Journal of Microbiology (2018) Vol. 56, No. 3, pp.

172–182 eISSN 1976-3794

DOI 10.1007/s12275-018-8032-4 pISSN 1225-8873

REVIEW

Mind-altering with the gut: Modulation of the gut-brain axis with

probiotics

al., 2011). The scaffolding of the gut-brain axis includes the

Namhee Kim, Misun Yun, Young Joon Oh, gastrointestinal tract, central nervous system (CNS), auto-
and Hak-Jong Choi* nomic nervous system (ANS), enteric nervous system (ENS),
neuroendocrine system, and immune system (Grenham et al.,
Microbiology and Functionality Research Group, World Institute of 2011). Recent studies have shown that the gut microbiota is
Kimchi, Gwangju 61755, Republic of Korea
involved in the neurodevelopment and diverse brain func-
tions through regulating the gut-brain axis (Carabotti et al.,
(Received Jan 21, 2018 / Revised Feb 7, 2018 / Accepted Feb 12, 2018)
2015; Erny et al., 2015). Gastrointestinal symptoms, such as
constipation, diarrhea, and abdominal pain, are common co-
It is increasingly evident that bidirectional interactions exist
morbidities in many neurological diseases (Westfall et al.,
among the gastrointestinal tract, the enteric nervous system,
2017). Moreover, recent advances in metagenomic sequenc-
and the central nervous system. Recent preclinical and clinical
ing have revealed that dysregulation in the composition of
trials have shown that gut microbiota plays an important role
gut microbiota (gut dysbiosis) is present in a variety of neu-
in these gut-brain interactions. Furthermore, alterations in gut
rological diseases. Consequently, the importance of main-
microbiota composition may be associated with pathogenesis
taining a healthy microbiota community (gut symbiosis) in
of various neurological disorders, including stress, autism, de-
the regulation of the gut-brain axis cannot be overly empha-
pression, Parkinson’s disease, and Alzheimer’s disease. There-
sized. The term microbiota-gut-brain (MGB) axis was intro-
fore, the concepts of the microbiota-gut-brain axis is emer-
duced to highlight the role of the microbiota in the gut-brain
ging. Here, we review the role of gut microbiota in bidirec-
axis.
tional interactions between the gut and the brain, including
Probiotics are defined as living microorganisms that, when
neural, immune-mediated, and metabolic mechanisms. We
ingested in adequate quantities, confer a health benefit on
highlight recent advances in the understanding of probiotic
the host; these microorganisms have been reported to exert a
modulation of neurological and neuropsychiatric disorders
wide range of effects (Hill et al., 2014). Although their mech-
via the gut-brain axis.
anisms in modulating host physiology are not yet fully elu-
cidated, probiotics might be able to modulate host immune
Keywords: probiotics, gut microbiota, nervous system, gut-
system (Bermudez-Brito et al., 2012). For example, Weissella
brain axis, gut dysbiosis, neurological disorders
cibaria WIKIM28 isolated from kimchi ameliorates atopic
dermatitis symptoms by regulating dendritic cell functions
and inducing regulatory T cell responses (Lim et al., 2017).
Introduction
Probiotic bacteria not only modulate host immune responses,
but also create a healthy gut environment through balanc-
The human gastrointestinal tract is inhabited by nearly 100
ing of the intestinal microflora. Ingestion of probiotics may
trillion microorganisms that are believed to play important
restore the composition of the gut microflora to a state more
roles in physiology (Gill et al., 2006). These microorganisms,
favorable for beneficial microorganisms (Choi et al., 2015;
collectively known as gut microbiota, are proposed as an es-
Mountzouris et al., 2007). Probiotics recently have attracted
sential “organ” in the maintenance of immune function, car-
attention in the context of brain function and health because
bohydrate metabolism, and metabolic homeostasis (Tremaroli
they serve to alter gut microflora toward a beneficial state,
and Backhed, 2012).
which could affect the gut-brain axis (Bravo et al., 2012).
Bidirectional communication between the brain and the gut,
In this review, we will focus on the role of gut microbiota in
known as the gut-brain axis, has long been recognized: the
crosstalk between the gut and brain, as well as how the mi-
brain modulates the gastrointestinal tract by regulating of mo-
crobiota affects a variety of neurological disorders. Finally,
tility, secretion, absorption, and blood flow; concurrently,
we will discuss recent findings in probiotic modulation of
the gut can affect brain function and behavior (Grenham et
brain function and neurological diseases.

*For correspondence. E-mail: hjchoi@wikim.re.kr; Tel.: +82-62-610-1729;

Fax: +82-62-610-1850
Copyright G2018, The Microbiological Society of Korea

Interactions within the gut-brain axis
Gut and brain regulate each other bidirectionally via multiple
mechanisms and pathways, including neural, neuroendocrine,
and immunological signals. Here, we highlight key commu-
nication pathways for a comprehensive understanding of the
gut-brain axis.
Neural communication between the gut and brain
Neural communication is mainly conducted within the ENS
in the gastrointestinal tract. The ENS is a main division of the
ANS and regulates gastrointestinal tract functions such as
intestinal motility, mucous secretion, and blood flow (Brown-
ing et al., 2017). The ENS interacts with the ANS and CNS via
neurotransmitters (adrenaline, noradrenaline, and acetyl-
choline), as well as sensory and motor neurons, all of which
convey signals from the gut to the brain.
The intestinal microbiota regulates electrophysiological thre-
sholds in ENS neurons (Sarkar et al., 2016). For example, a
strain of Lactobacillus reuteri was shown to activate a calcium-
dependent potassium channel in neurons within rat colon
myenteric plexus (Kunze et al., 2009). Metabolic compounds
by Bifidobacterium longum NCC3001 elicited reduction of
action potential spikes in myenteric neurons, following elec-
trical stimulation (Bercik et al., 2011b). In germ-free mice,
myenteric sensory neurons exhibited decreased excitability,
compared with normal mice (McVey Neufeld et al., 2013).
Moreover, these neurons in conventionalized germ-free mice
(conventionalized with intestinal bacteria from convention-
ally-raised mice) revealed increased excitability following hy-
perpolarization (McVey Neufeld et al., 2013). In addition to
their actions on myenteric neurons, gut bacteria also play a
crucial role in initial colonization and homeostasis of glial
cells in the intestinal mucosa (Kabouridis et al., 2015).
Another neuronal pathway in gut-brain communication uti-
lizes the vagus nerve (cranial nerve X that runs from brain-
stem to gastrointestinal tract) which has both efferent and
afferent roles (Cryan and Dinan, 2012). Approximately 80%
of vagal fibers are sensory, conveying information regarding
the state of the body’s organs to the CNS (Thayer and Stern-
berg, 2009). The vagus nerve regulates several vital functions,
including bronchial constriction, heart rate, and gut motility.
Many known effects of gut microbiota or probiotics strains
are dependent on vagus nerve activity (Goehler et al., 2008;
Bercik et al., 2011b; Bravo et al., 2011). For example, chronic
treatment with L. rhamnosus JB-1 induced increases in γ-
Aminobutyric acid (GABA) mRNA expression within spe-
cific brain regions, in addition to reducing stress-induced
corticosterone and anxiety-and depression-related behavior
(Bravo et al., 2011). Moreover, based on experiments in vago-
tomized mice, the vagus nerve was identified as a major mo-
dulator in the gut-brain communication pathway (Bravo et
al., 2011). However, vagus nerve-independent mechanisms
also exist in gut–brain communication, as antimicrobial treat-
ments failed to show gut-brain dependence on vagus nerve
activity (Bercik et al., 2011a).
Immune system mediated interaction
Gut microbiota can directly affect the immune system; this
Probiotics modulate the gut-brain axis 173
constitutes a key indirect route for communication between
the gut microbiota and the nervous system (Macpherson and
Uhr, 2004; Bengmark, 2013). The gut houses the gut-asso-
ciated lymphoid tissues (GALT) which are the largest collec-
tion of lymphoid tissues in the human body; theses tissues
protect the body from microbial invasion via the gut. A va-
riety of gut and GALT immune cells, such as T cells, macro-
phages, and dendritic cells (DCs) can cross the blood-brain-
barrier (BBB) and affect neurons and glia in the brain (Dia-
mond et al., 2011). In the brain, there are also resident im-
mune cells, such as macrophages and DCs in the choroid
plexus, microglia in the parenchymal region of brain, and
leukocytes in the cerebrospinal fluid (CSF) (Wang and Kas-
per, 2014). Therefore, gut microbiota, known to shape the
host immune system, can also modulate the activity of these
resident immune cells, in addition to their effects on neuro-
nal cells in the CNS (Berer and Krishnamoorthy, 2012). More-
over, a recent study of germ-free mice has revealed that gut
microbiota can alter the immune system of the CNS by regu-
lating microglial activation and homeostasis (Erny et al., 2015).
Microglia in germ-free mice exhibited global defects in cel-
lular proportions and in maturation, thereby leading to di-
minished innate immune responses (Erny et al., 2015).
Systemic circulation of immune factors, cytokines, and che-
mokines influences the brain via the vagus nerve and circum-
ventricular organs (Hosoi et al., 2002). In addition, another
pathway consists of direct transport by saturable transport
systems along the BBB (Banks, 2005). In the brain, pro-in-
flammatory cytokines can trigger further neuro-inflamma-
tion in the nervous system, thereby causing increased per-
meability of the BBB (McCusker and Kelley, 2013). Leakage
of the BBB leads to immune cell infiltration, exacerbation of
inflammatory responses, and reactive gliosis (reactive changes
of glial cells in response to damage); causing neurodegenera-
tion eventually (Obermeier et al., 2013). In addition, cyto-
kines alter the concentrations of several neurotransmitters
in the brain, including serotonin, dopamine, and glutamate
(Miller et al., 2013). Non-inflammatory cytokines also serve
as mediators for intestinal microbes to regulate brain func-
tion. For example, antibiotic exposure in neonatal mice pro-
duced reductions in the level of plasma granulocyte colony
stimulating factor (G-CSF) (Deshmukh et al., 2014). G-CSF
can stimulate neurogenesis in the brain by crossing the BBB;
further, it has a protective role in ischemic injury, as well as
in certain models of Parkinson’s disease and Alzheimer’s di-
sease (Shyu et al., 2004; Meuer et al., 2006; Prakash et al.,
2013; Wallner et al., 2015). Thus, by promoting the produc-
tion of G-CSF, the gut microbiota may provide a potential
therapeutic agent for normal neurodevelopment, as well as
to combat the progression of neurodegenerative diseases.
Additionally, recent findings regarding drainage of the lym-
phatic system into the brain provide more decisive evidence
of direct cytokine entry into the brain, enabling interaction
with neural tissues (Louveau et al., 2015; Sun et al., 2017).
Effects of neuroactive compounds and metabolites from gut mi-
crobes on the central nervous system
Gut microbiota is capable of producing a spectrum of neu-
rotransmitters, neuroactive compounds, and metabolites.
Neurotransmitters and neuroactive compounds that have
174 Kim et al.
been isolated from bacteria include GABA, serotonin, cate-
cholamine, and acetylcholine (Table 1). For example, Lacto-
bacillus and Bifidobacterium species can produce GABA;
Escherichia, Bacillus, and Saccharomyces spp. can produce
norepinephrine; Escherichia, Bacillus, Lactococcus, Lacto-
bacillus, and Serratia can produce dopamine. Gut microbiota
also indirectly controls the production of neurotransmitters
by regulating available precursors of neuroactive chemicals
or by stimulating host enteroendocrine and neuroendocrine
cells (Desbonnet et al., 2010; Yano et al., 2015). B. infantis
has been reported to increase the availability of tryptophan,
a precursor of 5-hydroxytryptamine (5-HT; a synonym of
serotonin), in the plasma, thereby raising 5-HT concentra-
tion in the brain (Desbonnet et al., 2008; Desbonnet et al.,
2010). Spore-forming gut microbiota stimulates host enter-
ochromaffin (EC) cells to produce 5-HT; the majority of 5-
HT in the body is directly synthesized by EC cells from tryp-
tophan (Yano et al., 2015). Thus, probiotics producing neu-
rotransmitters or promoting host cells to synthesize these
neurochemicals may be used as delivery vehicles for neuro-
active compounds (Lyte, 2011).
Other well-known bacterial neuroactive metabolites include
short-chain fatty acids (SCFAs), such as acetate, butyrate, lac-
tate, and propionate (Horn and Klein, 2013; Overduin et al.,
2013). SCFAs are produced via the fermentation of complex
polysaccharides and demonstrated to possess immunomo-
dulatory effects (Macfarlane and Macfarlane, 2003). SCFAs
can directly interact with the nervous system, thereby activat-
ing sympathetic neurons, and can also pass through the BBB,
thereby influencing behavior and neural signaling (Kimura
et al., 2013; Frost et al., 2014; Rios-Covian et al., 2016). For
instance, butyrate can act as a potential epigenetic modifier
by inhibiting histone deacetylases (HDACs) and stimulate
the hypothalamus-pituitary-adrenal (HPA) axis (Gagliano
et al., 2014; Stilling et al., 2014). By inhibiting of HDACs,
butyrate can act as an anti-inflammatory agent by inhibit-
ing nuclear factor κB (NF-κB) activation in colon cells (Inan
et al., 2000). Further, butyrate inhibits intestinal inflamma-
tion by relieving HDAC inhibition of Foxp3, a transcription
factor exclusively expressing in regulatory T cells (Tregs), thus
promoting the generation of Tregs (Furusawa et al., 2013).
Moreover, glial cells, especially in the developing brain, up-
take SCFAs as an energy source for cellular metabolism (Ra-
fiki et al., 2003). SCFAs also stimulate the secretion of gut
hormone peptides, such as glucagon-like peptide-1 (GLP-1)
and peptide tyrosine tyrosine (PYY), from enteroendocrine
Table 1. List of neuroactive compounds detected within various bacteria
Gut microbiota
Lactobacillus, Bifidobacterium spp.
Bifidobacterium infantis, Streptococcus, Escherichia, Enterococcus,
Lactococcus, Lactobacillus, Candida,
Clostridium sporogenes, Ruminococcus gnavus
Escherichia, Bacillus, Saccharomyces
Escherichia, Bacillus, Lactococcus, Lactobacillus, Serratia
Lactobacillus, Bacillus
Lactococcus, Lactobacillus, Streptococcus, Enterococcus
Bacillus sp. JPJ
cells expressing free fatty acid receptors (Psichas et al., 2015).
Secreted gut peptides can act in the hypothalamus, a pri-
mary brain center for regulation of food intake and energy
homeostasis (Goldstone, 2006).
Recent findings have revealed that commensal bacterial
metabolites called N-acyl amides are enable to interact with
G-protein-coupled receptor 119 (GPR119) which is highly
expressed in the small intestinal enteroendocrine cells that
secrete gut hormone peptides. In vivo mouse and in vitro
cell-based analyses demonstrated that these lipid compounds
can serve as endogenous ligand to regulate metabolic hor-
mones and glucose homeostasis (Cohen et al., 2017). Besides
these ligands, commensal and pathogenic bacteria produce
neurotoxins, formyl peptides, pathogen-associated molec-
ular patterns (PAMPs), and lipopolysaccharides (LPS), all
of which are closely tied to the function of the enteric and
central nervous system, as well as the pathogenesis of neu-
rological disorders (Yang and Chiu, 2017).
CNS influences gastrointestinal microbiota composition
The CNS can alter gut microbiota composition and total bio-
mass through regulation of satiety. Changes in dietary pat-
terns (e.g., through central nervous system regulation) may
affect the ability of intestinal microbiota to access required
nutrients, ultimately influencing their composition (Wang
and Kasper, 2014). In addition, the nervous system plays
an important role in the regulation of gut functions, such as
gastrointestinal mobility, as well as secretion of acid, bicar-
bonate, and mucus, all of which are prominent in the main-
tenance of the mucous layer and biofilm (Rhee et al., 2009).
Thus, by altering the normal mucosal habitat, the central ner-
vous system can affect gut microbiota composition (Rhee
et al., 2009).
This direct influence is mediated by neurotransmitters, which
are produced by host neurons, and neurotransmitter recep-
tors, which are expressed on gut microbiota. Binding of host-
generated neurotransmitters with bacteria affects the func-
tion of microbial components, thereby promoting increased
susceptibility to inflammatory and infectious stimuli (Ca-
rabotti et al., 2015). For instance, Pseudomonas fluorescens
internalizes GABA with neurotransmitter-binding charac-
teristics (Guthrie and Nicholson-Guthrie, 1989); for another
example, Escherichia coli O157:H7 contains host-derived ad-
renergic receptors that activate virulence genes in response
to inter-kingdom cross-signaling (quorum sensing) (Clarke
et al., 2006).
Neurochemical References
GABA Barrett et al. (2012)
Serotonin (5-HT) Özogul (2011), Holzer and Farzi (2014)
Tryptamine Williams et al. (2014)
Norepinephrine Holzer and Farzi (2014)
Dopamine Özogul (2011), Holzer and Farzi (2014)
Acetylcholine Kawashima et al. (2007)
Landete et al. (2008), Thomas et al. (2012),
Histamine
Hemarajata et al. (2013)
L-dopa Surwase and Jadhav (2011)
 Probiotics modulate the gut-brain axis 175

The CNS also directly or indirectly regulates release of other
signaling molecules, cytokines, and antimicrobial peptides
into the gut lumen by neurons, enteroendocrine cells, im-
mune cells, and Paneth cells which are in charge of α-de-
fensin secretion. These secreted products affect microbial
survival and their surrounding environment (Carabotti et
al., 2015).
The nervous system also regulates microbiota composition
by altering epithelial permeability, thereby allowing the pen-
etration of bacteria and facilitating host-microbiome inter-
action in the mucosa. Under stress, the HPA axis releases cor-
tisol, a stress hormone, thereby regulating gut movement and
immune system responses (via cells, cytokines, and secretory
immunoglobulin A). Stress increases intestinal permeability
via corticotropin-releasing hormone (CRH)-mediated mast
cell activation. Elevated intestinal permeability facilitates mi-
crobial access to immune cells and neuronal cells of the ENS;
consequently, this stress-based permeability alters the in-
testinal microbial profile. Restraint and social stress in rodents
as well as maternal separation in non-human primates, lead
to disrupted gut microbial composition (Bailey and Coe, 1999;
Bailey et al., 2004, 2010; O’Mahony et al., 2009; Tillisch,
2014).
The gut dysbiosis in CNS disorders
Given that the gut microbiota can affect the function of the
brain via many complex pathways and components, it is not
surprising that many neurological diseases are associated
with dysbiosis in the gut (Table 2). Although autoimmune-
mediated CNS disorders, such as multiple sclerosis (MS),
experimental autoimmune encephalomyelitis (an animal mo-
del of MS), and neuromyelitis optica, are also closely related
with gut microbiota, we specifically focus on gut dysbiosis
within neuro-psychiatric disorders and neurodegenerative
diseases.
Autism spectrum disorder (ASD) is a class of neurodevel-
opmental disorders that are characterized by deficits in both
social and cognitive functions. Gastrointestinal disturbances,
including constipation, diarrhea, increased intestinal perme-
ability, and abdominal pain, are frequently reported in ASD
children (Coury et al., 2012). This evidence suggests that gas-
trointestinal disturbances, perhaps linked to gut dysbiosis,
may be associated with ASD (Cryan and Dinan, 2012). Con-
sistent with this hypothesis, both an animal model of ASD
and clinical studies with ASD patients showed reductions in
Bacteroides and increased levels of Clostridium species (Fine-
gold et al., 2010; Hsiao et al., 2013). A similar imbalance in
Bacteroidetes and Firmicutes has also been reported in ASD
patients (Finegold et al., 2010; Strati et al., 2017). Moreover,
altered levels of other gut microbiota have been found in stool
samples from children with ASD; alteration affected the rel-
ative abundances of Bifidobacterium, Lactobacillus, Sutterella,
Prevotella, and Ruminococcus genera (Adams et al., 2011; Kang
et al., 2013; Wang and Kasper, 2014). A recent study of an
autistic cohort has revealed that the constipation in autistic
patients is associated with increase in Escherichia/Shigella and
Clostridium cluster XVIII (Strati et al., 2017).
According to several studies, propionic acid and related
SCFAs are generated by ASD-associated bacteria (Bactero-
idetes, Clostridia, and Desulfovibrio), and these SCFAs can
induce ASD-linked neurochemical changes and behavior de-
ficits in rat, including abnormal motor movements, repeti-
tive interests, cognitive deficits, and impaired social interac-
tions (Macfabe, 2012).
Depression is a stress-related mood disorder that is associ-
ated with alterations in the HPA axis and immune responses.
In a maternal separation rodent model of depression, a di-
versity of gut bacteria were decreased, along with hyperacti-
vation of the HPA axis and increased expression of pro-in-
flammatory cytokines (O’Mahony et al., 2009; Vetulani, 2013).
Infant monkeys undergoing maternal separation showed
decreased fecal Lactobacillus (Bailey and Coe, 1999). Unlike
animal models, there has been little evidence of intestinal
microbial changes in depressed patients. However, in a re-
cent study, fecal pyrosequencing comparing patients with
depression against healthy controls revealed increased fecal

Table 2. Links between altered gut microbiota composition and a variety of neurological and psychiatric disorders
Disease Altered gut microbiota References
Porphyromonadaceae  Bailey et al. (2010)
Stress Clostridium , Bacteroides  Bailey et al. (2011)
Oscillibacter , Anaerotruncus , Peptococcus, Lactobacillus  Golubeva et al. (2015)
Bifidobacterium , Lactobacillus  Aizawa et al. (2016)
Depression
Bacteroidetes , Proteobacteria , Actinobacteria , Firmicutes  Jiang et al. (2015)
Clostridium  Song et al. (2004), Parracho et al. (2005)
Sutterella spp. , Ruminococcus torques , Akkermansia muciniphila  Wang et al. (2011, 2013)
Clostridium , Sutterellaceae , Enterobacteriaceae , Bifidobacterium  De Angelis et al. (2013)
Autism
Collinsella , Corynebacterium , Dorea , Lactobacillus , Alistipes , Bilophila ,
Strati et al. (2017)
Dialister , Parabacteroides , Veillonella 
Desulfovibrio , Bacteroides vulgatus , Ruminococcus , Bifidobacterium  Finegold et al. (2010)
Association with bacterial and viral infection Bu et al. (2015)
Bacteroidetes , Tenericutes , Firmicutes , Verrucomicrobia , Proteobacteria G
Alzheimer’s disease Harach et al. (2017)
Actinobacteria , Allobaculum , Akkermansia G
Bacteroidetes , Firmicutes , Bifidobacterium  Vogt et al. (2017)
Ralstonia , Blautia , Coprococcus , Roseburia , Faecalibacterium  Keshavarzian et al. (2015)
Parkinson’s disease
Enterobacteriaceae , Prevotellaceae G Scheperjans et al. (2015)
176 Kim et al.

bacterial alpha diversity in depressed patients. In particular,
relative abundances of the phyla Bacteroidetes, Proteobacteria,
and Actinobacteria were increased, with concurrent signi-
ficant reduction in the level of Firmicutes (Jiang et al., 2015).
Alzheimer’s disease (AD) is a prevalent neurodegenerative
disease and the most common form of dementia. According
to the amyloid hypothesis, the aggregation and cerebral de-
position of amyloid-β (Aβ) peptides into plaques is an ini-
tial influence that drives AD pathogenesis (Hardy and Selkoe,
2002; Harach et al., 2017). A recent study using the Aβ pre-
cursor protein (APP) transgenic mouse model has suggested
that alterations in gut microbiota may contribute to amyloid
deposition (Harach et al., 2017). APP transgenic mice exhibit
reduction in Firmicutes, Verrucomicrobia, Proteobacteria,
and Actinobacteria, with concurrent increases in Bacteroi-
detes. A study using germ-free APP transgenic mice demon-
strates reductions in cerebral Aβ amyloid pathology, com-
pared with control transgenic mice. Moreover, colonization
with microbiota from conventional APP transgenic mice in-
creased cerebral Aβ pathology in germ-free transgenic mice,
whereas control colonization using wild-type microbiota was
less effective in increasing cerebral Aβ levels (Harach et al.,
2017). Furthermore, clinical studies of the gut microbiota of
AD patients reveal decreased microbial diversity and changes
in composition compared with controls; these changes in-
clude decreased levels of Firmicutes and Bifidobacterium and
increased levels of Bacteroidetes (Vogt et al., 2017).
A remarkable recent study has revealed that post-mortem
brains from AD patients exhibit increased bacterial popul-
ations, as well as different proportions of specific bacteria,
compared with healthy brain. During 16S rRNA gene sequen-
cing, read counts of Actinobacteria, primarily those of the
Propionibacteriaceae family, were significantly increased in
AD samples, compared with controls. These findings sup-
port the idea that bacterial migration into the CNS could con-
tribute to the onset of neurological disease, or facilitate the
pathogenesis of disease (Emery et al., 2017).
Parkinson’s disease (PD) is recognized as the second most
common neurodegenerative disorder and mainly affects the
central motor system. Degeneration of dopamine neurons in
the substantia nigra region results in decreased dopamine
levels in the brain, thereby causing abnormal brain activity.
Most PD patients experience constipation even before the
onset of movement defects (Boursi et al., 2016). In clinical
studies, fecal pyrosequencing results showed the reduced
relative abundance of Prevotellaceae and increased that of
Enterobacteriaceae in PD patients, compared with controls
(Scheperjans et al., 2015). Furthermore, Enterobacteriaceae
was positively associated with the severity of motor symp-
toms, including postural instability and gait difficulty (For-
syth et al., 2011; Cassani et al., 2015; Scheperjans et al., 2015).
Another clinical study, using fecal and mucosal samples
from PD patients, showed that butyrate-producing bacteria,
including the Blautia, Coprococcus, and Roseburia genera,
were significantly reduced in PD patients (Keshavarzian et
al., 2015). As mentioned above, butyrate exhibits anti-inflam-
matory effect (Furusawa et al., 2013). The presence of the
putative pro-inflammatory bacteria Ralstonia in PD patients
suggested that pro-inflammatory dysbiosis in gut microbiota
may be part of the constellation of symptoms in PD patients.

Table 3. Effects of probiotics on brain function and behavior

Probiotic strain Model Duration Effects References
Rodent (maternal separation Normalized the immune response, Desbonnet et al.
Bifidobacterium infantis 45 days
model of depression) reduced behavioral deficits (2008, 2010)
Rodent (maternal immune Reversed ASD-related behavior,
Bacteroides fragilis 6 days Hsiao et al. (2013)
activation) improved gut barrier integrity
A mixture of Lactobacillus helveticus R0052
Rodent (healthy) 2 weeks Reduced anxiety-like behavior Messaoudi et al. (2011a)
and Bifidobacterium longum R0175
Bifidobacterium longum 1714, Bifidobacterium Rodent (innately anxious
6 weeks Reduced anxiety-like behavior Savignac et al. (2014)
breve 1205 BALB/c)
A mixture of Bifidobacterium animalis subsp. lactis,
Influenced brain activity in emotional
Streptococcus thermophilus, Lactobacillus bulgaricus, Human (healthy) 4 weeks Tillisch et al. (2013)
centers
and Lactococcus lactis subsp. lactis
Lactobacillus helveticus R0052 and Bifidobacterium Messaoudi et al.
Human (healthy) 30 days Less psychological distress
longum R0175 (2011a, 2011b)
Human (healthy, exposed Reduced stress–related gastrointestinal
Lactobacillus casei Shirota 11 weeks Kato-Kataoka et al. (2016)
to academic stress) symptoms
Lactobacillus casei Shirota Human (healthy) 3 weeks Improved mood Benton et al. (2007)
A mixture of Bifidobacterium bifidum W23, Bifido-
bacterium lactis W52, Lactobacillus acidophilus W37,
Reduced rumination and aggressive
Lactobacillus brevis W63, Lactobacillus casei W56, Human (healthy) 4 weeks Steenbergen et al. (2015)
cognition
Lactobacillus salivarius W24, and Lactococcus lactis
(W19 and W58)
Reduced D-arabinitol level in urine,
Kaluzna-Czaplinska
Lactobacillus acidophilus Human (autistic children) 2 months improvement in ability of concen-
and Blaszczyk (2012)
tration and carrying out orders
VSL#3 (VSL Pharmaceuticals Inc.), a multi-strain Human (ASD child, case Improved autistic core symptoms,
4 weeks Grossi et al. (2016)
mixture of ten probiotics report) relieved gastrointestinal symptoms
Lactobacillus casei Shirota Human (PD) 5 weeks Reduced constipation Cassani et al. (2011)
Lactobacillus acidophilus, Lactobacillus casei, Bifido-
Human (AD) 12 weeks Improved cognition Akbari et al. (2016)
bacterium bifidum, and Lactobacillus fermentum

Further, this dysbiosis may trigger systemic inflammation,
thereby facilitating the development of PD pathology (Kesha-
varzian et al., 2015).
Together, these studies highlight that dysbiosis in gut mi-
crobiota may play important roles in the initiation or pro-
gression of various diseases, including neurological disease.
Although the exact mechanism remains to be elucidated,
these studies suggest that microbiota may modulate the gut-
brain axis.
Modulation of gut-brain axis by probiotics
The connections between many neurological diseases and
the composition of the intestinal microbiota has led to an
interest in improvement of intestinal microbiota through
probiotics. A growing body of evidence supports the idea
that certain probiotics may positively impact the pathoge-
nesis of neurological disorders. Clinical data is less compel-
ling than the animal model data, but is rapidly emerging
(Table 3).
Animal studies
A variety of probiotics have been investigated in animal mo-
dels of neurological disorders. Bifidobacterium and Lacto-
bacillus are the main genera that have shown beneficial ef-
fects on neurological diseases (e.g., anxiety, depression, stress,
and ASD).
Recent studies used a maternal separation model to induce
early-life stress in infant rats. Maternally separated rat pups
showed a poor performance in the forced swim test, as well
as increased inflammation and mRNA expression of corti-
cotrophin release factor in the amygdala region of brain.
Treatment with probiotic B. infantis in this animal model
resulted in reversal of behavior deficits and inflammation
(indexed by interleukin [IL]-6 release), as well as showed
elevation of plasma tryptophan, a serotonergic precursor
(Desbonnet et al., 2008, 2010).
The maternal immune activation (MIA) mouse model of
ASD exhibited gastrointestinal barrier defects and altered
microbial composition, both of which are known features of
ASD. Oral treatment with the human commensal bacterium,
Bacteroides fragilis, corrected the abnormalities in gut per-
meability and microbial composition, as well as ASD-related
behaviors including communication defects, anxiety-like be-
haviors, and sensorimotor behaviors. Normal levels of se-
veral metabolites were also restored upon treatment with
Bacteroides fragilis. Among those restored metabolites, changes
in 4-ethylphenylsulfate are sufficient to cause anxiety-like
behavior (Hsiao et al., 2013).
A recent study has provided direct evidence for modulation
of neurotransmitter concentrations by probiotics treatment,
using magnetic resonance spectroscopy. Mice treated with
L. rhamnosus JB-1 showed increased levels of glutamate,
N-acetyl aspartate, and GABA in the brain, indicating that
probiotics could regulate brain activity via metabolic path-
ways and suggesting possibility for clinical translation of this
probiotic approach into therapies for neurological disorders
(Janik et al., 2016).
Many other studies have been performed to elucidate the
Probiotics modulate the gut-brain axis 177
mechanism by which probiotics act on the gut-brain axis.
One of approach examined the alleviation of inflammation
by probiotics. B. infantis 35624 and L. rhamnosus were found
to increase the concentration of IL-10, an anti-inflamma-
tory cytokine, and to decrease the concentration of inter-
feron (IFN)-γ and tumor necrosis factor (TNF)-α, in plasma
(O’Mahony et al., 2005; Donato et al., 2010). Modulation of
inflammation by probiotics could be related to improvement
of BBB integrity and concomitant reduction of neuroin-
flammation in patients with neurological disorders (Felger
and Lotrich, 2013; Miller et al., 2013). Additionally, admin-
istration of B. infantis to germ-free mice induced brain-de-
rived neurotrophic factor (BDNF) and N-methyl-D-aspar-
tate (NMDA) receptor subunit 2a (NR2a) expression; these
molecules play a crucial role in learning and memory pro-
cesses in the cortex and hippocampus, and exhibit reduced
expression in the germ-free mouse (Sudo et al., 2004).
Human studies
Although there are fewer human clinical studies than animal
studies, there is increasing evidence that probiotics are effec-
tive in reducing depression and anxiety-like symptoms.
Oral administration of a probiotic formulation, consisting
of L. helveticus R0052 and B. longum R0175, over 30 days
was shown to improve mood in generally healthy volunteers.
Compared with the placebo group, probiotic-treated volun-
teers exhibited alleviation of anxiety and depressive symp-
toms, as measured by the global scores of Hospital Anxiety
and Depression scale, and the global severity index of the
Hopkins symptoms checklist. Urinary free cortisol was also
decreased in probiotic formulation-treated participants, sug-
gesting a decreased level of stress (Messaoudi et al., 2011a,
2011b). These studies indicate the beneficial effects of pro-
biotics treatment on anxiety and depression-related beha-
viors in human volunteers (Liu et al., 2015).
The stress-reducing effects of L. casei strain Shirota have
also been investigated under academic stress. Healthy me-
dical students, who were approaching an examination for
academic advancement, consumed either L. casei-fermented
milk or a placebo milk for 8 weeks, followed by the exam. The
administration of L. casei Shirota significantly reduced sali-
vary cortisol levels before the examination and alleviated gas-
trointestinal symptoms. Moreover, the probiotics group had
significantly higher numbers of gut microbial species in their
feces, compared with the placebo group, and the percentage
of Bacteroidaceae was significantly lowered in the probiotics
group (Kato-Kataoka et al., 2016).
Taken together, these animal and human studies show that
probiotics may play an important role in the bidirectional
communication between the gut and the brain, and that they
can modulate brain function (Fig. 1). Although many research
groups have attempted to demonstrate a mechanism on how
probiotics modulate the gut-brain axis in normal and diseased
conditions, however, the exact mechanisms have not been
yet well-defined. Therefore, for effective usage of probiotics
in neurological disorders, it would be necessary to elucidate
their veiled interactions in the gut-brain axis.
178 Kim et al.
Conclusion
Accumulated information from animal and human research
suggests that the gastrointestinal microbiota has an impor-
tant role in bidirectional communication between the gut
and brain. It interacts with the nervous system via compli-
cated direct and indirect pathways including neuronal, im-
mune-mediated and neuro-endocrine-mediated signaling.
Imbalance in the gut microbiota is associated with neuro-
developmental defects and neurological disorders, includ-
ing stress response, anxiety, depression, and neurodegener-
ative diseases. Thus, a variety of laboratory and clinical stu-
dies N-methyl-D-have been conducted to determine how
alterations in gut microbiota can serve as indicators certain
neurological diseases. Especially, administration of probiotics
has shown to partially or completely restore perturbations in
commensal microbiota, alleviating a variety of neurological
disease symptoms
Further studies are definitely needed to clarify the mecha-
nism for regulation of brain function by gut microbiota, as
well as to determine whether changes in commensal bacteria
composition cause the disease development or are the result
of disease progression. Moreover, to use probiotics for pre-
vention and treatment of neurological disorders, there must
be greater investment in clinical trials of probiotics.
Fig. 1. Modulation of the gut-brain axis
by probiotics. The routes of communica-
tion between the gut and the brain include
neuronal, immune-mediated, and meta-
bolite-mediated pathways. Gut dysbiosis
leads to increased inflammation, as well
as, activation of the HPA axis, and altered
levels of neurotransmitters and bacterial
metabolites; these may contribute to ab-
normal signaling through the vagus nerve.
Reduced integrity of the gastrointestinal
barrier triggers bacterial migration (“leaky
gut”) and inflammation. Inflammatory
cytokines induce the disruption of blood-
brain barrier integrity. Probiotics have
the potential to normalize such processes
(Abbreviations: HPA axis, hypothalamus-
pituitary gland-adrenal gland axis; NE,
norepinephrine; GABA, γ-aminobutyric
acid; BBB, blood brain barrier; EEC, en-
teroendocrine cell; EC, enterochroma-
ffin cell); GLP-1, glucagon-like peptide-1;
PYY, peptide tyrosine tyrosine; 5-HT,
5-hydroxytryptamine; SCFAs, short-chain
fatty acids.
Acknowledgements
This research was supported by grants from the World Ins-
titute of Kimchi (KE1802-1 and KE1802-1-1), funded by
the Ministry of Science and ICT, Republic of Korea.
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