REVIEW

Brain-Gut-Microbiota Axis and Mental Health

Timothy G. Dinan, MD, PhD, and John F. Cryan, PhD

ABSTRACT
Objective: The brain-gut-microbiota axis has been put forward as a new paradigm in neuroscience, which may be of relevance to mental
illness. The mechanisms of signal transmission in the brain-gut-microbiota axis are complex and involve bidirectional communications
that enable gut microbes to communicate with the brain and the brain to communicate with the microbes. This review assesses the potential
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usefulness and limitations of the paradigm.

Methods: A selective literature review was conducted to evaluate the current knowledge in clinical and preclinical brain-gut-microbiota
interactions as related to psychiatric disorders.
Results: Most published studies in the field are preclinical, and there is so far a lack of clinical studies. Preliminary studies in psychiatric
populations support the view of a dysbiosis in some conditions, but studies are often small scale and marred by potential confounding var-
iables. Preclinical studies support the view that psychobiotics (“bacteria which when ingested in adequate amounts have a positive mental
health benefit”) might be of use in treating some patients with mental health difficulties. To date, we have no well-conducted studies in
clinical populations, although there are some studies in healthy volunteers. A cocktail of probiotics has been shown to alter brain activity
as monitored by functional magnetic resonance imaging, and Bifidobacterium longum was reported to alter brain electrical activity.
Conclusions: It has yet to be convincingly demonstrated that the exciting findings of psychobiotic efficacy demonstrated in preclinical
models of psychiatric illness will translate to patients.
Key words: brain-gut-microbiota axis, psychobiotics, depression, autism, anxiety, schizophrenia.

INTRODUCTION extrapyramidal adverse effects of the earlier compounds, but they

are no more efficacious (with the exception of clozapine) and

T he complexity of psychiatric illnesses cannot be underesti-

mated, and despite major advances in molecular neurobiology
and neuroimaging, there have been no major advances in therapeu-
tics. As a discipline, psychiatry has had many false dawns, and the
objectives of this review are to assess the newly emerging paradigm
of the brain-gut-microbiota axis and to critically assess its value in
generating new therapeutic strategies.
The 1950s was a watershed in the history of psychiatry with the
emergence of the first effective antipsychotics and antidepressants
(1). The demonstrated efficacy of chlorpromazine in treating schi-
zophrenia, a molecule synthesized by Charpentier, was undoubtedly
a landmark (2). In terms of depression treatment, the antidepressant
iproniazid emerged (3). It is a monoamine-oxidase inhibitor that had
originally been used in the treatment of tuberculosis. Shortly after-
ward, imipramine, the first tricyclic antidepressant, was synthesized
and originally considered useful as an antipsychotic. However, it
soon became clear that it has little efficacy in this regard but showed
promise in the management of depression (4).
Since the 1950s, there have been no fundamental new advances
in psychopharmacology. Undoubtedly, the emergence of selective
serotonin reuptake inhibitors such as fluoxetine in the eighties was
an advance in the treatment of depression in terms of adverse effects.
However, the selective serotonin reuptake inhibitors failed to yield
improvements in terms of efficacy or speed of therapeutic onset
(5). Likewise, the emergence of atypical antipsychotics such
as olanzapine and risperidone provided treatments without the
prone to cause considerable weight gain frequently leading to
a metabolic syndrome (6).
There are those who would argue that the major new paradigm
in psychiatry has been the emergence of more effective psycholog-
ical interventions such as cognitive behavior therapy and mindful-
ness. Hundreds of studies on mindfulness have been published in
the past few years and almost all have reported positive findings
(7). Although these therapies benefit many patients, their efficacy
may be exaggerated by the large number of studies with small
samples sizes and very varying definitions of response (8). Many
studies of these therapies have used designs that exaggerate the effect
size of the interventions (9,10). Few, if any, of the studies are designed
with the capacity to compare efficacy with a true placebo response.
Many, for example, use a waiting-list comparison or a comparison
with treatment as usual. Both of these controls will exaggerate
the effect size of any intervention. A recent meta-analysis of cog-
nitive behavior therapy trials concludes that control conditions are
often less than optimal (11). Despite such reservations, many patients
do benefit from these treatments when used appropriately.
BBB = blood-brain barrier, BGOS = β-galactooligosaccharides,
C. difficile = Clostridium difficile, cFos = immediate early gene prod-
uct, 5-HT = serotonin, HPA = hypothalamic-pituitary-adrenal axis,
IBS = irritable bowels syndrome, LcS = Lactobacillus casei strain
Shirota, L. rhamnosus = Lactobacillus rhamnosus, SCFAs = short-
chain fatty acids, WAS = water avoidance stress

From the APC Microbiome Institute (Dinan, Cryan) and Departments of Psychiatry and Neurobehavioural Science (Dinan) and Anatomy and
Neuroscience (Cryan), University College Cork, Cork, Ireland.
Address correspondence and reprint requests to Ted Dinan, MD, PhD, Department of Psychiatry, University College Cork, Ireland. E-mail: t.dinan@ucc.ie
Received for publication July 29, 2016; revision received April 27, 2017.
DOI: 10.1097/PSY.0000000000000519
Copyright © 2017 by the American Psychosomatic Society

Psychosomatic Medicine, V 79 • 920-926 920 October 2017

Copyright © 2017 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

EVIDENCE FOR NOVEL PARADIGM
The brain-gut-microbiota axis is the focus of the latest paradigm in
neuroscience that has been put forward as a potential game changer
(12,13). An exponentially accumulating volume of evidence sup-
ports the view that gut microbes have a profound impact on central
neurochemistry and behavior, especially stress-related responses
(14). How do gut microbes exert such a powerful central influence
and how might targeting the brain-gut-microbiota axis yield effec-
tive therapies for psychiatric illnesses?
Until February 2017, there were 142 articles focusing on gut
microbes and the brain, listed on PubMed. Twenty-three of these
articles centered on gut microbes and mental illness, whereas 35
articles focused on psychobiotics. Taking a broader perspective,
looking at probiotics and mental health, there were 50 articles.
Of the 142 articles on the gut microbiota and the brain, 111 were
reviews and 31 were experimental studies, of which only 4 were
human studies. This latter fact pinpoints the current weakness of
this nascent field.
MICROBE TO BRAIN COMMUNICATION
The brain-gut-microbiota axis (Fig. 1) is a bidirectional communi-
cation system that enables gut microbes to communicate with the
brain, and the brain in turn to communicate with the gut (15). Al-
though brain-gut communication has been a subject of investiga-
tion for decades, an exploration of gut microbes as a mediator
within this context has only recently been addressed. The mecha-
nisms of signal transmission are complex and not fully elucidated,
but it is clear that they include neural, endocrine, immune, and
metabolic pathways (16–18). Preclinical studies have implicated
the vagus nerve as a fundamental neural route of communication
between gut microbes in the periphery and centrally mediated
behavioral effects, as illustrated by the elimination of central
Lactobacillus rhamnosus effects after full truncal vagotomy
(19). Interestingly, it has been demonstrated that individuals who
underwent a full truncal vagotomy for treatment of peptic ulcer
disease have a decreased risk for certain neurological disorders
such as Parkinson disease when they enter old age (20). The gut
microbiota also regulates central neurotransmitters such as
serotonin (5-HT) by altering levels of precursors; for example,
Bifidobacterium infantis has been demonstrated to elevate plasma
tryptophan levels and thus influence central 5-HT (21). Tryptophan
is the precursor of 5-HT and the human brain has limited storage
capacity, therefore requiring a continual replenishment from the
intestine. In addition to producing precursors, many bacteria can
synthesize and release neurotransmitters, for example, Lactobacillus
and Bifidobacterium species can produce γ-aminobutyric acid;
Escheridia, Bacillus, and Saccharomyces species can produce
norepinephrine; Candida, Streptococcus, Escheridia, and
Enterococcus species can produce 5-HT; Bacillus can produce
dopamine; and Lactobacillus can produce acetylcholine (22,23).
These microbe-produced neurotransmitters can cross the mucosal
layer of the intestine, although it is improbable that they directly
influence brain physiology. Even if they enter the blood stream,
which is by no means certain, they are incapable of crossing the
blood-brain barrier (BBB). Their impact on brain function is likely
to occur by acting locally on the enteric nervous system. Short-
chain fatty acids (SCFAs), which include butyrate, propionate, and
acetate, are essential metabolic products of gut microbial activity
Psychosomatic Medicine, V 79 • 920-926
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Brain-Gut-Microbiota Axis in Psychiatry
and may exert central effects through G protein–coupled receptors,
although such receptors are sparsely concentrated in the mammalian
brain and the half-life of SCFAs is exceedingly short in the plasma.
They may, however, act as epigenetic modulators through histone
deacetylases (24). Immune signaling from the gut to the brain
mediated by cytokine molecules is another well-documented route
of communication (25). Cytokines produced at the level of the
gut can travel via the bloodstream to the brain. Under normal
physiological circumstances, they do not cross the BBB, but
increasing evidence indicates an ability to signal across the BBB
and to influence brain areas such as the hypothalamus and
circumventricular organs, where the BBB is deficient. It is through
the latter mechanism the cytokines interleukin 1 and interleukin 6
activate the core stress system, the hypothalamic-pituitary-adrenal
axis (HPA), bringing about the release of cortisol. This is regarded
as the most potent activating mechanism of the stress system and
is of relevance in conditions such as the depression that emerges
with interferon therapy for hepatitis or induced by infections (26)
and also inflammatory bowel disorders and irritable bowel syndrome
(IBS), which frequently have psychiatric comorbidities (27).
PSYCHOPATHOLOGY AND GUT DYSBIOSIS
There is increasing evidence that some psychiatric and neurologi-
cal disorders may be associated with a gut dysbiosis. The extent to
which such a dysbiosis is central to the pathophysiology of these
conditions has not been fully elucidated.
DEPRESSION
O'Mahony and colleagues (28) studied the gut microbiota in a
maternal separation model of depression in rats. They reported
an overactive HPA response in such animals, together with an in-
crease in proinflammatory cytokines and a decrease in the diver-
sity of gut microbes. In a recent study, the fecal microbiota was
sequenced in a depression study (29). Forty-six patients with de-
pression and 30 healthy controls were recruited. High-throughput
pyrosequencing showed that, according to the Shannon index,
increased fecal bacterial α-diversity was found in those currently
depressed but not in a group who had responded to treatment.
Bacteroidetes, Proteobacteria, and Actinobacteria were increased,
whereas Firmicutes were significantly reduced. Despite the pro-
found interindividual variability, levels of several predominant
genera were differed between those with depressive symptoms
and the controls. Most notably, the individuals with depressive
symptoms had increased levels of Enterobacteriaceae and Alistipes
but reduced levels of Faecalibacterium. The authors conclude that
further studies are necessary to elucidate the temporal and causal re-
lationships between gut microbiota and depression and to evaluate
the suitability of the microbiome as a biomarker. In our study, de-
pressed patients had elevated cortisol output together with decreased
fecal microbial richness, and when rats were given a humanized mi-
crobiota from depressed patients, as opposed to healthy controls,
they developed a depressive phenotype from a behavioral and im-
mune perspective (30).
ANXIETY DISORDERS
There are no published studies exploring the gut microbiota in
any specific anxiety disorder. Of the anxiety disorders, obsessive-
compulsive disorder has been most consistently associated with
921 October 2017
 REVIEW

FIGURE 1. The brain-gut-microbiota axis in health and disease. The routes of communicate between gut and brain include neural, humoral,
and immune pathways. Gut dysbiois leads to altered immunology, activation of the HPA, and altered levels of SCFAs and tryptophan,
together with aberrant signaling through the vagus nerve. Psychobiotics have the potential to normalize such processes. HPA =
hypothalamic-pituitary-adrenal axis; SCFAs = short-chain fatty acids; CRH = corticotropin-releasing hormone; CORT = cortisol; ACTH =
adrenocorticotropic hormone; IL = interleukin. Color image is available only in online version (www.psychosomaticmedicine.org).

infection, especially respiratory tract infection with group A
β-hemolytic streptoccus (31). No studies of probiotics in patients
with obsessive-compulsive disorder have been undertaken, although
a rodent study suggests that L. rhamnosus might be effective (32).
Lyte et al. (33) found that oral gavage of the pathogen Campylo-
bacter jejuni, in subclinical doses, which did not produce an overt
immune response, resulted in anxiety-type behavior in rodents. They
also noted that areas of brainstem, such as the nucleus tractus solitarius
and lateral parabrachial nucleus, are involved in the processing that
results in autonomic, neuroendocrine, and behavioral responses.
In a recently published study, Bruch (34) interrogated the Medical
Expenditure Panel Survey to prospectively determine the relationship

Psychosomatic Medicine, V 79 • 920-926 922 October 2017

Copyright © 2017 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

between intestinal infection and future onset of an anxiety disorder. A
total of six 2-year panel data sets, which consisted of five consecutive
rounds, were amalgamated from 2007 to 2013. This included the data
for all respondents who were 18 years or older and who importantly
did not have an anxiety disorder at baseline. Within the study popula-
tion, there were 2577 participants with an intestinal infection in Round
1 and 4239 with an anxiety disorder that commenced in Round 2, 3,
4, or 5. In total, an intestinal infection in Round 1 was associated with
a 1.34 (p < .01) odds ratio of an emerging anxiety disorder starting
in Round 2, 3, 4, or 5. Does this association apply to other infections
such as respiratory or urinary tract? Respiratory infection was asso-
ciated with a 1.36 (p < .01) odds ratio of having an anxiety disorder
that began in Round 2, 3, 4, or 5, but other infections were unre-
lated. This major epidemiological study provides convincing evi-
dence of a link between intestinal infection and the subsequent
development of anxiety.
AUTISM
Autism is a neurodevelopmental disorder whose prevalence is
regarded by some as on the increase (35). It is characterized by a fail-
ure of language acquisition, obsessional traits, and a lack of sociability
and is frequently associated with gastrointestinal symptoms (36), the
relevance of which has been a long-standing source of controversy.
Up to 70% of patients with the syndrome report abdominal symptoms
and hence the view that it is a disorder of the brain-gut axis (37).
At the APC Microbiome Institute, the behavior of mice raised
in a germ-free environment was examined (38,39). The mice were
tested in a three-chamber apparatus that assesses social interaction.
Here, a germ-free animal was put in the middle chamber with a
familiar mouse in Chamber 1 and a novel mouse in Chamber 3.
The germ-free mouse interacted with the familiar mouse for a sim-
ilar amount of time to that of the novel mouse. This contrasts with
the behavior of conventionally colonized mice, which spend less
time with the familiar than the novel mouse. Germ free mice are
as likely to interact with objects as with other animals, a very un-
usual pattern of behavior for a sociable animal. Conventional col-
onization of the germ-free mice does, to some extent, normalize
their behavior. The behavioral anomalies s are related to underly-
ing alterations in neural circuitry.
Work by the Hsiao group (40) in an animal model demonstrated
that the microbiota mediates the behavioral and biochemical anom-
alies associated with neurodevelopmental disorders including au-
tism. They made use of the maternal immune activation model,
which they induced by polyinosinic-polycytidylic acid injection
during pregnancy and found significant changes in gastrointestinal
barrier function as well as microbiota anomalies. Oral treatment
with the human commensal Bacteroides fragilis was shown to
normalize gut permeability and, most interestingly, stereotypic
and other aberrant behaviors. Even more importantly, a metabolite
found in the abnormal animals was observed to transfer the pheno-
type to naïve animals and to be reduced by B. fragilis.
There is currently a lot of attention focused on oxytocin, the
hypothalamic peptide, released from the posterior pituitary, which
has been demonstrated to increase sociability. The oxytocin recep-
tor knockout mouse in behavioral tests has major deficits in social
behavior (41), and small-scale studies in humans have shown that
that intranasally administered oxytocin positively impacts social
behavior. Large-scale clinical trials of oxytocin in autism spectrum
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Brain-Gut-Microbiota Axis in Psychiatry
disorder are currently under way (42). There is controversy as to
whether or not the preclinical findings translate to the clinical set-
ting and, assuming they do, which subsets of patients are most
likely to respond. A recent study indicates that a probiotic can
modulate HPA activity and elevate oxytocin levels. If this is repli-
cated in humans, it may be that social behavior patterns can be al-
tered via oxytocin by targeting gut microbes (43,44).
The gut microbiota in patients with autism spectrum disorder
has been sequenced (45). In the most recently published study,
Tomova et al. (45) studied the microbiota in Slovakian children
with autism. They found a significant decrease in the Bacteroidetes/
Firmicutes ratio and elevation in Lactobacillus species numbers.
There was a modest elevation in Desulfovibrio species and a corre-
lation with the severity of autism. A probiotic in the diet was found
to normalize the Bacteroidetes/Firmicutes ratio and Desulfovibrio
species levels. An analysis by Mayer and colleagues (12) concludes
that there is a shortage of large comprehensive studies of the mi-
crobiome in autism, and one can only agree with this assessment.
Furthermore, the issue of which comes first is fundamental; are
these microbiota changes epiphenomenal, induced by unusual diets
seen in many individuals as a product of obsessional ruminations, or
are they core to the disease pathophysiology? Many studies to date
fail to adequately address the heterogeneous aspect of this disorder.
Future studies will need to do so if progress is to be made. More
comprehensive and accurate phenotyping is required.
Nutrition is clearly an important variable in any microbiota stud-
ies and especially in the context of autism. This was clearly demon-
strated in a microbiome composition study that showed an elevation
in the low-abundance cyanobacteria/chloroplast genus in children
diagnosed as having autism spectrum disorder (Son et al., 2015
(46)). However, because of availability of dietary information, it
was found that this was probably due to intake of chia seeds,
which are often present in specialized diets.
SCHIZOPHRENIA
It has been argued that our social and cognitive development, in
evolutionary terms, has been aided by our symbiotic relationship
to microbes. Disruption in social and cognitive functioning is cen-
tral to the pathophysiology of schizophrenia. Given this fact, there
has been recent focus on the microbiota in the disorder, although
no large-scale studies have yet been published.
Toxoplasma gondii, the protozoa, is known to cause major
changes to the gut microbiota (47) and is an established environ-
mental risk factor for schizophrenia (48). In mice, it can radically
alter behavior patterns resulting in reckless behavior in the presence
of predators. (49). An intriguing human study reported that latent
infection in healthy elderly can result in deficits in goal-directed
learning, associated with underlying changes in dopaminergic neu-
ral transmission (50).
In the elderly, Clostridium difficile infection can be treatment
refractory and a few cases of schizophrenia have been reported
in association with C. difficile infection. Perhaps the association
is entirely coincidental, although it has been postulated as medi-
ated by a phenylalanine derivative synthetized by the bacteria
(51). C. difficile is also found in some babies born by cesarean de-
livery, in whom it does not create obvious difficulties. However,
there are no published studies available on the long-term outcome
of such babies.
923 October 2017
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To date, no systematic analysis of the gut microbiota in schizo-
phrenia has taken place, although it has been argued that any geno-
mic analysis in the disorder should include an analysis of gut
microbial DNA (52).
PSYCHOBIOTICS
Fermented foods are a traditional part of the diet in many cultures,
and it is argued that such intake decreases the levels of mood dis-
orders (53). For example, in Japan, traditional dietary practice in-
cludes fermented soy products and this has been linked to lower
rates of depression (54).
Psychobiotics were first defined as “the family of bacteria that,
ingested in appropriate quantities, had a positive mental health
benefit” (55). Recently, the definition has been expanded to include
prebiotics, which are dietary, soluble fibers, for example, galacto-
oligosaccharides or fructooligosaccharides, that stimulate the growth
of “good” bacteria.
There is an expanding volume of preclinical data to support the
concept of psychobiotics. Understandably, clinical data are less
abundant but nonetheless are emerging. Given the demonstrated
efficacy of probiotics in IBS (56) and the high comorbidity between
IBS and stress-related mental health issues, such as anxiety and de-
pression, it is not surprising that certain probiotics might positively
have an impact on mental health.
Bifidobacterium longum 1714 in a placebo-controlled study in
healthy young volunteers not only reduced stress responses but
also enhanced cognitive activity. Morning cortisol was decreased
on the psychobiotic relative to that seen with placebo. In marked
contrast, a L. rhamnosus (JB1 strain) failed in translation; preclin-
ical studies found significant neurochemical and behavioral effects
(19), but no impact on healthy volunteers was found in a placebo-
controlled study (57).
Tillisch's group (58) at the University of California, Los Angeles,
administered healthy female participants either a placebo or a
fermented dairy drink made from the probiotics (Bifidobacterium
animalis lactis, Streptococcus thermophiles, Lactobacillus bulgaricus,
and Lactococcus lactis lactis), which were consumed for 4 weeks.
All participants underwent functional magnetic resonance imaging
to determine how probiotic ingestion affected brain function. Par-
ticipants were shown emotional faces that are known to capture
attention and cause brain activation. Relative to placebo, probiotic-
treated participants showed decreased activity in a “functional net-
work associated with emotional, somatosensory, and interceptive
processing, including the somatosensory cortex, the insula, and
the periaqueductal grey.” In marked contrast, placebo-treated par-
ticipants showed increased activity in these regions in response to
same stimuli. The authors interpret this as evidence of a probiotic-
induced reduction in network-level neural reactivity to negative
emotional information. The study is noteworthy because it is the first
to demonstrate the capacity of probiotics to alter brain physiology.
A recent prebiotic study carried out in Oxford found a significant
impact on stress responses (59). Healthy male and female partici-
pates consumed either β-galactooligosaccharide (BGOS), fructool-
igosaccharides, or a placebo. In comparison to the other two groups,
participants who consumed BGOS showed significantly reduced
waking cortisol responses, which are a robust marker of anxiety,
stress, and depression risk (60). Participants also completed an emo-
tional dot-probe task measuring vigilance, or attention to negative
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stimuli, which is a marker of anxiety and depression. Participants
taking BGOS showed substantially attenuated vigilance on this task,
suggesting reduced attention and reactivity to negative emotions.
Overall, the data support the view that the specific prebiotic has an-
xiolytic activity.
Another study of a psychobiotic on stress-related parameters
was carried out by Takada and colleagues (61). They conducted
a placebo-controlled trial of Lactobacillus casei strain Shirota
(LcS) exploring both psychological and physiological parameters.
The study group comprised healthy medical students who were
participating in an examination. This is a well-established stress
paradigm. Participants were randomized to receive either LcS-
fermented milk or placebo daily for 8 weeks followed by the ex-
amination. All participants completed anxiety scores and provided
saliva samples for cortisol measurement. Any adverse effects were
carefully documented. Academic stress resulted in increases in sal-
ivary cortisol and an increase in physical symptoms, both of which
were significantly suppressed in the LcS group. No significant ad-
verse effects were reported.
In a parallel animal study, rats were fed a regular diet with or with-
out LcS for 14 days. They were then subjected to a water avoidance
stress (WAS) test. Blood was drawn from a tail vein for corticoste-
rone measurement, and the expressions of cFos and corticotropin-
releasing factor in the paraventricular nucleus were determined after
the WAS test. In animals treated with LcS, WAS-induced elevations
in corticosterone were attenuated, and the number of corticotropin-
releasing factor–expressing neurons in the paraventricular nucleus
was decreased. A mechanistic understanding of these findings is pro-
vided by the fact that intragastric infusion of LcS stimulated gastric
vagal afferent activity and did so in a dose-dependent manner. The
results suggest that LcS may positively impact stress responses by
acting through the vagus nerve.
A large-scale cross-sectional study has examined the impact of
probiotics on measures of social anxiety (62). Seven hundred ten
young adults completed measures of dietary intake and personality
traits. Controlling for relevant variables, it was shown that exercise,
neuroticism, and fermented food consumption were significantly
predictors of social anxiety. The data indicate that fermented food
intake interacts with the personality trait of neuroticism in predicting
social anxiety. Those participants with high neuroticism scores but a
high frequency of fermented food intake had lower symptoms of so-
cial anxiety. The data support the view that fermented foods contain-
ing psychobiotics have a preventive effect against social anxiety in
those at high genetic risk.
Steenbergen et al. (63) tested a polybiotic (multistrain probiotic)
containing Bifidobacterium bifidum, Bifidobacterium lactis, Lacto-
bacillus acidophilus, Lactobacillus brevis, L. casei, Lactobacillus
salivarius, and L. lactis in normonthymic (nondepressed) individ-
uals using a triple-blind, placebo-controlled, randomized design,
Twenty healthy participants received 28 days of polybiotic treat-
ment, whereas 20 controls received an inert placebo. Participants
who received the probiotics showed a statistically significant reduc-
tion in cognitive reactivity to sad mood. The results provide evi-
dence that probiotics may help reduce negative mood responses
at least in healthy participants.
Romijn and Rucklidge (64) in their systematic review add a
note of caution to the previously mentioned optimistic findings
concluding that more well-conducted studies are required before
any definitive conclusions about the efficacy of probiotics in
924 October 2017

mental illness can be drawn. Further studies of a translational na-
ture are certainly required.
DEFINING DYSBIOSIS
What is a “normal” gut microbiota? We still cannot say with cer-
tainty what the ideal composition of the gut microbiota is for opti-
mal well-being. With the decreasing costs of sequencing and the
large-scale studies currently underway, this issue is likely to be re-
solved in the not too distant future. At this point, we have small-
scale studies in clinical populations that at best can be described
as preliminary and, from a bioinformatics perspective, are worry-
ingly underpowered. We urgently require a profiling of the micro-
biota in the common psychiatric disorders in large numbers of
well-phenotyped patients, who are preferably drug naïve, in the
early stages of their illness and whose nutritional status is well doc-
umented. We are far from this point at present, and therefore, the
extent to which a dysbiosis may play a role in mental illness is
far from certain.
LOST IN TRANSLATION?
As the pharmaceutical industry has learned, therapeutic data ac-
quired from rodent studies are frequently lost in translation. There
have been numerous false-positive studies of compounds that
looked promising in animal models but failed to achieve effects
beyond those of placebo in clinical trials. In the development of
psychobiotics, it is unclear whether a single strain is preferable
to the use of multiple strains or whether prebiotics, which may in-
fluence a wide range of bacteria, may be more impacting than ad-
ministering bacteria. Neither do we know what the most effective
in vitro screening techniques for detecting psychobiotics are. One
approach might be the use of in vitro assays to detect bacteria
showing promising anti-inflammatory activity. B. infantis 35624,
which is effective in treating IBS, was initially detected by such
a screen. Another approach might be to profile the metabolic output
of bacteria by studying the content of the supernatants for SCFAs
and neurotransmitters. We know, for example, that most lactobacilli
secrete the inhibitory neurotransmitter γ-aminobutyric acid to vary-
ing extents. Are bacteria capable of improving gut barrier function
likely to have positive mental health benefits?
If psychobiotics for treating depression are to emerge, the pro-
tection of intellectual property in the field is essential. This is an
evolving legal area and far more complex than the protection of
traditional small molecules. Spending large sums of money devel-
oping a psychobiotic, only to find that a dietary supplement com-
pany markets related bacteria with no efficacy data, is unlikely to
be attractive to big pharmaceutical companies. Appropriate regula-
tion in this area is of paramount importance to attract investment.
Perhaps the main attraction to industry is the potential for rap-
idly developing psychobiotics in a manner not possible with small
molecules. Bacteria that have GRAS status (generally regarded as
safe) do not need time-consuming and expensive toxicological
analysis. This conceivably means that the average 10-year develop-
ment program for an antidepressant can be significantly shortened.
As we documented in this review and elsewhere (65), research
on microbiota has shown promising results in preclinical models
of psychiatric illness that may translate to patient care.
Will the next decade be for psychobiotics and the brain-gut-
microbiota axis what the 1950s was in terms of antidepressant
Psychosomatic Medicine, V 79 • 920-926
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Brain-Gut-Microbiota Axis in Psychiatry
and antipsychotic development? Only time will tell if the new par-
adigm is a fruitful one or a false dawn. However, what is certain is
that this paradigm is currently at an embryonic level of develop-
ment, requiring major financial investment if it is to progress.
Source of Funding and Conflicts of Interest: No conflicts of inter-
est to declare. The authors are supported in part by Science Founda-
tion Ireland in the form of a center grant (Alimentary Pharmabiotic
Centre Grant No. SFI/12/RC/2273) and by the Health Research
Board of Ireland (Grant Nos. HRA_POR/2011/23 and HRA_POR/
2012/32) and received funding from the European Community's
Seventh Framework Programme Grant MyNewGut under Grant
Agreement No. FP7/2007-2013. The center has conducted studies
in collaboration with several companies including GSK, Pfizer,
Cremo, Suntory, Wyeth, and Mead Johnson.
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