www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No.

32), pp: 53829-53838

Review
Microbiota-gut-brain axis and the central nervous system
Xiqun Zhu1,*, Yong Han2,*, Jing Du3,*, Renzhong Liu1, Ketao Jin4 and Wei Yi1
1
Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China
2
Clinical Research Institute, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, P.R. China
3
Department of Gastroenterology, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, P.R. China
4
Department of Gastrointestinal Surgery, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing,
Zhejiang, P.R. China
*
These authors contributed equally to this work
Correspondence to: Wei Yi, email: [email protected]
Ketao Jin, email: [email protected]
Keywords: gut microorganism, microbiota-gut-brain axis, central nervous system, disorders
Received: April 19, 2017     Accepted: April 26, 2017     Published: May 10, 2017
Copyright: Zhu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY
3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT
The gut and brain form the gut-brain axis through bidirectional nervous,
endocrine, and immune communications. Changes in one of the organs will affect
the other organs. Disorders in the composition and quantity of gut microorganisms
can affect both the enteric nervous system and the central nervous system (CNS),
thereby indicating the existence of a microbiota-gut-brain axis. Due to the intricate
interactions between the gut and the brain, gut symbiotic microorganisms are closely
associated with various CNS diseases, such as Parkinson's disease, Alzheimer's
disease, schizophrenia, and multiple sclerosis. In this paper, we will review the
latest advances of studies on the correlation between gut microorganisms and CNS
functions & diseases.

INTRODUCTION development of gut-associated lymphoid tissue and by

preventing the colonization of pathogens, and they can
Gut microorganisms affect the energy metabolism and mitochondrial function
of the host. The intricate relationship governing host
The human gut contains various microorganisms, and microorganism interactions suggest that when this
such as bacteria, fungi, parasites, and viruses, and more relationship is abnormal, the microorganisms may cause
than 100 million bacteria reside in human gastrointestinal the pathogenesis of disease or promote the progression
tract, which is 10-100 times the number of eukaryotic of disease. Therefore, recent research has focused on
cells in our body. After years of common development determining the diversity of these microorganisms to
with the human body, the gut bacteria have reached clarify the physiological roles they play and eventually
a mutually beneficial symbiotic state with the human to prevent and treat diseases by controlling the
body. The gut bacteria mainly include six major phyla of microorganism species. For example, recent studies
Firmicutes, Bacteroidetes, Proteobacteria, Actinomycetes, demonstrated that gut bacteria can enhance the efficacy of
Verrucomicrobia, and Fusobacteria, with Bacteroidetes commonly used chemotherapy drugs [3].
and Firmicutes being the dominant flora [1]. Age and diet, in particular, can have a significant
Gut microorganisms play an important role in impact on gut microbiota [4, 5], and numerous human and
promoting adult development and homeostasis; for animal studies have demonstrated that different diets can
example, they can affect human metabolic functions by cause a significant change in the microbiota. For example,
decomposing the complex polysaccharides in food. In the species of colonized bacteria in the gut of Europeans
addition, gut microorganisms can regulate gut movement, significantly differs from that of people from rural Africa
the gut barrier system and fat distribution [2]. Gut due to the difference in their daily diets [6]. By examining
microorganisms can affect immune function through the the stool samples of 98 people, Wu et al. [7] found that

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 Bacteroides were mainly associated with a diet that was information transmitted from both ENS and CNS nerves.
high in animal fat and proteins, whereas Prevotella was The third level is the CNS. After integrating various pieces
mainly associated with a high-carbohydrate diet. Infection of information from various centers of the brain and
and disease can also have an adverse effect on the normal spinal cord when they receive signals regarding internal
gut flora of the host, thereby causing deleterious effects or external environmental changes, the CNS transmits
on the host; for example, disrupting gut microorganisms its regulatory information to the ENS or directly acts
in rats will cause long-term visceral pain and stress- on gastrointestinal effector cells through the autonomic
related disorders, such as irritable bowel syndrome [8]. nervous system and the neuroendocrine system to regulate
The microbiota organisms, which are symbiotic with the smooth muscle, glands and blood vessels. The fourth
the human body, constitute a complex micro-ecological level consists of advanced brain centers; information from
system, and a change in the quantity and quality of the the cortex and the subcortical region converges downward
gut microorganism population may affect the gut barrier to specific brain stem nuclei from the basal ganglia. This
function, increase the secretion of toxic substances, and type of neuroendocrine network, which connects the
decrease the secretion of substances that are beneficial to gastrointestinal tract with the CNS at different levels, is
human body, leading to enteral and external diseases. the structural basis for the function of the microbiota gut-
There are three main methods for detecting gut brain axis. Disorders of neurological control at any level
microorganisms: the bacteria culture technique, the will affect the function of the gut and brain. The gut has a
traditional molecular biology technique that is independent direct neural connection with the brain through the vagus
of culture, and high-throughput sequencing technology. nerve, and bacteria can stimulate the afferent neurons of
The former is mainly used for stool culture, this method the ENS [10]. Disorders of the microbiota gut-brain axis
is time-consuming, and the bacterial species obtained are are associated with depression, anxiety, irritable bowel
limited. The latter two mainly isolate the bacterial DNA syndrome, inflammatory bowel disease, CNS diseases and
from the stool for the detection, the detection is fast, and other diseases.
the bacterial species are complete. The vagus nerve of the body can control the function
of multiple organs, such as heart rate and gut motility; the
Microbiota gut-brain axis vagus nerve can also transmit peripheral immune signals
to the CNS. The vagus signal from the gut can trigger an
The central nervous system (CNS) is closely anti-inflammatory response against the sepsis induced by
related to the gastrointestinal tract, and the CNS plays an microorganisms. Gut microorganisms can affect brain
important role in regulating gut function and homeostasis. functions through the vagus nerve; after a vagotomy, the
In turn, the gut flora may affect the CNS and nerve cells, microorganisms will not be able to regulate behaviors [11].
participate in the regulation of nervous system function, After vagotomy in mice, no behavioral change was found
affect the pathogenesis and progression of nervous even for mice that were treated with probiotics. Similarly,
system-related diseases. Due to the complex relationship the bifidobacteria treatment, which had been previously
between the gut microorganism population and the host, reported to be effective, did not improve the behavior of
the authors proposed a new concept: the microbiota gut- vagotomized mice [12].
brain axis. The microbiota gut-brain axis is the focus of Because gut microorganisms can directly affect
recent research on the gut microecology. In addition to the immune system, immune activation may be the
studies of the relationship between the gut microecology pathway for transmitting microbial actions to the CNS
and neurological function, recent studies have emphasized [13]. Microorganisms can also enhance the anti-tumor
how this relationship affects human health. immune effect of drugs by promoting T cell accumulation
The brain and gut can be connected through a and transformation [14, 15], and microorganisms are very
variety of pathways, including the enteric nervous system important for the immune function of organisms. The
(ENS), vagus nerve, the immune system, or the metabolic immune system plays an important role in maintaining
processes of gut microorganisms. health by maintaining gut homeostasis. The elderly have
The gastrointestinal tract is an organ that is co- a decreased immune function, resulting in a change in
dominated by the CNS, the autonomic nervous system, the microorganism-brain connection and subsequent
and the ENS. Regulation of enteric nerves consists of four behavioral change. Microglia are immune cells in the
levels of nervous regulation [9]. The first level is the local CNS, and studies have found that the metabolism of gut
regulation by the ENS. The ENS consists of two nerve microorganisms can regulate the maturation and function
plexuses, the myenteric and submucosal plexuses, and the of microglia, thereby affecting CNS function [16].
motor neurons and the sensory neurons of the ENS connect Microorganisms can also cause neurophysiological
to each other to perform an independent information changes in the host by producing chemical substances that
integration and processing function, which is similar to bind to the receptors inside and outside of the gut. Bravo
the situation for the brain and the spinal cord. The second et al. found that mice fed L. rhamnosus (JB-1) probiotics
level is located at the prevertebral ganglia, which receives exhibited fewer anxiety-like and depressive behaviors and

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 a change in the GABA Aα2 mRNA content in the brain In 2004, Sudo et al. were the first to report that
area that controls specific behaviors [11]. Short-chain symbiotic gut microorganisms were associated with
fatty acids (SCFAs) are produced from the dietary fibers the hypothalamic-pituitary-adrenal (HPA) axis [25]. In
fermented by gut microorganisms in the large intestine. In response to stress, the levels of corticosteroid hormone
animal models, SCFAs can improve the neurodevelopment and adrenal hormones were higher in sterile mice than in
and cognitive function of animals with neurodegenerative mice harboring normal microorganisms. Gut colonization
disorders [17]. However, Macfabe injected a specific type by Bifidobacterium can attenuate the increased HPA
of SCFA, i.e., propionic acid (PPA), into rats, which then response; however, this inhibition can only be initiated
exhibited autism-related characteristics and neurochemical in the early stages of life, indicating that the most
changes [18]. These neurochemical changes included primitive exposure to microorganisms is necessary for the
neuroinflammation, increased oxidative stress, and inhibition of neural regulation by the HPA axis. The HPA
depletion of antioxidants, thereby leading to mitochondrial axis is very important for learning and memory, and an
dysfunction. Other microorganism-derived molecules, HPA disturbance can lead to impairment of hippocampal
such as the neural activation molecules serotonin, memory. The brain-derived neurotrophic factor (BDNF),
melatonin, histamine, and acetylcholine also have a role N-methyl-D-aspartate (NMDA), c-fos levels are reduced
in the microbiota gut-brain axis [19]. in sterile mice [26], and these substances have a role in
In addition, studies have shown that the microbiota memory retention, cognitive function, and other brain
may affect the CNS by altering adult hippocampal functions.
neurogenesis (AHN). The adult hippocampus and The change in gut microorganisms found in sterile
lateral ventricle have the function of generating new animals or with the use of probiotics, antibiotics, and
neurons. AHN has a role in learning and memory and colonization with fecal microorganisms can influence
can have affect on the pathogenesis of many neurological the cognitive function of the host. For example,
disorder-related diseases and symptoms, such as epilepsy, supplementation with probiotics for a week prior to
depression, Alzheimer’s disease (AD), and Parkinson’s infection can not only prevent the microorganism
disease (PD) [20]. In a recent study, Ogbonnaya et al. disturbance caused by the infection but also prevent the
found a difference between the hippocampal neurons of changes in cognitive behavior caused by stress [26]. Liang
sterile mice and those of normal mice and that microbiota et al. found that probiotics could significantly improve the
colonization after weaning did not alter the amount of cognitive dysfunction induced by chronic restraint stress
AHN, suggesting that early in life, microorganisms play [27]. In a human experiment, fMRI tests found that the
an important role in AHN [21]. activities in the brain regions that control brain memory
and the processing of sensation were altered after female
Microorganisms and brain function volunteers consumed fermented milk that contained
probiotics [28]. The above various studies found that the
The impact of microorganisms on behavior and stability of the equilibrium state of normal microorganisms
cognition has been increasingly recognized. Microbial in the gut was closely related to brain development and
signals can regulate important functions of healthy human function.
bodies, and growing evidence has demonstrated that many
diseases are due to disturbances of gut microorganisms Microbiota-gut-brain axis and CNS disorders
[22]. Early studies in animals showed that the introduction
of single, unique flora could lead to the development of Microbiota-gut-brain axis and neuropsychological
anxiety-like behavior, and this change was accompanied disorders
by the activation of neurons in the brain that relied on
the gut information transmitted to the brain via the vagus Schizophrenia is a neuropsychological disorder,
nerve [23]. A subsequent study found that colonization and whole-genome analysis suggests that immunity-
of the fecal microorganisms from the mice of a certain related genes may be changed in schizophrenia patients.
behavior type into another type of mice could cause the Song et al. [29] found that increases in the immune
receptor mice to show behavior similar to that of the donor response and inflammatory state in schizophrenia
mice. When the microorganisms of specific-pathogen-free patients. Microorganisms can regulate BDNF and
(SPF) Swiss mice were transferred to the bodies of sterile NMDA receptors [25], and these neurotrophic factors
BALB/c mice, the exploration behavior of sterile BALB/c and proteins have a role in brain development and
mice increased; however, when the microorganisms of neural plasticity. The change in BDNF expression leads
SPF BALB/c mice were transferred to the body of sterile to the cognitive dysfunction of schizophrenia patients,
Swiss mice, the exploration behavior of sterile Swiss and antagonists of the NMDA receptor can produce
mice became lower than that of normal Swiss mice, thus schizophrenia symptoms. When the NMDA receptor
indicating that behavior type may be directly associated function in a host is enhanced, the patients’ symptoms can
with microorganisms [24]. be relieved, and their cognitive ability can be improved

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 [30]. Microorganisms and intestinal mucosal cells can related symptoms; therefore, it is thought that ASD is
regulate the changes in chemical factors, such as the associated with impairment of the gut-brain axis [40].
proinflammatory interleukin-8 (IL-8) and IL-1 or the anti- The majority of autistic patients have diarrhea, abdominal
inflammatory IL-10 and transforming growth factor β pain, constipation, gastroesophageal reflux, and other
(TGFβ). The serum levels of proinflammatory cytokines gastrointestinal symptoms. Mazurek et al. studied 2,973
in schizophrenia patients are higher than those of normal ASD patients and found that 24% of the patients had at
controls, and the levels of serum inflammatory markers least one type of gastrointestinal disease [41], and Adams
are positively correlated with the clinical symptoms of et al. found that ASD child patients showed significantly
schizophrenia patients [31]. Additionally, the ratio of T greater occurrence of diarrhea, abdominal distension, and
helper cell type 1 (Th1) to Th2 in schizophrenia patients constipation than normal children, and the gastrointestinal
is increased, suggesting that the inflammatory response symptoms were also closely associated with the severity
in the patients is increased; after an effective treatment of ASD [42]. Moreover, ASD patients have a significantly
with drugs, this ratio will be corrected [32]. After female higher content of the genera Faecalibacterium and
rats were fed Zyprexa, a significant change in gut bacteria Clostridium in the gut than normal children [43, 44].
was detected, including an increase in Firmicutes and a Desbonnet et al. placed sterile mice and normal mice in
decrease in Bacteroidetes [33], and the levels of systemic two separate spaces, and the sterile mice would develop
inflammatory response markers in these rats, such as autistic behavior, whereas recolonization of symbiotic
IL-6, IL- 8, tumor necrosis factor-α (TNF-α) and IL-1β, flora was able to restore the partially defective social
increased significantly. behavior in the mice [45]. Impaired immune function is
Gut bacteria can also produce harmful substances a common feature of ASD patients, and the increase in
that damage the intestinal epithelial barrier, causing the genera Faecalibacterium may be the main reason for
neurotoxic bacterial products and proteins to enter the immune dysfunction in ASD patients [43].
circulatory system [34]. Severance et al. [35] found that Obese pregnant mice exhibit changes in social
the concentration of antibodies against saccharomyces behavior, oxytocin cells, synaptic plasticity, and the
cerevisiae was higher in the body of schizophrenia microorganism composition of the microbiota, but
patients, and this genus was a marker of gut inflammation. Lactobacillus reuteri could reverse these changes [46].
An increase in the levels of circulating pathogen antigen Because gut flora imbalance can increase the permeability
can cause the host to respond to its own tissues and cells of the intestinal mucosa, the metabolic products of gut
through a form of molecular induction [36], and this microorganisms and certain cytokines can enter the
response is the central process of autoimmune diseases. circulation system and cause damage to the CNS, resulting
Compared with the normal population, schizophrenia in a delay in the early neurological development in child
patients have a higher probability of developing patients. Christensen used metabolomics to identify
autoimmune disorders, and specific brain regions a large number of bacteria-derived metabolites that
of schizophrenia patients, such as the hippocampus, might be associated with ASD-related behaviors [47].
amygdala, and frontal cortex, have higher levels of Adams found that the levels of SCFAs, which are very
autoimmune antibodies [37]. Gut symbiotic flora can important for the development of neurological functions,
cause an immune response that produces more Th17 cells, in the stool samples of autistic children were lower than
leading to the occurrence of an autoimmune response. those of normal children [42]; similarly, the PPA levels
Additionally, schizophrenia patients have a higher were also reduced. The exposure of pregnant rats to PPA
proportion of Th17 cells [38]. Krych L et al. [39] found before giving birth impaired the social behavior of their
that rodents that received a long-term treatment with newborn and adolescent rats [48]. Moreover, following
phencyclidine would show schizophrenia-like behavior, PPA injection into the brain ventricles of adult rats, the
and this behavior was accompanied by a change in the rats exhibited a behavioral change similar to that of human
core gut microorganisms. When ampicillin was used to ASD, and the injection also induced changes in ASD-
reduce the gut microorganisms, the cognitive behavior of related genes, including genes for neurotransmitters, nerve
the animals could be corrected. The above experiments cell adhesion factors, and oxidative stress [18].
show the impact of changes in gut microorganisms on The bacterial metabolites, 4-ethyl-phenylsulfate and
schizophrenia. 3-(3-hydroxy phenyl)-3-hydroxypropionic acid, can cause
Autism spectrum disorder (ASD) is a type of mice to develop ASD-like symptoms [49, 50]. In addition,
extensive brain function development disorder that begins the serum lipopolysaccharide (LPS, cell wall components
during the early stages of growth (< 36 months), and it of gram-negative bacteria) levels are significantly higher
is manifested as different levels of interpersonal barriers, in ASD patients than in normal subjects, and LPS has
language development disorders, and stereotyped behavior. a clear association with social disorders [51]. Most
Environmental factors (especially gut dysbacteriosis) children with ASD have a history of infection before
are involved in the development of ASD, and as many age 2, and the frequency of their use of antibiotics is
as 70% of autistic patients exhibit gastrointestinal tract- also significantly higher than that of normally developed

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 children [52]. Antibiotics destroy the physiological ε-toxin produced by this pathogen could cause damage to
balance of the inherent gut flora, and the newly colonized the blood-brain barrier (BBB), thereby damaging neurons
microorganisms produce neurotoxins, thereby inducing and oligodendrocytes [56]. Consequently, Clostridium
chronic diarrhea and ASD. For example, an abnormal perfringens type B is thought to be the initiating factor
increase in Clostridia and Bacteroidetes in the gut can for susceptible individuals to experience the pathological
promote gastrointestinal symptoms and ASD behaviors change of autoimmune demyelination in the future. In
[18]. Therefore, both the imbalance of gut flora and the addition to the toxic effects, MS patients may have an
entry of excessive amounts of bacterial metabolites into imbalance of various bacteria of the Bacillus genus and
the brain through the circulation are associated with the species. For example, Jhangi et al. [57] found that MS
onset of ASD. patients had an increase in the genus Methanobrevibacter,
whereas the Lachnospiraceae content was reduced.
Microbiota-gut-brain axis and Tremlett H et al. [58] found that child MS patients had an
neurodegenerative diseases increase in Desulfovibrio, whereas the Lachnospiraceae
and rumen bacteria contents were decreased. These results
Multiple sclerosis (MS) is a chronic inflammatory suggest that gut microorganisms can affect the parenteral
demyelinating disease of the nervous system, and its and CNS immune response and self-flora imbalance to
etiology is still unclear. MS is associated with a significant promote the development and progression of EAE.
increase in the number of cells that have immune PD is an extensive neurodegenerative disease,
response to the patients’ own nervous system because gut its pathogenic mechanism is complex, and a change in
microorganisms play an important role in the development α-synuclein is an important pathogenic mechanism of
of the autoimmune system and are associated with a this disease. Changes in the gut microbial composition
variety of autoimmune and metabolic diseases. Therefore, may affect the gut barrier function and gut permeability,
it is speculated that gut symbiotic microorganisms play an thereby affecting intestinal epithelial cells and the immune
important role in the susceptibility to MS. system. The primed immune response initiated by gut
Experiments have been performed to study the microorganisms can enhance the inflammatory response
role of gut microorganisms in an animal model MS- to brain amyloid (α-synuclein), thereby causing the
experimental allergic encephalomyelitis (EAE). Ochoa- misfolding of α-synuclein [59]. Fireland [60] reported
Reparaz et al. [53] used a mixture of antibiotics to alter gut that bacterial proteins could cause inflammation, oxidative
microorganisms before inducing EAE in mice, and they stress, and cytotoxicity and consequently induce or affect
found that treatment with orally administered antibiotics the progression of PD. The neuroinflammatory response in
could significantly reduce fecal and gut microorganisms PD patients is associated with the upregulation of Toll-like
and could markedly impair the development of EAE and receptor-2 (TLR2) and the activation of microglia [61].
mitigate the severity of EAE, compared with those for In animal models of PD, the peripheral inflammatory
the intraperitoneal injection treatment and no treatment. response can induce the complement pathway in microglia
Other studies showed that when the mice were treated and cause damage to dopaminergic neurons [62].
with orally administered antibiotics, the production of Proinflammatory factors associated with chronic
the anti-inflammatory factor IL-10 was increased, thereby bowel diseases can induce intracranial inflammation, lead
improving EAE. Sterile mice may be immune to EAE, to the death of dopaminergic neurons, and eventually
and even when they do have EAE, their disease course is cause the development of PD [63]. Scheperjans F et al.
milder [54]. Sterile mice have a relatively lower number [64] found that PD patients had a decrease in Prevotella.
of interferon-γ (IFN-γ)-producing CD4+ Th1 cells and By comparing the stools of 34 PD patients and 34 normal
IL-17A-producing CD4+ Th17 cells in their body, and controls, Unger MM et al. [65] found that PD patients
these two substances are both very important for the had a decrease in Bacteroidetes and Prevotella in their
development of EAE. Re-colonization of segmented stool, which was accompanied by a reduction in SCFAs.
filamentous bacteria into sterile mice can significantly As symbiotic gut bacteria, Prevotella are involved in
increase the severity of EAE and increase the number the mucus formation of the mucosal layer of the gut
of Th1 and Th17 cells in the nervous system. When and the production of the neuroactive SCFAs through
spontaneous EAE transgenic mice were housed in a sterile fiber fermentation. The reduction of Prevotella causes a
environment, these mice did have EAE, and the number decrease in gut mucus and an increase in gut permeability,
of Th17 cells in the gut lymph node tissues decreased. increasing local and systemic susceptibility to the influence
Moreover, the amount of IL-17 and IFN-γ produced by of bacterial antigens and endotoxins, thereby inducing the
the cells also decreased. expression and misfolding of a large amount of α-synuclein.
The drug resistance of ε-toxin in the plasma of The inflammatory changes observed in PD patients and
MS patients is also higher than that of normal people. PD animal models are associated with increased gut
Vartanian et al. [55] found the colonization of Clostridium permeability [66]. LPS is a gut-derived proinflammatory
perfringens type B in patients with recurrent MS, and the bacterial endotoxin that can cause changes in the substantia

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 nigra, and it can act as a PD-promoting substance [67]. Gut microorganisms can also affect brain functions
Similarly, Keshavarzian A et al. [68] used high-throughput through the synthesis of various substances. Serotonin is
sequencing technology to examine the stool samples from very important for cognitive function, 95% of serotonin
38 PD patients and 34 healthy individuals, and they found is synthesized in the gut, and gut microorganisms play an
that the LPS synthesis gene was significantly higher in PD important role in serotonin synthesis. The gut serotonin
patients than in normal controls. level in sterile mice was 60% lower than the normal value
AD is a degenerative disease of the CNS, its onset is [73]. The use of serotonin reuptake inhibitors can reduce
recessive, and its disease course is chronically progressive. Aβ-protein levels in the brain, indicating that serotonin can
The pathological markers of AD include extracellular reduce the formation of Aβ plaques, thereby reducing the
β-amyloid (Aβ) senile plaques and intracellular risk of AD [74]. In sterile mice, BDNF was significantly
neurofibrillary tangles. The number and maturation of reduced, and this change was accompanied by cognitive
microglial cells in sterile mice are abnormal, resulting function changes. Similarly, in AD patients, the BDNF
in damage to the immune system and ultimately leading levels in the brain and in the serum were significantly
to the development of neurological diseases, such as AD reduced [75]. The Aβ production and clearance in the
[16]. Cognitive behavior impairment is a characteristic CNS is a dynamic change, and some bacteria and fungi
of AD patients, and the influence of gut microorganisms can secrete amyloid, resulting in an increase of amyloid
on cognitive behavioral capability has demonstrated the levels in the CNS that disrupts the dynamic balance of the
role of gut microorganisms in the pathogenesis of AD. Aβ protein, which leads to Aβ-protein aggregation in the
Bruce-Keller fed C57BL/7 mice with a normal diet and brain and a high AD risk [76]. Therefore, an imbalance
a high-fat diet, and the mice in the high-fat diet group in gut microbiota may promote the development of AD
would show impairment in cognitive behavior. When by affecting intestinal function and the synthesis and
the gut microorganisms in the high-fat diet mice were secretion of substances.
transferred to the mice who had a normal body weight but
had an antibiotics-induced paucity of microorganisms, Summary
the mice that received the gut microorganisms from the
high-fat diet group mice showed selective impairment The interactive relationship between the brain
in exploratory behavior, cognitive behavior, and gut and the gut includes neurology, metabolism, hormones,
permeability, and their systemic and central inflammatory immunity, and other aspects, and changes in any
responses increased [69]. This finding suggests that the component may lead to a functional change in the two
behavior changes induced by a high-fat diet may be due to interactive systems. The normal ecological balance
changes in gut microorganisms, and the microorganisms in of gut microorganisms plays an important role in the
turn change the cognitive behavioral capacity. maintenance of this relationship. Microorganisms affect
The integrity of the BBB is important for brain the development and function of the CNS through the
function and development. The inflammation caused by microbiota-gut-brain axis. The mechanisms of many
the changes in gut microorganisms will lead to changes in CNS diseases are still unclear, and the discovery of this
BBB integrity, which in turn affects brain function. Under complex relationship, the microbiota gut-brain axis,
normal conditions, LPS cannot enter the bloodstream due has provided a new research direction for the study
to the tight junction between intestinal epithelial cells. of CNS diseases that do not have a clear pathogenic
However, when the tight junction of cells is disrupted mechanism.
and the permeability is increased, LPS can enter the
bloodstream and induce inflammatory response. Studies ACKNOWLEDGMENTS
found that the plasma LPS concentration in AD patients
is three times that of normal patients [70]. Furthermore, This work was supported by the National
intraperitoneal injection of LPS into mice can cause an Natural Science Foundation of China (No. 30973073,
Aβ-protein increase in hippocampus, cognitive defects, No. 81172402 and No. 81374014). Zhejiang
and memory impairment [71]. The increase of the inflow Provincial Science and Technology Projects (grants
and the decrease in the outflow of the Aβ protein in no. 2015C33264, 2017C33212 and 2017C33213),
AD patients cause the aggregation of the Aβ protein in Natural Science Foundation of Zhejiang Province (No.
AD patients, and this finding suggests a decrease in LY17H160065), Research Foundation of Zhejiang
the capacity to clear the Aβ protein and an increase in Provincial Administration of Traditional Chinese
BBB permeability in AD patients [72]. The increased Medicine (No. 2016ZB018) and Zhejiang Provincial
concentration of plasma LPS in AD patients implies an Medical and Healthy Science and Technology Projects
impairment of the gut barrier function and increased gut (Grants No. 2013KYA228 and 2016KYA180). The
inflammation and permeability, which further suggests that funding body have no role in the design of the study and
gut microbiota may participate in the pathophysiological collection, analysis, and interpretation of data and in
process of AD. writing the manuscript.

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 CONFLICTS OF INTEREST via the vagus nerve. Proc Natl Acad Sci U S A. 2011;
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The authors declare that they have no competing 12. Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X,
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