Lead Article

Relationship between the gut microbiome and brain function

M. Hasan Mohajeri, Giorgio La Fata, Robert E. Steinert, and Peter Weber

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It has become increasingly evident in recent years that the gut microbiome and the
brain communicate in a bidirectional manner, with each possibly affecting the
other’s functions. Substantial research has aimed to understand the mechanisms of
this interaction and to outline strategies for preventing or treating nervous system–
related disturbances. This review explores the evidence demonstrating how the gut
microbiome may affect brain function in adults, thereby having an impact on
stress, anxiety, depression, and cognition. In vitro, in vivo, and human studies
reporting an association between a change in the gut microbiome and functional
changes in the brain are highlighted, as are studies outlining the mechanisms by
which the brain affects the microbiome and the gastrointestinal tract. Possible
modes of action to explain how the gut microbiome and the brain functionally af-
fect each other are proposed. Supplemental probiotics to combat brain-related dys-
function offer a promising approach, provided future research elucidates their
mode of action and possible side effects. Further studies are warranted to establish
how pre- and probiotic interventions may help to balance brain function in healthy
and diseased individuals.

INTRODUCTION diverse microbial community that plays a critical role in

both the maintenance of human health and the pathogen-
According to a statement by the World Health esis of disease. The gastrointestinal (GI) tract is home to
Organization, probiotics, when consumed in appropri- various microorganisms, whose collective genome is
ate amounts, are beneficial to human health and well- termed the gut microbiome.10 Advances in DNA sequenc-
being.1 The benefits of probiotics include, but are not ing technology combined with novel bioinformatics tools
limited to, improved skin health, enhanced resistance to have enabled scientists to describe the gut microbiome
allergens, immune system support, reduction of patho- with unprecedented precision. It is estimated that the
genic microorganisms, and protection of macromole- number of bacteria inhabiting the healthy human GI tract
cules (DNA, proteins, lipids) from oxidative damage.2–5 reaches up to 50 different phyla, 1000 different bacterial
Human health can be both positively and negatively species, and 1014 viable bacteria per gram of luminal con-
affected by the microorganisms living in the gut, known tent.11,12 The density of the human microbiome is highest
collectively as the gut microbiota,6 which consists of bacte- in the colon, where Firmicutes, Bacteroidetes,
ria, bacteriophages, viruses, fungi, protozoa, and ar- Proteobacteria, and Actinobacteria11,13 are the most abun-
chaea.7–9 There is increasing evidence that the intestinal dant organisms, constituting approximately 64%, 23%,
microbiota resembles a remarkably densely populated and 8%, and 3% of the population, respectively.7–9
Affiliation: M.H. Mohajeri, G. La Fata, R.E. Steinert, and P. Weber are with the Department of Human Nutrition, DSM Nutritional Products,
Basel, Switzerland.
Correspondence: M. Hasan Mohajeri, DSM Nutritional Products, PO Box 2676, 4002 Basel, Switzerland. Email: [email protected],
[email protected].
Key words: Alzheimer, anxiety, cognition, depression, memory, microbiome, prevention, probiotics, stress.
C The Author(s) 2018. Published by Oxford University Press on behalf of the International Life Sciences Institute.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://
creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium,
provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please
[email protected]

doi: 10.1093/nutrit/nuy009
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Figure 1 Schematic presentation of the gut–brain axis. (A) The upper part of the gastrointestinal (GI) tract, shown in yellow, includes the
esophagus and the stomach. The small intestine (duodenum, jejunum, ileum) is shown in light blue; the large intestine (cecum and the as-
cending, transverse, and descending colon) is shown in green. The interactions between the GI tract and the autonomous and central nervous
system are indicated by red lines. The short bidirectional blue arrows indicate afferences and efferences. The hypothalamic–pituitary–adrenal
(HPA) axis is shown in dark yellow. (B) Simplified representation of the crosstalk between the microbiota, the brain, and the immune system.
The gut microbiota and the immune system affect each other by releasing immunomodulators and/or cytokines, with potential systemic
effects on the host. Short-chain fatty acids and other microbial metabolites are produced by the GI microbiota and may influence brain func-
tion, whereas several neurotransmitters are involved in the bidirectional communication between the host and the microbiota (see text for
details). Abbreviations: ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing hormone; SCFA, short-chain fatty acids.

Diet is an important factor to influence the gut Scientific evidence accumulated in recent years
microbiome. For example, short-term consumption of suggests that the gut microbiota affects some aspects of
diets composed entirely of animal or plant products brain function and behavior, including emotional be-
rapidly changes structures of the microbial community, havior and related brain systems.15 Figure 1 schemati-
overwhelming interindividual differences in microbial cally outlines routes of communication between the gut
gene expression.14 and the brain. This review will examine the mechanisms

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of action of this communication and explore the impli- nutrients available to the body. In addition to produc-
cations for human health and daily living. ing energy, vitamins, and other metabolites, some bene-
ficial bacteria also help restrict the access of pathogenic
THE GUT MICROBIOME: ALTERATIONS microorganisms to the gut tissue by building a protec-
THROUGHOUT LIFE tive biofilm.25
It is now known that the benefits of human–
In healthy individuals, the gut microbiome is highly microbe symbiosis can be extended to human mental

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variable because the taxonomic variability within the GI health, and in recent years evidence has shown that the
tract depends on many factors, including genetic, physi- gut–brain axis, or the bidirectional communication be-
ological, psychological, and environmental determi- tween the resident microbes of the GI tract and the
nants.16–18 Despite the notion that each person’s brain,15 plays a key role in maintaining brain health.
microbiota is unique, it is thought that humans might The GI microbiota influences human behavior and may
share a core microbiome and have a similar coloniza- affect the pathophysiology of mental illnesses.26 The
tion of the GI tract by microbiota throughout life.19 It knowledge gained in recent years about the function
has been recently shown that bacteria can be found in and importance of the microbiome has broadened
amniotic fluid, placenta, and the meconium of new- the concept of the gut–brain axis to the “microbiota–
borns,20 which may help to explain the similarity of the gut–brain axis,” emphasizing the importance of the
microbiome in infants after a period of adaptation. microbiome in the regulation of gut–brain communica-
Notably, developing embryos are exposed to bacteria in tion.27–29
utero.20 While infants born vaginally receive a seed of Several systems are at work to ensure the efficient
their microbiota during passage through the birth canal
functioning of the microbiota–gut–brain axis, including
via exposure to maternal vaginal and perhaps fecal
the central, autonomic, and enteric nervous systems,
microbes, infants born by cesarean delivery receive their
the immune system, and the endocrine system.16,26,30,31
first major exposure to bacteria from their mother’s
The central nervous system (CNS), the enteric nervous
skin and the hospital environment.21 Bifidobacterium,
system (ENS), the sympathetic and parasympathetic
Lactobacillus, Enterobacteriaceae, and Staphylococcus
branches of the autonomic nervous system, and neuro-
are the most populous organisms in the GI of the
endocrine and neuroimmune pathways are all involved
healthy, vaginally delivered infant GI tract, followed by
in communication with the gut microbes.16 The neuro-
Veillonella and Lachnospiraceae.22 The composition of
nal interaction between the GI tract and the brain is fa-
the infant’s gut microbiota is unstable until approxi-
cilitated by efferent and afferent nerves.32 As a
mately 2 years of age, ie, until the child begins to eat
consequence, the CNS regulates the secretory and sen-
solid food.21 Breastfed infants have a different micro-
biome than formula-fed infants, and by age of 3 years, sory functions as well as the mobility of the GI tract.33
the microbiota of most infants stabilizes and develops The microbiota has the potential to affect neuronal
toward what becomes the adult microbial function directly or indirectly through vitamins, neuro-
composition.20 transmitters, and neuroactive microbial metabolites
In healthy adults, the gut microbiota is dominated such as short-chain fatty acids.16,33 How these metabo-
by only a few phyla, as noted above,7–9 and is character- lites affect brain function is difficult to ascertain, as the
ized by a wide diversity of bacterial species.17 The hu- presence of the blood–brain barrier and various feed-
man microbiome changes with age, normally becoming back mechanisms impede a direct access to the brain.
less diverse in the elderly as a result of higher numbers Experimental data suggest that the microbiota may
of Bacteroides species and reduced numbers of send signals to the brain by activating afferent sensory
Clostridium groups.23 Even if the microbiome of adults neurons of the vagus nerve via neuroimmune and neu-
is relatively stable when compared with that of infants roendocrine pathways.19
or elderly, several factors can dramatically influence its The study of germ-free animals shows that brain
composition over a relatively short period of time.24 development is abnormal when the gut microbiome is
Such factors include antibiotic treatment, stress, infec- missing.21,34 The gut microbiome influences the inflam-
tion, host genetics, and diet.19 matory reactions within the brain by modulating the ac-
tivation of microglial cells35 and affecting myelination36
THE MICROBIOTA–GUT–BRAIN AXIS and neurogenesis in adult brains.37 Fecal transplanta-
tion between mouse strains with different levels of anxi-
The commensal bacteria benefit from a nutritionally ety has demonstrated that the microbiota can even
rich and protected habitat in the human GI tract, while change behavioral characteristics of mammals by alter-
they in turn benefit the host by making indigestible ing brain chemistry.38

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 Irritable bowel syndrome (IBS) and inflammatory gut of conventionalized germ-free mice was similar to
bowel disease in humans are 2 conditions that exem- that in controls, whereas expression in germ-free ani-
plify the consequences of a faulty gut–brain communi- mals was significantly less than that in either the con-
cation.39,40 The involvement of the gut microbiota in ventionalized mice or the controls.59,60 Calbindin
the pathophysiology of IBS has been shown repeatedly, expression is linked to nutritional status because it
as symptoms of IBS develop after the disruption of the depends on vitamin D concentrations in the nerve and
microbiome due to acute gastroenteritis (ie, postinfec- intestinal cells.61,62 These findings may indicate that the

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tious IBS)41,42 or following the use of antibiotics.43 In ENS is plastic, ie, it can sense and react to changes in
addition, gastrointestinal dysfunction such as bowel dis- GI tract microbes. Since the sensory neurons in the
eases are frequently accompanied by comorbid psychi- ENS are connected to the brain via the vagus nerve,
atric conditions.44,45 there may be an avenue of communication whereby in-
The ENS, which is part of the automatic nervous formation about the bacterial contents of the gut can be
system, innervates the wall of the GI tract, covering the conveyed to the brain.
entire length from the esophagus to the anus. In addi- The hypothalamic–pituitary–adrenal (HPA) axis,
tion, the gut also receives input from the vagus nerve which regulates the body’s response to stress, represents
and from central spinal and sacral afferent termi- another route of gut–brain crosstalk. It is a complex set
nals.32,46 An important feature of the ENS is that it can of involuntary influences and feedback interactions be-
operate independently of the spinal cord and brain de- tween 3 endocrine glands: the hypothalamus, the pitui-
spite being connected to the CNS.47,48 Apart from the tary gland, and the adrenal glands. The HPA axis is
ENS, the vagus nerve is instrumental for the flow of in- directly and indirectly controlled by neural activity
formation from the gut to the brain.32,49 Vagotomy throughout the forebrain and brainstem.63 It not only
experiments underline the importance of the vagus controls the body’s reaction to stress but is also impli-
nerve for microbiota–gut–brain communication,50–52
cated in controlling digestion, the immune system,
even though this connection does not seem to be neces-
mood and emotional status, sexuality, and energy stor-
sary for all microbes.27,50 There is great interest in clari-
age and expenditure. Dysregulation of HPA activity is
fying how probiotic species modulate neuronal
associated with mental health disorders such as depres-
pathways, thereby affecting neuronal function and be-
sion and schizophrenia, both of which are known to af-
havior. The neuronal population affected varies,
fect the microbiota composition.63–65 Stress response by
depending on the bacteria used and the experimental
HPA activity involves the secretion of corticotrophin-
paradigm employed. Recent data provide evidence that
releasing factor by neurons in the medial parvocellular
related bacterial species can interact specifically with a
portion of the hypothalamic paraventricular nucleus,
variety of different neuronal populations. For example,
causing the endocrine cells (corticotrophs) in the ante-
Lactobacillus helveticus R0052 affects the functioning of
CNS neurons in the hippocampus and amygdala,53 rior pituitary to secrete adrenocorticotropic hormone.
whereas Lactococcus lactis subsp cremoris H61 modu- Adrenocorticotropic hormone, in turn, stimulates the
lates the activity of auditory brain stem neurons54 and endocrine cells, primarily in the zona fasciculata of the
Lactobacillus reuteri (DSM 17938) is implicated in the adrenal cortex, to secrete the glucocorticoid hormones
function of visceral nociceptive neurons of the gut.55 cortisol and/or corticosterone (reviewed by Spencer
This diverse specificity of microorganisms to interact and Deak66). Cortisol is released in response to stress,
with specific neural circuitries suggests great potential and low blood-glucose concentration affects the re-
to design dedicated interventions targeted to affect spe- sponse to stress in addition to other metabolic and
cific neuronal functions. The ability of the ENS system immune-related functions.66
to adapt to altering microbial populations in the GI Finally, the role of the immune system in
tract has been known for over 30 years.56 Indeed, the microbiota–gut–brain communication seems to be
ENS responds to changing bacterial populations by species-specific. Germ-free mice lacking all gut bacteria
adapting the neuronal physiology and by changing gene exhibit specific abnormalities in immune, neuronal, GI
expression. The intracellular recordings of afterhyper- tract, and metabolic function,67 and infection of mice
polarization neurons and of sensory neurons residing with a pathogen, Citrobacter rodentium, induced
in the gut wall are different in germ-free mice than in anxiety-like behavior.52 Moreover, the abnormal gut
normal mice. Afterhyperpolarization neurons are less and neuronal function in B- and T-cell–deficient Rag1
excitable in germ-free mice, an abnormality that is knockout mice was partially normalized by probiotic
normalized after conventionalization with gut micro- treatment, providing evidence of a role for the adaptive
biota.55,57,58 In addition, expression of the calcium- immune system in maintaining intestinal and brain
binding protein calbindin in the enteric neurons in the health.68

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 A number of recent studies provide evidence of the TNF-a levels. These data are in agreement with an older
interplay between the microbiome and brain function, report showing that VSL#3 treatment reduced circulat-
which may affect mammalian behavior ing TNF-a levels, which were associated with improved
(Table 1).27,34,51,52,68–84 Germ-free mice exhibit learning neuropsychiatric outcomes in patients with chronic
deficits80 and show anxiolytic-like behavior85–88 and re- liver disease.90 Thus, TNF-a causes sickness behaviors
duced sociability.88,89 In addition, they also demonstrate in the murine model by cerebral microglial activation
an exaggerated HPA stress response.69 Importantly, the and the recruitment of monocytes into the brain vascu-

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enhanced HPA response of germ-free mice could be lature and brain parenchyma.72 The mechanisms of or-
partially corrected by reconstitution with pathogen-free gan inflammation in the peripheral organs, leading to
feces of normal animals at an early age, but not at a later alteration of brain functions, are of great importance
age, demonstrating that exposure to microbes at an for the design of clinically acceptable therapeutic agents
early developmental stage is required for the HPA sys- to prevent peripheral inflammation.
tem to become fully susceptible to inhibitory neural reg- The influence of gut microbiota on neuroinflam-
ulation. These results suggest that commensal mation and motor deficits was demonstrated recently in
microbiota can affect the postnatal development of the an animal model of Parkinson’s disease.84 Sampson
HPA stress response in mice.69 et al.84 demonstrated that the gut microbiome plays a
Recent work in germ-free mice demonstrated role in nervous and intestinal dysfunctions specific to
hypermyelinated areas in the prefrontal cortex and de- Parkinson’s disease in a mouse model. Briefly, it was
fective microglial cells with reduced capacity for activa- shown that the presence of the normal gut microbiome
tion after bacterial or viral challenge.36 This suggests is required for Parkinson’s disease–related motor and
that germ-free mice have a compromised ability to brain pathology and that the production of short-chain
mount appropriate immune responses in the CNS.35 fatty acids promoted microglial activation and en-
The same authors showed that limited diversity in the hanced Parkinson symptoms. When the microbiome
microbiota composition, achieved by antibiotic treat- was depleted in these mice, reduced activation of micro-
ment, resulted in defective microglia and that recoloni- glia and a reduced level of pathology were observed, pro-
zation with a complex microbiota partially restored viding the direct evidence of the contribution of the gut
microglial features.35 In addition, mice deficient for the microbiome to Parkinson’s disease pathophysiology in
short-chain fatty acids receptor FFAR2 had the same this model.84 In addition, mice that received fecal trans-
microglial defects found in germ-free mice. plantation from patients with Parkinson’s disease, but not
Taken together, these findings suggest that host mice that received fecal samples from healthy controls,
bacteria are crucial for regulating microglial maturation exhibited significant impairment of motor functions, again
and function and that microglial impairment can be providing strong evidence of the involvement of the gut
ameliorated to some extent by the microbiota.35 microbiome in the pathophysiology of Parkinson’s disease.
Moreover, the consequences of antibiotic treatment re- Taken together, these data add to the understanding of
semble the findings in germ-free animals, such as defi- how probiotics may influence brain function by modifying
cits in social and cognitive behaviors, increased anxiety, immune system signaling to the brain.
and reduced microglial activation and expression of
brain-derived neurotrophic factor.27,34,35 MODULATION OF MAMMALIAN BEHAVIOR BY GUT
The role of the microbiome in influencing the MICROBIOTA
crosstalk between periphery and the brain was studied
further in a murine model of experimentally induced Depression and anxiety
sickness behavior: mice exhibited elevated levels of in-
flammatory cytokines such as tumor-necrosis factor-a Major depressive disorder, specifically recurrent unipo-
(TNF-a) and interleukin 6.72 Sickness behaviors are de- lar depression (normally referred to as depression), is a
bilitating symptoms in patients with systemic inflam- common, serious, stress-related, debilitating, and, if
matory diseases such as irritable bowel disease, untreated, life-threatening psychiatric disorder, affect-
rheumatoid arthritis, or chronic liver disease. In a ro- ing over 100 million individuals worldwide.91 The HPA
dent model, an oral gavage of a mixture of 8 bacterial axis is dysregulated in depressive patients, which leads
species (VSL#3) was shown to dampen sickness behav- to abnormally high circulating levels of cortiocotropin-
ior by a mechanism involving reduced activation of releasing factor and cortisol. Often, elevated concentra-
microglial cells and reduced infiltration of monocytes tions of proinflammatory cytokines are also found in
into the brain.72 The authors convincingly showed that the plasma of patients with depression. In recent years,
the amelioration of behavioral symptoms was related to the prospect of using compounds that modulate the gut
changes in systemic immune activation, such as lowered microbiome, such as probiotics, for treating psychiatric

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 Table 1 Animal studies providing evidence of the modulatory role of the microbiota in brain-related pathological conditions

486
Reference(s) Treatment Animal model Pathological Outcome Proposed mechanism of action
condition
Sudo et al. (2004)69, Bifidobacterium infantis Germ-free mice Anxiety Antidepressant-like activity Modulation of HPA response
Desbonnet et al.
(2010)70
Bravo et al. (2011)51 Lactobacillus rhamnosus BALB/c mice Anxiety Antidepressant-like activity Modulation of neurotransmis-
JB-1 sion, expression of GABAA and
GABAB receptors
Bravo et al. (2011)51, Lactobacillus rhamnosus Germ-free mice Anxiety Reduced stress-induced corticoste- Higher expression of GABAB and
Stilling et al. (2015)71 rone levels and anxiety- and de- GABAA receptors; higher ex-
pression-related behavior pression of serotonin receptor
1A; involvement of vagus
nerve
D’Mello et al. (2015)72 Model of liver inflammation C57BL/6 mice Sickness behavior Reduced symptoms Monocyte recruitment to the
and probiotic mixture brain in response to systemic
VSL#3 TNF-a signaling, leading to
microglial activation
Messaoudi et al. (2011)73 Lactobacillus helveticus Rats Anxiety Reduced anxiety-like behavior Crosstalk between the micro-
R0052 and biome and enteric nervous
Bifidobacterium longum system as well as CNS
R0175
Desbonnet et al. (2008)74 Bifidobacterium infantis Rats Anxiety No effect in naive rats but signifi- Increased plasma concentrations
cantly attenuated IFN-c, TNF-a, of tryptophan and kynurenic
and IL-6 cytokines following mi- acid; reduced 5-HIAA concen-
togen stimulation tration in the frontal cortex in
DOPAC in the amygdaloid
cortex
Gareau et al. (2007)75 Lactobacillus rhamnosus Rat pups Stress due to mater- Change in gut flora composition Normalization of HPA axis
R0011 and Lactobacillus nal separation observed activity
helveticus R0052 (5%) leading to
dysbiosis
Desbonnet et al. (2015)34, Antibiotic treatment Mice Depletion of the gut Altered gut microbiota, decreased Change in microbial metabolites
Frohlich et al. (2016)76 microbiota spleen weights in adulthood. and in expression of BDNF,
Reduced anxiety, induced cog- NMDA receptor subunit 2B,
nitive deficits, altered dynamics serotonin transporter, neuro-
of the tryptophan metabolic peptide Y, and vasopressin
pathway
Li et al. (2009)77 Ground beef diet CF1 mice None Increased bacterial diversity in the TBD
beef-supplemented diet; im-

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proved working and reference
memory
(continued)

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 Table 1 Continued
Reference(s) Treatment Animal model Pathological Outcome Proposed mechanism of action
condition
Ohland et al. (2013)78 Western-style diet and WT and IL-10–de- Western diet in- Probiotics alone decreased anxi- Inflammatory pathways
Lactobacillus helveticus ficient 129/SvEv creased weight ety-like behavior in WT mice on

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ROO52 mice gain, changed gut a chow diet
microbiota and
cytokine expres-
sion, and altered
anxiety-like
behavior

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Davari et al. (2013)79 Lactobacillus acidophilus, Diabetic rats Memory impairment Improved the impaired spatial Stimulation of Schaffer collater-
Bifidobacterium lactis, related to diabe- memory in diabetic animals als in hippocampus, restora-
Lactobacillus fermentum tes mellitus tion of long-term potentiation,
activation of superoxide dis-
mutase, and increased serum
insulin level
Gareau et al. (2011)80 Citrobacter rodentium in ad- C57BL/6 mice and None Memory impairment observed in Modulation of HPA axis and hip-
dition to water avoid- germ-free C57BL/6 after stress Memory pocampal plasticity
ance stress Swiss-Webster impairment observed in germ-
mice free mice
Lyte et al. (1998)81 Campylobacter jejuni CF-1 male mice Anxiety Decreased exploratory behaviors Activation of immune–neural
and increased nonexploratory mechanisms
behaviors
Lyte et al. (2006)52 Citrobacter rodentium CF-1 male mice IBD Increased anxiety-like behavior Mediated via vagal sensory
(model of IBD) neurons
Smith et al. (2014)68 Lactobacillus rhamnosus B- and T-cell–defi- Memory deficit, anx- Improved baseline impairments Modulation of intestinal micro-
R0011 and Lactobacillus cient Rag1 / iety, dysbiosis biota, HPA axis, and cFos
helveticus R0052 mice expression
Bercik et al. (2011)27 Microbiota of SPF NIH Germ-free mice Baseline behavior of Altered the composition of the Changes in brain chemistry and
Swiss and BALB/c mice germ-free mice microbiota and increased ex- in hippocampal expression of
ploratory behavior BDNF
Gacias et al. (2016)82 Microbiota of nonobese di- C57BL/6 mice Social avoidance Improvement in social avoidance Changes in gene expression and
abetic mice observed in myelination in frontal
cortex
Zheng et al. (2016)83 Microbiota of humans with Germ-free mice Depression Mice developed depressive Neurotransmission, others
depression symptoms
Sampson et al. (2016)84 Microbiota of patients with a-Synuclein over- PD pathology PD-like motor deficits observed in Changes in SCFAs modulated
PD expressing transplanted germ-free mice neuroinflammation and micro-
germ-free mice glia activation
Abbreviations: BDNF, brain-derived neurotrophic factor; DOPAC, 3,4-dihydroxyphenylacetic acid; HPA, hypothalamic–pituitary–adrenal; IBD, inflammatory bowel disease; IFN, interferon; IL,
interleukin; NIH, National Institutes of Health; NMDA, N-methyl-D-aspartate; PD, Parkinson’s disease; Rag1, recombination activating gene 1; SCFAs, short-chain fatty acids; SPF, specific
pathogen–free; TBD, to be determined; TNF, tumor necrosis factor; WT, wild type; 5-HIAA, 5-hydroxyindoleacetic acid.

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disorders has gained great interest among neuroscient- in patients with major depressive disorder than in their
ists, even though the mechanisms of action of the healthy counterparts,83,106 but others failed to confirm
microbiota on mood in humans remain elusive. this.107 Mechanistically fascinating is the result of 1
Several lines of evidence in preclinical models that study (Table 1) in which germ-free mice were inocu-
include bacterial infections, probiotic treatment, fecal lated with fecal samples of depressive patients. The
transplantation, and analysis of germ-free animals sug- transplanted mice developed depressive-like behav-
gest that the gut microbiota can influence brain func- iors.83 This strongly hints for the involvement of the gut

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tion and, consequently, alter behavior.16 Anxiety and microbiome in regulating depressive symptoms in
depression are among the brain-related behavioral humans. In a randomized, double-blind, placebo-con-
changes that are modified by changes in the gut micro- trolled trial, petrochemical workers who consumed a
biome.34,51,70,73,87,92–95 Sudo et al.69 were among the probiotic yogurt or a multispecies probiotic capsule for
first groups to study the effect of the microbiome on the 6 weeks showed improved mental health as measured
HPA axis. Their seminal study showed that stressed by a general health questionnaire and a depression anxi-
germ-free mice have an overly responsive HPA axis. ety and stress scale.96 These data are in line with those
The overreaction of the HPA response was reduced by from an older study in which supplementation with
supplementing mice with a single bacterial strain, probiotic yogurt improved the mood status of healthy
Bifidobacterium infantis.69 In 2011, Bravo et al.51 elderly individuals, especially those with decreased
showed that chronic treatment of BALB/c mice with mood scores at baseline.97 Lastly, probiotic treatment
Lactobacillus rhamnosus JB-1 moderated anxiety and (containing Lactobacillus acidophilus, Lactobacillus
antidepressant-related behavior, probably by inducing casei, and Bifidobacterium bifidum) for 8 weeks in
neurochemical changes. The lower anxiety level of patients with major depressive disorder was reported to
L rhamnosus–treated animals was concomitant with improve clinical signs of depression as assessed by the
alterations in the expression of c-aminobutyric acid Beck Depression Inventory in a recent randomized,
(GABA) receptors, both GABAA and GABAB receptors, double-blind, placebo-controlled trial performed in
across a variety of brain regions. Importantly, the neu- central Iran (Table 2).103
rochemical and behavioral effects were not found in Analysis of fecal samples reveals that the micro-
vagotomized mice, thus identifying the vagus as a major biome of depressive patients differs from that of healthy
modulatory pathway between the gut and the brain.51 controls.51,106 Indeed, changes in the microbiome of de-
This study showed that L rhamnosus had antidepres- pressive patients can be linked to the severity of depres-
sant/anxiolytic activity and demonstrated that, in this sion. These reports revealed a negative correlation
animal model, dietary intake of a bacterial strain may between Faecalibacterium organisms and the severity of
alter brain function and behavior. Moreover, the depressive symptoms and an altered composition of the
authors identified the vagus nerve as the route of com- gut microbiota in acutely depressed patients.106
munication between the gut microbiome and the brain. Patients with depression show changes in counts
Bercik et al.27,50 showed that fecal transplantation may of both gram-positive and gram-negative bacteria.106,107
result in the transfer of behavioral traits from the donor Increases are reported for Roseburia,
mouse to the recipient mouse. A recent study con- Phascolarctobacterium, Megamonas, Clostridium,
firmed the above findings by showing that the gut Lachnospiraceae incertae sedis, Blautia, Oscillibacter,
microbiome determines behavioral changes in another Parasutterella, Parabacteroides, and Alistipes, whereas
model, ie, the nonobese diabetic mouse.82 The transfer Ruminococcus, Dialister, Prevotella, Faecalibacterium,
of intestinal microbiota from nonobese diabetic mice to and Bacteroides are reduced in people with depres-
C57BL/6 mice was sufficient to induce social avoidance sion.108 The genus of Bifidobacterium has been studied
and changes in gene expression and myelination in the in detail in relation to depression. B infantis was found
prefrontal cortex in the C57BL/6 mice, a phenotype of to normalize the exaggerated HPA axis response and
the nonobese diabetic mouse. In conclusion, these ani- ameliorate depressive symptoms in animal models.70,109
mal data provide evidence that microbes of the GI tract Another gram-positive bacterium, Lactobacillus farcimi-
are implicated in the pathophysiology of depression and nis, is also able to reverse stress-induced elevation of
anxiety and that some strains confer a certain degree of HPA axis activity and neuroinflammation in vivo.110
resilience against these conditions. Lactobacillus rhamnosus was shown to alter emotional
Several studies in humans (Table 2)73,96–104 support behavior and central GABA receptor expression in vivo
the data from animal studies and show that the gut via the vagus nerve, thereby decreasing both anxiety
microbiota may play a role in modulating depression and depression-like symptoms in mice.51 Messaoudi
and anxiety.73,97,105 Some researchers have reported et al.73 studied probiotic treatment with a combination
that the composition of the microbiome was different of L helveticus and Bifidobacterium longum in rats and

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 Table 2 Nonexhaustive list of human studies supplementing probiotics to normal and diseased human populations
Supplementation Study population Behaviors tested Outcome Reference(s)
Probiotic yogurt or a multi- Normal population Depression, anxiety, Improvement in partici- Mohammadi
species probiotic capsule stress pants supplemented et al. (2016)96
(Lactobacillus acidophilus with probiotic yogurt
LA5 and Bifidobacterium or probiotic capsule
lactis BB12)
Probiotic yogurt Normal elderly indi- Mood status Improvement in partici- Benton et al.

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(Lactobacillus casei Shirota) viduals with de- pants in bottom third (2007)97
creased mood of the depressed/elated
dimension at baseline
Lactobacillus helveticus & Healthy individuals Anxiety, stress Alleviation of psychologi- Messaoudi et al.
Bifidobacterium longum cal distress (2011)73
Bifidobacterium longum 1714 Healthy individuals Stress response, Change in electroenceph- Allen et al.
cognition, brain alographic activity, (2016)98
activity dampened stress
response, and
enhanced cognitive
performance
Fermented milk product with Healthy women Emotion, attention Altered activity of brain Tillisch et al.
probiotic containing regions that control (2013)99
Bifidobacterium animalis central processing of
subsp lactis, Streptococcus emotion and sensation
thermophilus, Lactobacillus by functional MRI
bulgaricus, Lactobacillus
lactis subsp lactis
Lactobacillus helveticus Healthy elderly Cognition Improvement in cognitive Chung et al.
IDCC3801 individuals functioning during (2014)100
cognitive fatigue tests
Bifidobacterium infantis Patients with IBS IBS symptoms Improvement in Brenner et al.
35624 symptoms (2009)101
Probiotic milk containing Patients with Cognitive functions, Significant improvement Akbari et al.
Lactobacillus acidophilus, Alzheimer’s antioxidative in MMSE score (2016)102
Lactobacillus casei, disease status (in plasma malondial-
Bifidobacterium bifidum, dehyde, serum
and Lactobacillus hs-CRP, and serum TG
fermentum
Lactobacillus acidophilus, Patients with major Depression Improvement in clinical Akkasheh et al.
Lactobacillus casei, depressive signs (2016)103
Bifidobacterium bifidum disorder
FOS or Bimuno GOS Healthy individuals Stress Significantly lower Schmidt et al.
cortisol awakening (2015)104
response (assessed in
saliva) after Bimuno
GOS intake
Abbreviations: FOS, fructooligosaccharides; GOS, galactooligosaccharide; hs-CRP, high-sensitivity C-reactive protein; IBS, irritable bowel
syndrome; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; TG, triglycerides.

humans. The treatment was effective in decreasing stress modulate cortical dopamine metabolites, thereby amelio-
levels, anxiety, and depressive scores in both the animal ex- rating depressive symptoms.74 In addition, rat studies
periment and the clinical trial, providing the evidence that, showed that the consumption of L rhamnosus is associated
in this case, animal models are a reliable model for condi- with improved depressive scores.51 Together, these studies
tions in humans. Resident gut bacteria can also have nega- suggest that probiotics may improve mood status in
tive effects on the host. For example, Campylobacter jejuni humans and that (unhealthy) nutrition may be a risk factor
was shown to induce anxiety-like behavior without induc- for depression. Therefore, a healthy diet could have a pre-
ing immune activation in mice.81 As noted, in vivo models ventive effect against depression.111
provide evidence that a heightened HPA axis response and
depressive-like symptoms can be reversed by the adminis- Stress
tration of probiotic bacteria such as B infantis.70 Moreover,
probiotics may elevate blood tryptophan concentrations, The gut microbiome and the stress response are interre-
modulate serotonin levels in the frontal cortex, and lated in mammals. Sudo et al.69 showed that germ-free

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mice under stress conditions exhibited a strong HPA age,120 as these are periods of life with the highest vul-
response when compared with control animals. Their nerability and the greatest demand for nutrients. To
study showed that fecal transfer from specific pathogen- date, the majority of mechanistic evidence for the in-
free mice was able to partially normalize the exagger- volvement of the gut microbiota in cognition is pro-
ated stress response in germ-free animals. Most inter- vided by animal experiments of induced infections,80,121
estingly, the abnormal stress response was age- antibiotic and dietary manipulations,34,76,77,78 and pro-
dependently reversed when animals were treated with biotic interventions.78,79

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the probiotic B infantis.69 Supporting data were pro- Animal studies suggest that the microbiome may
vided by a study in which probiotic treatment of rat influence neurodevelopment.87,88,71 Short-chain fatty
pups normalized corticosterone release and ameliorated acids, the major metabolites produced by the micro-
colonic dysfunction induced by stress due to maternal biome, are implicated in the functionality of the blood–
separation.75 These data are in line with a report in brain barrier and thus have a direct role in determining
healthy volunteers following prebiotic supplementation. the accessibility of circulating factors to the brain.122
Prebiotic supplementation with fructooligosaccharides Short-chain fatty acids may control gene transcription
or a commercially available powder containing galac- in the brain via epigenetic mechanisms. Among these,
tooligosaccharides (Bimuno, DSM Nutritional butyrate is shown to be brain active and capable of facil-
Products, Basel, Switzerland) for 3 weeks revealed that itating long-term potentiation and the formation of
the cortisol awakening response, as assessed by salivary long-term memory in rats via an extracellular signal-
samples, was significantly lower after intake of Bimuno regulated kinase (ERK)-dependent signaling mecha-
powder than after placebo intake. In addition, partici- nism.123 These early reports were confirmed by subse-
pants showed decreased attentional vigilance to nega- quent studies showing that sodium butyrate facilitates
tive vs positive information in a dot-probe task after neuronal plasticity and memory formation124 via a
Bimuno powder intake than after placebo intake. No pathway that mimics the beneficial effects of environ-
effects were found after the administration of fructooli- mental enrichment.125 These studies have also pointed
gosaccharides, indicating the specificity of the observed to butyrate as the most important short-chain fatty acid
effects.104 Thus, the above-mentioned studies indicate involved in epigenetic modulation of brain function.
that the neuroendocrine function of the brain can be af- The positive effect of butyrate on cognition after sys-
fected by the gut microbiome. As outlined in the temic and local injections prompted scientists to test it
Introduction, the interaction between the gut and the in models of neurodegenerative diseases to counteract
brain is bidirectional in both rodents and humans. cognitive impairment. In animal models of Alzheimer’s
Evidence for the effect of the brain on the gut micro- disease, butyrate showed positive effects on pathology
biome can be found in studies documenting that paren- and memory performance.125,126 In models of other
tal stress,112,113 early-life stress,114,115 and psychological neurodegenerative disorders, including Parkinson’s dis-
stress116–119 change the composition of the gut ease,127 amyotrophic lateral sclerosis,128 Huntington’s
microbiota. disease,129 and ataxia,130 butyrate exhibited neuropro-
To further validate that preclinical results could be tective effects and helped restore, at least partially, neu-
translated to healthy humans, Allen et al.98 tested ronal function.
whether the consumption of B longum strain 1714 At the cellular level, butyrate’s effects are mediated
affects brain-related functions. They showed that this by various receptors, including G protein–coupled
probiotic modulated electroencephalographic activity, receptors, free fatty acid receptors, and transporters,71
dampened the stress response, and enhanced cognitive and by the utilization of butyrate as an energy source
performance in healthy volunteers.98 This study con- via the b-oxidation pathway.71 Butyrate inhibits histone
firmed older data showing that supplementing healthy deacetylase, thereby promoting histone acetylation and
women with a fermented milk product containing the epigenetic regulation of gene expression in human
Bifidobacterium animalis subsp lactis, Streptococcus cells. Therefore, some have proposed it be tested experi-
thermophilus, Lactobacillus bulgaricus, and L lactis mentally to treat cognitive impairment and neurological
subsp lactis altered activity of brain regions that control disorders ranging from depression to neurodegenera-
central processing of emotion and sensation in a func- tive diseases in humans (reviewed by Stilling et al.71).
tional magnetic resonance imaging study.99 Probiotics were also employed in human studies
examining cognitive performance of both healthy and
Cognition diseased study participants. Probiotic treatment
(L helveticus IDCC3801) of healthy elderly individuals
The chance of providing cognitive support to humans was shown to improve scores on cognitive fatigue
may be greatest during gestation, infancy, and older tests.100 Another study suggests that consumption of a

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fermented probiotic milk product modulates brain ac- prebiotics elevates levels of brain-derived neurotrophic
tivity during an emotional attention test in healthy factor, NMDA receptor subunits, and D-serine in the
women.99 In addition, prebiotic intake reduced the rat brain. They also showed that prebiotic supplementa-
waking cortisol response and altered emotional bias in tion normalizes lipopolysaccharide-induced anxiety and
healthy volunteers, resulting in improved performance cortical levels of serotonin 2 A receptor and
of healthy individuals in an emotional attention task.104 interleukin 1b in male mice. Moreover, supplementing
Promising results were reported recently by Akbari germ-free animals with L rhamnosus led to higher ex-

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et al.,102 who showed that supplementing Alzheimer’s pression of both the GABA receptor in the amygdala
disease patients with a probiotic milk containing and the serotonin 1 A receptor in the hippocampal for-
L acidophilus, L casei, B bifidum, and Lactobacillus fer- mation.51,71 These data suggest the possibility of treat-
mentum (each organism: 2  109 CFU/g of milk) for ing neuropsychiatric disorders by manipulating the
12 weeks positively affected cognitive function. If these microbiome with specific prebiotics and probiotics.
results can be replicated by independent research Gaseous metabolites of bacteria, including carbon
groups, they would be groundbreaking because they monoxide, hydrogen sulfide, nitric oxide, and others,
would indicate the potential usefulness of probiotics as are also implicated in the neuronal control of gut func-
a viable and affordable strategy for improving cognitive tions by muscarinic cholinergic, vasoactive intestinal
capacity in both healthy individuals and patients with peptide.135,136 The interaction with the nerve cells is in-
Alzheimer’s disease. direct and involves enteric glia, a collection of glial cells
residing within the walls of the intestinal tract137,138 and
Mechanistic evidence of microbial influence on within epithelial and smooth muscle cells,46 interstitial
neuronal signaling cells of Cajal,135 and immune cells.139 Enteric glia are
crucial for the above-mentioned interactions, as they
The gut and the brain communicate with each other via also communicate with various types of non-neuronal
central and systemic routes. The major route of central cells in the gut wall, such as enterocytes, enteroendo-
communication between the gut and the brain is the va- crine cells, and immune cells and are therefore impor-
gus nerve.16,131 The incoming information from the gut tant local regulators of diverse gut functions. Several
via the vagus nerve to the brain is processed in the nu- studies have emphasized the importance of enteric glia
cleus tractus solitarius, which has large projections that as modulators of ENS function, owing to the respon-
include the parabrachial nucleus, which further projects siveness of enteric glia to microbial, luminal, and in-
to the prefrontal cortex as well as the amygdala, a region flammatory signals.46,138,140–143 Thus, enteric glial cells
susceptible to microbial transcriptional regulation.71,132 regulate intestinal barrier function, immune responses,
Moreover, recent findings indicate that gut microbes intestinal secretion, and gut motility and are hypothe-
induce excitability of the intrinsic primary afferent neu- sized to be moderators of neurotransmission and neu-
rons in the intestine after hyperpolarization. This ele- roplasticity in the intestine.144
vated excitability was not observed in germ-free Bile acids are also able to modulate neuronal activ-
animals, suggesting that colonization restores normal ity, thus affecting both the host and microbiota, for ex-
neuronal excitability.57 Furthermore, neuroactive ample, by activating G protein–coupled bile acid
metabolites of microbiota, such as short-chain fatty receptors on intrinsic primary afferent neurons.145 This
acids, constitute a route of information flow between effect, however, depends on the specific bile acid, as
the gut and the brain.133 Despite the information pro- some promote bacterial growth, whereas others inhibit
vided by the above-mentioned research, the role of it.146,147
microorganisms in the regulation of neuronal activity is Quorum sensing, used by bacteria to coordinate
far from being fully understood. The mechanisms of in- gene expression according to the density of their local
volvement of the gut microbiota in brain function and population, represents a communication route within
disorders, including anxiety and depression, may be re- the gut by which bacteria may react to external (ie,
lated to the ability of the microbiota to synthesize solu- host) factors. The centrally produced neurotransmitter
ble factors (eg, neuromodulators) and modulate their noradrenalin, a major catecholamine neurotransmitter
absorption and function.134 A study by Neufeld et al.86 in the sympathetic nervous system, is known to serve as
showed that the expression of an N-methyl-D-aspartate a potent quorum sensing signal in bacteria such as
(NMDA) receptor subunit (NMDArec2B) is reduced in Escherichia coli.148–152 Hence, the host nervous system
the amygdala (a region implicated in the emotional may regulate bacterial growth, biofilm formation, and
processing of external cues) of germ-free animals. virulence mechanisms, including toxin production in
Savignac et al.93 confirmed the involvement of the the intestine, via noradrenalin-dependent neurotrans-
microbiome in gene expression by showing that feeding mission. Catecholamines, on the other hand, have been

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linked to the virulence of 2 pathogenic bacteria, namely profound effect on the function and responsiveness of
enterohemorrhagic E coli and C jejuni (reviewed by the HPA axis.69 This effect is age dependent, as the ab-
Savidge153). These varying effects of the same neuro- normal HPA response could be partially normalized af-
transmitter on different microbes demonstrate that ter recolonization at an early stage, but not at a late
much about the optimal utilization of microbes for spe- stage, clearly showing that the microbiome modulates
cific health benefits is still unknown. Nevertheless, it is the HPA response to stress, an effect that is most prom-
evident from the above data that microbes in the GI inent during the postnatal period.69

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tract interact with the ENS, thereby influencing both
host and microbial functions. DISCUSSION
There is considerable evidence that the microbiome
plays a role in modulating mood disorders, stress, and Elucidating the mechanisms by which microbes affect
anxiety, all conditions that are influenced by serotoner- brain function constitutes an exciting field of research.
gic neurotransmission.33,154 Bravo et al.51 demonstrated In vivo data have been instrumental in showing that the
that L rhamnosus regulates emotional behavior in mice excitability of enteric and vagal afferent neurons may be
by modulating central GABA receptor expression via a modulated by the microbiota131 and that the brain
mechanism that involves the vagus nerve. They also modulates intestinal motility, intestinal secretion, and
showed that mice are less anxious and exhibit less immune function.161 Research in preclinical models
depressive-like behavior following L rhamnosus supple- suggests that the effect of the microbiome on behavior
mentation. Undoubtedly, nutrition has a major influ- may be related to changes in the amygdala and hippo-
ence on the composition of the gut microbiome. For campus.67,162 A significant difference in the volume and
example, it is known that a Western diet changes the dendritic morphology of the amygdala and hippocam-
gut microbiome and induces anxiolytic effects in pus was observed between conventionally colonized
mice.155 The synthesis of serotonin as well as the avail- mice and germ-free mice, including shorter neurites, a
ability of its precursor tryptophan is highly regulated smaller degree of branching, and thinner spines in
during the life span. Metabolism of tryptophan, how- germ-free mice,162 suggesting that the microbiota is re-
ever, is altered after consumption of a Western diet.155 quired for the normal morphology and ultrastructure of
Tryptophan is the precursor of serotonin, which there- brain neurons. The authors argue that dysbiosis and the
fore links diet, the microbiome, neurotransmission, and consequent neural remodeling may contribute to the
effects on behavioral change to each other.156 This is maladaptive stress responsivity and behavioral profile
supported by the findings of Desbonnet et al.,34 who de- observed in germ-free mice.162 On the other hand, the
pleted the gut microbiome in mice by antibiotic treat- nervous system controls the intestinal physiology. The
ment, resulting in a dramatic reduction in tryptophan involvement of neural circuits, neurotransmitters, and
levels in blood as well as a reduction in BDNF levels in receptors in the sympathetic regulation of intestinal
the hippocampus. It is worth noting that several bacte- function is well established. Dysregulated neurotrans-
rial strains, such as L lactis subsp cremoris, L lactis subsp mission, altered HPA response, and damage of enteric
lactis, Lactobacillus plantarum, and S thermophilus, neurons result in an abnormal microbiome. For exam-
have been shown to produce monogenic amines, in- ple, stress conditions can cause abdominal pain and
cluding serotonin.157 Moreover, levodopa, serotonin, constipation.148,152,163 In addition, psychological stress
dopamine, and noradrenaline were detected during the has been shown to shift the microbial colonization on
late growth phase of E coli K-12 cultures,158 and L plan- the mucosal surface and alter the susceptibility of the
tarum has been reported to produce acetylcholine.94 host to infection.152 Moreover, the ENS and the im-
Lastly, several strains of Lactobacillus brevis, mune system both play important roles in the develop-
Bifidobacterium adolescentis, Bifidobacterium dentium, ment of irritable bowel disease. Both the ENS and the
and B infantis have been reported to be GABA pro- CNS can modulate intestinal inflammation through se-
ducers.159 In addition, Romano et al.160 reported that cretion of neuropeptides or other soluble molecules.164
the intestinal microbiota composition modulates the In addition, the innervation of the GI tract by the sym-
bioavailability of choline. Most efficient in this regard pathetic nervous system controls the motility, fluid ex-
were strains of Anaerococcus hydrogenalis, Clostridium change, and blood flow in the gut of healthy
asparagiforme, Clostridium hathewayi, Clostridium spor- individuals.165 Lastly, human studies show that the
ogenes, Edwardsiella tarda, and Escherichia fergusonii HPA axis is dysregulated in depression; however, this
isolated from human samples.160 It is therefore possible can be reversed after the resolution of depression.26 The
that microbial-derived neurotransmitters can alter the stress response is immature at birth. Its maturation is
activity of the ENS and, perhaps, the CNS. Lastly, governed by genetic factors of the host, as different
changes in the microbiome composition have a mouse strains have been shown to exhibit different

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stress and behavior responses to environmental Author contributions. M.H.M. collected and analyzed
stimuli.26 the data and wrote the manuscript, G.L.F. drafted
Figure 1, and R.E.S. and P.W. read and made valuable
CONCLUSION comments about the text. All authors read and ap-
proved the final manuscript.
Many of the state-of-the art therapies for brain disor-
ders aim to restore dysregulated neurotransmission in Funding/support. No external funds supported this

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affected brain areas. As noted in this review, data are in- work.
creasingly showing that bacteria can produce important
neurotransmitters such as GABA, acetylcholine, and se- Declaration of interest. Authors are employees of DSM
rotonin. Research aiming to understand the communi- Nutritional Products, Basel, Switzerland.
cation between the intestinal microbiota and the brain
peaked in recent years but revealed multiple mecha-
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