Received: 16 August 2021

1. Introduction
Accepted: 15 September 2021
Published: 17 September 2021
When we think of the intestines, we associate them with rather basic and somewhat
primitive functions that include the processing of food to deliver energy to the body.
Publisher’s Note: MDPI stays neutral
However, this type of understanding of the role of the gut appears to be inaccurate. The
with regard to jurisdictional claims in
gut is innervated by the enteric nervous system (ENS), which acts independently from the
published maps and institutional affil- central nervous system (CNS). However, there is a connection between these two parts of
iations. the human nervous system that allows for the exchange of information [1]. Knowledge of
the gut function and its connection to the CNS through the ENS has prompted researchers
to postulate the existence of a specific network called the “gut–brain axis”. The network
is based on a complex system, including the vagus nerve, with both sympathetic and
Copyright: © 2021 by the authors.
parasympathetic input, as well as certain gut hormones and cytokines [2,3].
Licensee MDPI, Basel, Switzerland.
The gut microbiota is a crucial part of the gastrointestinal tract. Recent data suggest
This article is an open access article
that the connection between the gut and the brain should also be extended to the intestinal
distributed under the terms and microbiome, creating the specific “microbiota–gut–brain axis”, as the latter role of bacterial
conditions of the Creative Commons flora within the gut has significantly emerged. Interestingly, it is postulated that microbes
Attribution (CC BY) license (https:// may participate in the development of the nervous system. This hypothesis has been con-
creativecommons.org/licenses/by/ firmed in germ-free mouse models, which are considered the gold standard for microbiota
4.0/). studies. These studies have demonstrated impaired neurogenesis and morphology in the
Int. J. Mol. Sci. 2021, 22, 10028. https://doi.org/10.3390/ijms221810028 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2021, 22, 10028 2 of 19
hippocampus and amygdala of the tested animals [4,5]. Furthermore, a different study
conducted on germ-free mice revealed a disrupted microglia morphology and its processes,
resulting in disturbed activation and response to pathogens [6]. These results have led
to the establishment of a connection between pathological changes in the gut microbiota
and neurological diseases. This review summarizes recent findings connecting the areas of
microbiology, neurology, and the interplay between the gut microbiota and the brain in
selected neurological diseases.
2. Gut Microbiota
The gut microbiota can be defined as a collection of microorganisms, primarily bacte-
ria, which colonize the human gastrointestinal (GI) tract. The number of microorganisms
inhabiting the GI tract has been estimated to range between 1013 and 1014 , with an approx-
imate weight of 2 kg, outnumbering the cells in the whole human body [7]. The normal
human gut microbiota comprises two major anaerobic phyla, Bacteroidetes and Firmicutes.
Interestingly, the ratio between these two species may be a relevant biomarker of gut
dysbiosis in obesity [8]. Other identified types occur in small numbers and include some
species from the Proteobacteria, Cyanobacteria, Verrucomicrobia, and Actinobacteria phyla [9].
In order to explain the influence of microbiota on the human body, we can divide the
microorganisms that comprise the microbiota into “healthy” types, which exert a positive
impact on the body, and “unhealthy” types, which may cause harm to the host. By way of
illustration, it is believed that Actinobacteria, particularly Bifidobacterium sp., demonstrate
anti-inflammatory properties and exert a positive effect on the integrity of the intestinal
barrier [10]. By contrast, Clostridium difficile is the leading cause of diarrhea [11]. The
human gut microbiome contains around 4 million different genes, which is over 100 times
more than the total human genes present in the human genome [12].
2.1. Changes in the Composition of the Intestinal Microbiome through Life

It is believed that in normal conditions the fetus is germ-free, and the colonization
and further development of the microbiota commences at birth. Interestingly, the method
of delivery exerts a significant effect on the gut microbiota composition in newborns and
infants. A recent study revealed that children born through caesarian section display
diminished microbial diversity, primarily with decreased levels of Bacteroides or even
their absence, which perseveres throughout the years. Moreover, after some time, it is
only Bacteroides that differentiate the microbiota of babies delivered by C-section from the
microbiota of those delivered vaginally [13]. Furthermore, fecal microbiota in vaginally
delivered babies is broadly similar to that of their mothers, while in newborns delivered
through caesarian section there is only 41% resemblance [14].
Another factor that significantly affects the gut microbiota is the feeding method. It has
been demonstrated that breastfed infants show a higher level of dominance for Bifidobacteria,
while formula-fed babies may display an increased prevalence of Bacteroides [15]. New
studies reveal that environmental factors may cause modifications in the gut microbiota
throughout life. Due to these factors, considerable changes occur in a child’s microbiota
within the first 2–3 years of life. Following that, a certain degree of stabilization is achieved
in the third year of life [16,17], after which time the stability is gradually lost over the
years. Throughout life, the microbiota changes and diversifies, with a gradually increasing
proportion of Bacteroides and Clostridium. Centenarians, in particular, exhibit greater
abundance of Enterobacteriaceae [18,19].
2.2. Factors Influencing Gut Microbiota

Environmental factors such as diet, antibiotics, and infections may cause unhealthy
diversification of the microbiota and may lead to increased intestinal permeability known as
“leaky gut syndrome”. This might facilitate an improper and unnecessary immune response
that enhances inflammation that is already occurring in the digestive tract [20]. As diet has
a considerable impact on the gut microbiota composition, multiple studies have indicated
Int. J. Mol. Sci. 2021, 22, 10028 3 of 19
that it is the most important modifying factor [21,22]. The Western diet, characterized by an
increased dietary intake of saturated fat, sugar, and red meat, results in a shift to Firmicutes,
with a decreased abundance of Bacteroides and a disturbed Firmicutes/Bacteroidetes ratio [23].
In contrast, vegetarian or Mediterranean diets, characterized by the high consumption of
vegetables and fruit, healthy fats, and whole grains; moderate consumption of red wine;
and low consumption of red meat, result in healthier, more diverse microbiota. These
changes include an increase in Bacteroides, with a decrease in Firmicutes [24], which is
considered a neuroprotective factor associated with improved cognitive function and a
lower risk of Alzheimer’s disease (AD) [25–27].
Antibiotic consumption, and in particular antibiotic overuse, is one of the main factors
causing dysbiosis. As the majority of prescribed antibiotics are broad-spectrum antibiotics,
they eliminate both “good” and “bad” bacteria [28]. Furthermore, increased stress levels
caused by modern lifestyles may also exert a negative effect on the gut microbiota and its
diversity, and may result in an increased abundance of Clostridium [29]. However, there
are factors that can improve the gut microbiota such as exercise, which enhances microbial
diversity and promotes the presence of bacteria producing butyrate, known for its health-
promoting and anti-inflammatory properties, as well as its capacity to increase insulin
sensitivity [30–32]. Moreover, the consumption of polyphenols in green tea, red wine, and
other dietary products can also promote the growth of healthy and helpful bacteria [33].
2.3. Functions of the Gut Microflora

The main functions of the gut microbiota are nutrient metabolism and the synthesis
of vitamins. It also participates in the breakdown of drugs and other xenobiotics. During
these processes, the microbiota releases a wide range of metabolites and small molecules
that affect the body. The digestion of dietary fiber, a process that is possible only with the
participation of gut microbes, results in the production of short-chain fatty acids (SCFAs);
excretion of intestinal gases, such as methane and carbon dioxide; and the release of modest
amounts of lactate and alcohols [34]. Importantly, SCFAs are not only a source of energy
but they also affect the maturation of the microglia in the CNS. They may act as signaling
molecules within the CNS [6,35]. It has also been demonstrated that enteric microbes have
the ability to metabolize primary bile acids to secondary forms. These bile acids can also
perform metabolic activities, including their signaling role within the nervous system [36].
Any alterations in the composition, diversity, or excessive functionality of the gut
microbiota may constitute potential pathogenic factors. Importantly, normal gut microbiota
can stimulate the immune system and induce the release of proinflammatory cytokines
such as IL-1β, IL-6, or TNF-α [37]. As a result, the microbiota impacts the immune response,
thus protecting the host from pathogens [8]. Moreover, continual changes in epithelial
cells may serve as another protective mechanism within the gut that prevents enhanced
inflammation in the intestines [37]. Proliferation of intestinal epithelial cells is a clearing
mechanism that leads to the replacement of old cell layers and helps to isolate pathogens
from body cavities.
3. Gut–Brain Interplay
3.1. Metabolites Produced by the Gut Microbiota
The connection between the intestines and the CNS involves many pathways mediated
by various substances synthesized by microbes. The gut microbiota is capable of producing
and releasing some active metabolites that may serve as neuromediators participating in
communication with the CNS and affecting the brain. Short-chain fatty acids (SCFAs),
aromatic amino acids, and bile acids are the main substances from the microflora affecting
the brain. SCFAs consist mostly of acetate, butyrate, and propionate, which could be the
products of bacterial fermentation of carbohydrates. Interactions between these acids and
the gut may be mediated through binding to G-protein-coupled receptors [38].
(SCFAs), aromatic amino acids, and bile acids are the main substances from the
affecting the brain. SCFAs consist mostly of acetate, butyrate, and propion
could be the products of bacterial fermentation of carbohydrates. Interaction
these acids and the gut may be mediated through binding to G-protein-couple
Int. J. Mol. Sci. 2021, 22, 10028 [38]. 4 of 19
3.2. Direct and Indirect Effects of Gut Microbiota on the CNS

Neurotransmitters
3.2. Direct and Indirect and their
Effects of Gut Microbiota onprecursors
the CNS produced in the gut may also affe
els in the brain.
Neurotransmitters Besides
and their beingproduced
precursors obtained in from
the gutthe
may breakdown of food,
also affect their levels neurot
can also be produced by bacteria. By way of illustration, Escherichia
in the brain. Besides being obtained from the breakdown of food, neurotransmitters can coli can re
mine, serotonin,
also be produced by bacteria. and noradrenaline,
By way of illustration,while Lactobacilli
Escherichia produce
coli can release serotonin, GA
dopamine,
serotonin,choline,
and noradrenaline, while Lactobacilli produce serotonin, GABA, acetylcholine,
and histamine [39–41], which can influence the host brain. This mech
and histamine
been [39–41],
proposed which can influence
to play the host
an important rolebrain.
in theThis mechanism of
development hascertain
been neuro
proposed to play an important role in the development of certain neurological diseases,
eases, including Alzheimer’s disease, Parkinson’s disease (PD), depressive dis
including Alzheimer’s disease, Parkinson’s disease (PD), depressive disorders, and autism
autism spectrum disorders [42,43]. Furthermore, SCFAs are capable of indirect
spectrum disorders [42,43]. Furthermore, SCFAs are capable of indirectly affecting the gut–
brain axis the gut−brain
by inducing theaxis byofinducing
release some gutthe releasesuch
hormones, of some gut hormones,
as glucagon-like such as glu
peptide-1
(GLP-1) andpeptide-1 (GLP-1)
leptin, through and leptin, through
enteroendocrine enteroendocrine
cells. These enteric hormonescells.may
These enteric horm
interact
interact
with the vagus nervewith
and the
evenvagus nerve and
brain receptors even The
[44–46]. brain receptors
effects [44–46].
of the gut The on
microbiota effects of
the brain are presented in Figure 1.
crobiota on the brain are presented in Figure 1.
Figure 1. Pathways between

Figure the intestines
1. Pathways betweenand
the the central
intestines nervous
and system
the central (CNS).
nervous Figure
system illustrates
(CNS). how the gut mic
Figure illustrates
can interact with how
CNSthe through severalcan
gut microbiota pathways. Firstly,
interact with CNS through produced
through several metabolites
pathways. such asproduced
Firstly, through short-chain fatt
(SCFAs) [38]; secondly, directly
metabolites with
such neurotransmitters
as short-chain fatty acidsfor example
(SCFAs) [38];dopamine and serotonin
secondly, directly [39–41]; and lastly, ind
with neurotransmitters
influencing the release of enteric
for example hormones
dopamine [44–46].[39–41]; and lastly, indirectly influencing the release of enteric
and serotonin
hormones [44–46].
Interestingly, a number of studies indicate the contribution of SCFAs to t
Interestingly, a number of studies indicate the contribution of SCFAs to the mainte-
nance of physical barriers, such as the blood−brain barrier (BBB) or intestina
nance of physical barriers, such as the blood–brain barrier (BBB) or intestinal barrier by
impactingimpacting the tight
the tight junctions junctions
between between
cells [46–48]. cells [46–48].
Similarly, bile acidsSimilarly, bile
can activate acids can
recep-
tors in theceptors
host andin actthe host andparticles,
as signaling act as and
signaling particles,
can affect and can affect
barrier permeability barrier pe
[49,50].
[49,50].
Furthermore, Furthermore, lipopolysaccharide
lipopolysaccharide (LPS) produced
(LPS) produced by bacteria by bacteria
is able to influence BBBis able t
permeability
BBB bypermeability
inducing the release of inflammatory
by inducing cytokines
the release [51].
of inflammatory cytokines [51].
Int. J. Mol. Sci. 2021, 22, 10028 5 of 19
3.3. Relevance of Healthy Gut Microbiota

Experiments conducted on germ-free mice have confirmed the importance of normal
microbiota for many essential processes in the brain. One of them is the metabolism of
serotonin, a neurotransmitter responsible for mood and appetite, which is mostly produced
by enterochromaffin cells of the gastrointestinal tract [52]. Tryptophan is a precursor for
this neuromediator. Recent studies have demonstrated that germ-free mice had increased
tryptophan levels in plasma and decreased serotonin levels in the serum [53–55]. Moreover,
the rodents exhibited a decreased expression of a crucial neurotrophic factor, brain-derived
neurotrophic factor (BDNF), which is responsible for maintaining and promoting neuro-
genesis [56]. Furthermore, these animals also presented cognitive impairment, problems
with sociability, and depressive and anxious behaviors [55].
Although germ-free mouse models are the gold standard for gut microbiome re-
search, antibiotic-treated models constitute a more accessible and less expensive approach.
Antibiotics may be used to modify the gut bacteria, analyze changes in the microbiota,
and evaluate their impact on the brain [57]. It has been demonstrated that experimental
treatment with oral antibiotics not only induces intestinal dysbacteriosis, but also leads
to an imbalance in the gut–brain axis. Moreover, antibiotic-induced changes in microbial
composition also cause certain neurobehavioral alterations, such as increased anxiety and
“depressive-like” behaviors, as well as neuronal activation in different brain regions of
mice [58].
4. Gut and Neurological Diseases

Recent data suggest that neuroinflammation may be a pathogenic factor in several
neurodegenerative disorders. In a neuroinflammatory state, activation of the microglia
and the release of proinflammatory proteins, such as TNF-α, IL-6, or MCP-1, as well as
reactive oxygen species by glial cells and resident macrophages, might result in chronic
neuroinflammation [20,59]. As the gut microbiota is believed to contribute to various
pathogenic pathways, there are a growing number of studies linking changes in the healthy
microbiome to the development of a number of neurological diseases, including those
with neurodegenerative etiology, as well as to certain neuropsychiatric disorders [3,60,61].
Likewise, diminished microbiota diversity throughout life may be connected with neurode-
generation [62].
Although loss of intestinal epithelial cell integrity and chronic inflammation seem to
be the main consequences of changes in the gut microbiota, neuroinflammation as well as
neurodegenerative and neuropsychiatric disorders may also be the result of these changes.
The importance of a healthy gut microbiota and its diverse composition for normal brain
function has been confirmed in studies on rodent models [63]. It has been demonstrated
that the presence of Lactobacillus bacteria exerts a positive effect on the brains of rats with
experimental cerebral ischemia reperfusion injury via the inhibition of neural cell apoptosis
and the reduction of oxidative stress through the downregulation of the TLR4/NF-kB
signaling pathway [63]. As described in previous sections, a number of factors, including
diet, stress, infections, and antibiotic use, may result in gut microbiota dysbiosis. The
connection between changes in the gut and CNS disorders is shown in Figure 2, with
further description in later sections.
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Int. Mol.Sci.
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19
Figure 2.
Figure Schematic description
2. Schematic description of of disturbances
disturbancesin in the
the intestinal
intestinal microbiota
microbiota and
and diseases
diseases ofof the
the CNS.
CNS. The
The figure
figure depicts
depicts
major
major factors, such as stress [29], diet [21], infections, and antibiotic intake [28], which can promote dysbiosis in the gut
factors, such as stress [29], diet [21], infections, and antibiotic intake [28], which can promote dysbiosis in the gut
microbiota.
microbiota. Changes
Changes inin the
thecomposition
compositionofofthethemicrobiome
microbiome lead
lead to to
gutgut permeability,
permeability, influencing
influencing systemic
systemic inflammation
inflammation and,
and, as a result,
as a result, may may induce
induce diseases
diseases of theofCNS.
the CNS.
4.1.Alzheimer’s
4.1. Alzheimer’sDisease
Disease
Alzheimer’s disease is the
Alzheimer’s themost
mostprevalent
prevalentneurodegenerative
neurodegenerative disorder.
disorder. ADADis aisprogres-
a pro-
sive disease
gressive whose
disease whosefirst first
clinical symptoms
clinical symptoms appear decades
appear after after
decades the onset of pathological
the onset of patho-
changes
logical in the brain,
changes in thethus making
brain, thus older
making individuals the most affected
older individuals the mostage group.age
affected Hallmarks
group.
of the disease include progressive accumulation of amyloid-beta
Hallmarks of the disease include progressive accumulation of amyloid-beta (Aβ) plaques, (Aβ) plaques, formed
following
formed the cleavage
following of amyloid
the cleavage precursor
of amyloid protein (APP),
precursor proteinin(APP),
the brain andbrain
in the neurofibrillary
and neu-
tangles (NFTs),
rofibrillary which
tangles consist
(NFTs), of hyperphosphorylated
which tau protein tau
consist of hyperphosphorylated [64].protein [64].
The etiology
The etiologyof of AD
AD hashas not
not been
been fully
fully elucidated,
elucidated, butbut aa number
number of of factors
factors influence
influence
the pathogenesis of the disease. Proposed hypotheses on the origin
the pathogenesis of the disease. Proposed hypotheses on the origin of AD includes of AD includes gradual
grad-
accumulation of Aβ in the AD brain, followed by progressive
ual accumulation of Aβ in the AD brain, followed by progressive deposition of the deposition of the Tau protein.
Tau
AnotherAnother
protein. hypothesis suggests
hypothesis the rolethe
suggests of soluble oligomers
role of soluble of Aβ and/or
oligomers Tau protein
of Aβ and/or Tau pro- as
the most harmful factors affecting the brain tissue [65,66]. Moreover,
tein as the most harmful factors affecting the brain tissue [65,66]. Moreover, the contribu- the contribution
of the
tion of immune
the immune system to AD
system pathogenesis
to AD pathogenesis hashas
also been
also beensuggested.
suggested.Insoluble
Insolubledeposits
depos-
of of
its AβAβ may
may beberecognized
recognizedbybythe theimmune
immunesystem systemas asaa foreign
foreign material, triggering the
material, triggering the
inflammatory cascade, which leads to neuronal damage. Amyloid
inflammatory cascade, which leads to neuronal damage. Amyloid plaques and NFTs gen- plaques and NFTs
generate
erate inflammation
inflammation withinwithin the brain,
the brain, primarily
primarily throughout
throughout activation
activation of theofmicroglia
the microglia
and
and astrocytes.
astrocytes.
The neuroinflammation hypothesis in the pathogenesis of AD is associated with cer-
The neuroinflammation hypothesis in the pathogenesis of AD is associated with cer-
tain gut microbiota alterations. Neuroinflammatory processes occur with ongoing systemic
tain gut microbiota alterations. Neuroinflammatory processes occur with ongoing sys-
inflammation, which may further intensify neuroinflammation [20,67,68]. Furthermore, it
temic inflammation, which may further intensify neuroinflammation [20,67,68]. Further-
has recently been suggested that AD is initiated is the gut, and not the brain, from where
more, it has recently been suggested that AD is initiated is the gut, and not the brain, from
it subsequently proceeds to the brain. The hypothesis was confirmed in a study by Sun
where it subsequently proceeds to the brain. The hypothesis was confirmed in a study by
et al., in which Aβ oligomers were injected into the wall of the gastrointestinal tract of
Sun et al., in which 1–42Aβ1–42 oligomers were injected into the wall of the gastrointestinal tract
mice. Initially, the oligomers of Aβ1–42 were internalized into enteric cholinergic neurons,
Int. J. Mol. Sci. 2021, 22, 10028 7 of 19
but after one year of observation, relocated amyloid was found in the brain of rodents,
which exhibited gastrointestinal tract dysfunction and cognitive deficits [69]. The findings
confirmed that intra-gastrointestinal oligomers of Aβ1–42 could disturb not only enteric
function, but also induce AD in the studied animal model of AD. Moreover, as Aβ from the
periphery could contribute to the Aβ burden in the brain, these results may support the
hypothesis that Aβ has prion-like properties [70]. Furthermore, the discovery of amyloid
migration may prove the connection between the gut and neuroinflammation in AD.
Recent data also link changes in the gut microbiota with AD [71]. Changes in the
phyla Bacteroidetes and Firmicutes, unrelated to age, have been demonstrated in mouse
models of AD [72–74]. The results from animal models have also been confirmed in hu-
man studies using gene sequencing techniques. Human fecal samples showed similar
results, with alterations in the microbiome, including decreased Firmicutes and Bifidobac-
terium, but increased Bacteroidetes in AD patients [75]. Another study conducted among
cognitively impaired patients with brain amyloidosis revealed an increased abundance of
Escherichia/Shigella, known as pro-inflammatory bacteria, with a simultaneous decrease in
anti-inflammatory Eubacterium rectale in comparison with healthy controls and individuals
without amyloidosis in PET imaging. Additionally, in these patients, a positive correlation
was found between increased blood levels of pro-inflammatory cytokines, such as IL-1β
and CXCL2, and a component of the inflammasome complex NLR family pyrin domain
containing 3 (NLRP3), and abundance of Escherichia/Shigella [75,76]. When the CSF levels of
various AD biomarkers were investigated in a study by Vogt et al., a significant relationship
was revealed between YKL-40 concentrations, and an increased abundance of Bacteroides
and decreased presence of Turicibacter [75].
The connection between the gut and the brain in AD has also been confirmed in stud-
ies exploring the transfer of healthy microbiota from wild type mice to mouse models of
AD. Normalization of the gut microbiome led to the reduced formation of Aβ plaques and
neurofibrillary tangles, decreased glial reactivity, and improved cognitive performance [77].
Moreover, the results of the study are in line with human studies showing that transplan-
tation of healthy microbiota to AD patients suffering from Clostridium difficile infection
resulted in improved cognitive function, as demonstrated by the Mini-Mental State Exam
(MMSE) score [78,79]. On the other hand, it was revealed that pathological changes in
microbiota composition, e.g., a decrease in Bifidobacteria and the overgrowth of Clostridium
difficile, may stimulate a shift in the expression of proinflammatory molecules [3,18].
Interestingly, a specific kind of amyloid has also been identified on the bacterial
cell surface. The first discoveries of this protein were described in Escherichia coli curli,
the proteinaceous components of bacterial extracellular fibers [80]. Similar abilities to
produce bacterial amyloids have been discovered in other species, such as Staphylococcus,
Streptococcus, Salmonella, and Klebsiella. Bacterial amyloid plays an important role in the
building of a microbial biofilm, which prevents gut bacteria eradication [81]. Although the
primary structures of bacterial and CNS amyloids are not similar, their tertiary structures
reveal a significant similarity [82]. As a result, the presence of bacterial amyloid in the gut is
thought to affect the immune system, consequently intensifying reaction to the formation of
neuronal amyloids [81]. Knowing that bacterial amyloids can cross physiological barriers,
it has been suggested that they contribute to the development of AD [83].
Lipopolysaccharide (LPS), which is known for its pro-inflammatory properties, is
present in the membrane of Gram-negative bacteria such as Bacteroides. It has been proven
that LPS is capable of generating inflammation and may mediate the release of many proin-
flammatory cytokines through Toll-like receptor-4 (TLR-4) [84]. This receptor contributes
to the activation of the microglia at the earliest stages of Aβ deposition in the brain, which
has been demonstrated in mouse models of AD with TLR-4 deletion, showing enhanced
amyloidosis [85].
Another rodent study on bacterial LPS revealed that following the intraperitoneal
injection of LPS, mice showed elevated hippocampal levels of Aβ1-42 with simultane-
ous cognitive defects [86]. The importance of this bacterial endotoxin for amyloid fibril
Int. J. Mol. Sci. 2021, 22, 10028 8 of 19
formation has been confirmed by in vitro experiments that demonstrated that LPS from
Escherichia coli could potentiate Aβ organization in compact fibrils. These results confirm
that LPS is a key factor in the kinetics of Aβ fibrillogenesis [87]. Furthermore, a significant
increase in LPS levels has been observed in the brain samples obtained from AD patients
that were co-localized with Aβ plaques, suggesting that this bacterial molecule has the abil-
ity of to pass through physiological barriers into the brain [88,89]. Consequently, elevated
LPS levels have been found in the plasma of AD patients [90]. This finding is consistent
with the aforementioned hypothesis of the “leaky gut syndrome” and loss of integrity of
intestinal and BBB barriers with age, which contribute to neuroinflammation. Furthermore,
knowing that Bifidobacterium and Lactobacillus exert a beneficial effect on LPS levels and
barrier integrity, a decrease in the abundance of these bacteria may play a significant role
in the development of AD [91].
4.2. Parkinson’s Disease

Parkinson’s disease is the second most common neurodegenerative disorder [92],
which may also be linked to disturbances in the brain–gut–microbiota axis. PD is a chronic,
progressive disease characterized by both motor and non-motor features. It mostly occurs
in men and women over 40 years of age and its incidence increases with age [93,94]. Tremor,
bradykinesia, and postural instability are the primary motor symptoms, while cognitive
decline, sleep disturbances, depression, and anxiety are the main non-motor symptoms [95].
The causes of PD include deterioration of the dopaminergic neurons in the extrapyramidal
tract of the midbrain, which is believed to be responsible for motor dysfunction [96]. The
histopathological hallmark of PD is the presence of misfolded, insoluble α-synuclein,
which may aggregate into Lewy bodies in neurons, thus inducing neurodegeneration [97].
Similarly to AD, neuroinflammation also plays a role in the pathophysiology of PD, which
is evident in microgliosis and astrogliosis [98].
Non-motor symptoms attributable to the digestive system are particularly common
in patients with PD. Hypersalivation, which is the result of impaired swallowing, and
constipation, caused by motility changes, are the most common dysfunctions of the gas-
trointestinal tract [99]. These observations support the hypothesis that PD may originate
within the gut. Moreover, constipation may be linked to enteric nervous system degen-
eration caused by the aggregation of alpha-synuclein, increased intestinal permeability,
and local inflammation [100]. It has also been observed that there are strong associations
between changes in intestinal motility, which may predate neurological manifestations
of the disease by a number of years, a well as a subsequent diagnosis of PD. It has been
demonstrated that constipation significantly increases the risk of developing PD [101,102].
It has been suggested that disturbed gut microbiota, which is responsible for intestinal
motility, increased permeability, and chronic local inflammation, could be considered an
important factor in the pathophysiology of PD. As dysfunction of the gastrointestinal
system is a characteristic feature of PD, the gut microbiota composition in PD patients
has also been investigated. It has been shown that patients suffering from PD have an
increased abundance of Enterobacteriaceae, which was positively correlated with postural
instability [103]. In contrast, another study demonstrated that certain families of healthy
bacteria, such as Prevotellaceae and Lachnospiraceae, were reduced in the fecal samples in
PD patients [104]. Prevotellaceae are known for participating in the production of mucins,
which play a crucial role in maintaining intestinal permeability. Thus, their reduced
presence might be linked to the “leaky gut syndrome” [105]. Lachnospiraceae, such as
Blautia, Coprococcus, and Roseburia, participate in the production of SCFAs which are known
for their anti-inflammatory and gut protective properties, which may also contribute to
altered permeability [104,106].
Interestingly, studies on animal models of PD have demonstrated a connection be-
tween motor deficits, neuroinflammation, and the gut microbiota. Mouse models of PD
have shown a disturbed gut microbiota, with a decreased presence of Firmicutes and
Clostridiales and an increased abundance of Proteobacteria and Enterobacteriales. Experi-
Int. J. Mol. Sci. 2021, 22, 10028 9 of 19
mental transplantation of fecal microbiota not only ameliorated microbiota composition

and reduced SCFAs concentration in mouse feces, but also diminished the activation of
microglia and astrocytes within their brains [107].
A recent study demonstrated that providing germ-free mice with selected microbial
metabolites resulted in neuroinflammation and detectable PD-like physical symptoms [108].
Consequently, transplantation of the microbiota from healthy individuals to mice over-
expressing α-synuclein resulted in diminished motor impairments in comparison with
the animals treated with microbiota from PD patients [108]. Additionally, a recent study
conducted on aged rats with aggregated α-synuclein in the intestinal submucosal plexus,
which were exposed to transgenic E. coli that produced bacterial amyloids, displayed a
significant reaction to bacterial curli. It has been demonstrated that the production of
α-synuclein within the intestines and its accumulation in the brain of examined rodents is
intensified, which further prompts microgliosis and astrogliosis. Moreover, the rat brains
showed an increased expression of TLR-2, TNF-α, and IL-6, which may indicate that amy-
loids produced by bacteria provoke α-synuclein aggregation and, as a result, an innate
immune system response [109,110]. Another microbial metabolite, LPS, might be a crucial
factor in the pathophysiology of PD, similarly to AD. LPS-induced inflammation in rodent
models of PD activate the microglia, which results in dopaminergic neuron damage and
loss [99,111].
It is worth mentioning that a large number of PD patients are infected with Helicobacter
pylori. For a number of years, the presence of gastric ulcers, which are triggered by H. pylori,
has been linked to PD [112]. On the other hand, this bacteria is also known for impairing the
absorption of levodopa, a key drug in the treatment of motor aspects of PD [113]. It has been
demonstrated that comorbidity between PD and H. pylori infection is related to more severe
manifestations of PD and more significantly impaired motor function [114]. Interestingly,
the existence of H. pylori infection might also increase the incidence of PD [112,115].
4.3. Multiple Sclerosis

In contrast with AD and PD, multiple sclerosis (MS) is a disease affecting mostly young
adults, particularly women [116]. It is a demyelinating CNS disease with an inflammatory
component. MS is characterized by chronic inflammation both in white and grey matter
of the brain and the spinal cord, which causes destruction of the myelin that covers the
neurons [117]. Although the mechanisms underlying MS are not fully understood, it
is postulated that malfunction of the immune system is the most probable cause of the
disease [118]. Apart from chronic inflammation, altered selectivity of BBB in MS brain
has been observed. This state facilitates the migration of immune cells (mostly T-cells)
to the nervous system and penetration of the brain. Following infiltration into the CNS,
T-cells start to recognize myelin as a trigger to the immune system, which causes enhanced
inflammation and results in demyelination [117,119].
The pathophysiology of MS may be also linked to genetic and environmental fac-
tors [120]. Obesity in early life [121], decreased vitamin D levels in the blood, and in-
sufficient exposure to sunlight [122], as well as smoking [123], are the established and
most frequently described causes. All of these aspects can also indirectly affect the gut
microbiota. As microbes may control immunity by regulating T-cells, the gut microbiota
has received attention as an important factor in MS pathology.
It has been demonstrated that there are considerable differences between stool samples
from MS patients and those from healthy controls. MS samples revealed decreased levels
of Bacteroidetes, Clostridium, Fecalibacterium, and Prevotella taxa (the last one produces propi-
onate, which is a SCFA) [124–126]. Moreover, increased abundance of Methanobrevibacter
and Akkermansia muciniphila has been observed in different types of MS [127]. In addition,
transplantation of the microbiota from MS patients to germ-free mice resulted in intensified
experimental autoimmune encephalomyelitis (EAE), an animal type of demyelinating
diseases, in contrast with germ-free mice treated with healthy microbiota [128]. These
Int. J. Mol. Sci. 2021, 22, 10028 10 of 19
results suggest the potential involvement of the microbiota in the development of MS and
its impact on disease progression.
It has been revealed that various metabolites produced by commensal Clostridium,
such as SCFA butyrate, propionate, and acetate, may differentially induce T-regulatory
cells, affecting the balance between pro- and anti-inflammatory cells in MS patients [129].
Moreover, studies among MS patients treated with vitamin D have revealed an altered com-
position of the gut microbiota, with elevated levels of Faecalibacterium, an anti-inflammatory
bacteria that produces butyrate [125]. These results may also confirm the positive effect of
vitamin D supplementation for MS patients.
4.4. Major Depressive Disorder

Major depressive disorder (MDD) is a mental disorder and is one of the leading
causes of disability, morbidity, and mortality in developed countries. In 2017, more than
264 million people worldwide were affected by MDD [130]. The main symptoms of MDD
include low mood, difficulties in concentration, fatigue, appetite alteration, and digestive
and sleeping problems. For an appropriate diagnosis, the symptoms must be present
continuously for a minimum of a 2-week period [131]. The pathophysiology of MDD
is still not fully understood. However, it is suggested that deficiency in monoamine
neurotransmitters, such as serotonin, noradrenaline, and dopamine, may be the key cause
of the disorder [132]. Another cause of the disease may be systemic inflammation, with
elevated blood cytokine levels, which also demonstrates that depression is a systemic
disease. Systemic inflammation also leads to neuroinflammation and the activation of
microglia and astrocytes, contributing to the development of MDD, affecting behavior and
emotions [133–136].
As previously described, the gut and the brain communicate in a bidirectional manner
and interactions between these organs are important for the development of the CNS.
Moreover, the gut microbiota exerts a significant impact on the CNS and may act as a
mediator in communication between the gut and the brain. Studies on germ-free mice show
that changes in the gut microbes may promote anxiety-like behaviors in these animals,
whose effects persist after colonization with normal intestinal microbiota [137]. Interactions
between the gut and the brain are essential to the development of stress systems within
the CNS, with a possible critical time window, after which reconstitution of the microbiota
may not be able to normalize the behavioral phenotype. Another study in which the
microbiota from depressed patients was transferred to rats, revealed enhanced depression-
like behaviors in these animals, with disturbed tryptophan metabolism [138].
The existing body of knowledge of the gut microbiota and microbiota-released molecules
have prompted researchers to consider disturbances in the gut–brain axis as a new aspect of
MDD pathology. Some studies have revealed that gut microbiota composition in depressed
patients was significantly altered in comparison with healthy controls. MDD patients had
an increased abundance of Bacteroidetes and Proteobacteria, with a decrease in Firmicutes,
Bifidobacterium, and Lactobacillus [139–141]. Similar results have been obtained from ani-
mal studies, with an enhanced proportion of Bacteroidetes and a decreased proportion of
Firmicutes in various depression models [142–144].
Moreover, it has been identified that the presence of Coprococcus, a bacterial species
that produces a beneficial SCFA, butyrate, in the patient’s gut, is connected with indicators
of a higher quality of life, such as perceived health status, physical functioning, vitality,
emotional well-being, and social functioning. Interestingly, Coprococcus was found to
be diminished in MDD patients [145]. A recent meta-analysis demonstrated a decline
in depression scores in MDD patients after restoration of the microbiota with probiotics,
which also confirms essential connections between depression and the gut microbiota [146].
4.5. Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized
by impairments in communication and social interactions, repetitive and stereotyped
Int. J. Mol. Sci. 2021, 22, 10028 11 of 19
behaviors, and restricted interests [147]. It is commonly diagnosed in infants, mostly

boys, between 1 and 2 years of age [148]. However, as ASD consists of a broad range
of conditions, it may be diagnosed later in life, also in adults [149]. Although the exact
cause of ASD is not fully understood and is highly complicated, it is linked to genetic and
environmental input [150].
Apart from psychological aspects, ASD patients exhibit gastrointestinal symptoms,
such as diarrhea and/or constipation, as well as abdominal pain [151]. Recognizing the
relationship between the gut and the brain, researchers started investigating the micro-
biota of ASD patients. It has been demonstrated that people suffering from ASD show
an increased abundance of Clostridium and Lactobacillus species [152,153]. Furthermore,
Bacteroidetes dominate in the intestines, with a concurrent decrease in Firmicutes [154].
Another study revealed decreased levels of beneficial species Prevotella and Coprococcus
in the intestinal microflora of autistic children in comparison with healthy controls [155].
Similar results have been obtained in animal studies. It has been demonstrated that the
valproic acid rat model of autism exhibits changes in the diversity and number of species,
and has a composition of gut bacteria similar to those observed in human autism [156].
Moreover, significantly increased serum levels of bacterial LPS, as well as IL-1beta and
IL-6, the biomarkers of inflammation, have been observed in adult autistic patients in com-
parison with healthy controls. Furthermore, these results were inversely correlated with
socialization scores [157]. These findings confirm the role of microbiota in ASD. However,
the significance of low-grade endotoxemia in the pathophysiology of autism needs further
investigation.
Importantly, it seems that exposure in utero to inflammation resulting from distur-
bances in the maternal gut microbiota may increase the probability of ASD occurrence
in children. This has been confirmed in studies on mouse models, which indicate that
changes in the maternal gut microbiome promote neurodevelopmental abnormalities in
mouse offspring [158].
5. Conclusions
In recent years, the gut microbiota and its importance for the functioning of the human
body has generated considerable interest among researchers, although we still do not know
whether alerations in the microbiota trigger pathological changes or coexist with them.
However, a balanced composition of the gut microbiota and the production of various
bacterial metabolites have proven their profound significance for host health, including for
the CNS. The gut–brain axis, which may be defined as a complex interplay between the
function of the gastrointestinal system, including the enteric nervous system, the activity
of our intestinal microbes, and the CNS, may influence the development of various brain
diseases.
The body homeostasis may be affected by the pathological shift in the microbiome
and its altered metabolism, thus promoting the development of different neurological
and neuropsychiatric disorders. These gut microbiome-related diseases of the CNS in-
clude neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and
multiple sclerosis, as well as depression and autism spectrum disorders. Therefore, the
intestinal microflora can be seen as an important factor in the development of CNS and the
progression of various neurological diseases.
Although the gold standard in microbiota analysis is a fecal material examination, a
multiplatform analysis of its metabolites may also provide valuable information regarding
the state of the microbiome. Moreover, the gut microbiome could be a potential new target
for the treatment of these diseases. Prevention of gut dysbiosis by probiotics may also
provide protection from the disorders described above. A summary of the microbiota
changes observed in neurological diseases is presented in Table 1.
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 12 of 19
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Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
AD Alzheimer’s disease
ASD Autism spectrum disorder
Aβ Amyloid beta
BDNF Brain-derived neutrophic factor
CNS Central nervous system
ENS Enteric nervous system
GLP-1 Glucagon-like peptide
LPS Lipopolysaccharide
MDD Major depressive disorder
MS Multiple sclerosis
NFTs Neurofibrillary tangles
NLRP3 NLR family pyrin domain containing 3
PD Parkinson’s disease
SCFA Short-chain fatty acid
TLR-4 Toll-like receptor-4
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International Journal of

1 Department of Neurodegeneration Diagnostics, Medical University of Białystok, 15-269 Białystok, Poland;

Received: 16 August 2021

Int. J. Mol. Sci. 2021, 22, 10028. https://doi.org/10.3390/ijms221810028 https://www.mdpi.com/journal/ijms

2.1. Changes in the Composition of the Intestinal Microbiome through Life

2.2. Factors Influencing Gut Microbiota

2.3. Functions of the Gut Microflora

3.2. Direct and Indirect Effects of Gut Microbiota on the CNS

Figure 1. Pathways between

3.3. Relevance of Healthy Gut Microbiota

4. Gut and Neurological Diseases

4.2. Parkinson’s Disease

mental transplantation of fecal microbiota not only ameliorated microbiota composition

4.3. Multiple Sclerosis

4.4. Major Depressive Disorder

4.5. Autism Spectrum Disorder

behaviors, and restricted interests [147]. It is commonly diagnosed in infants, mostly

Institutional Review Board Statement: Not applicable.

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