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Psychosomatic Medicine 
Author’s Accepted Manuscript 
 
Article Title: Brain-gut-microbiota axis in psychiatry: 
novel paradigm or false dawn? 
 
Authors: Timothy G. Dinan and John Cryan 
 
DOI: 10.1097/PSY.0000000000000519 
 
Received Date: July 29, 2016 
Revised Date: Apr 27, 2017 
 
 
 
 
 
 
 
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Brain-gut-microbiota axis and mental health 
 
Timothy G. Dinan, MD, PhD1,2, and John F. Cryan, PhD1,3 
 
1APC Microbiome Institute, University College Cork, Cork, Ireland 
2Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, 
Ireland 
3Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland 
 
Corresponding author: 
Prof. Ted Dinan, Department of Psychiatry, University College Cork, Ireland. t.dinan@ucc.ie 
 
Conflicts of interest and Source of Funding 
No conflicts of interest to declare. The authors are supported in part by Science Foundation 
Ireland in the form of a centre grant (Alimentary Pharmabiotic Centre Grant Number 
SFI/12/RC/2273); by the Health Research Board of Ireland (Grant Numbers 
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 Centre has conducted studies in collaboration with several 
companies including GSK, Pfizer, Cremo, Suntory, Wyeth and Mead Johnson. 
 
Psychosomatic Medicine Publish Ahead of Print
DOI: 10.1097/PSY.0000000000000519
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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 which enables gut microbes to communicate with the brain, and the brain to 
communicate with the microbes. This review assesses the potential usefulness and limitations 
of the paradigm. 
METHODS: A selective literature review was conducted to evaluate the current knowledge 
in clinical and pre-clinical brain-gut-microbiota interactions as related to psychiatric 
disorders. 
RESULTS: The overwhelming majority of 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 variables. 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, though there are some studies 
in healthy volunteers. A cocktail of probiotics has been shown to alter brain activity as 
monitored by functional MRI and Bifidobacterium longum was reported to alter brain 
electrical activity. 
CONCLUSION: 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, bifidobacteria, lactobacilli 
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Abbreviations 
BBB Blood brain barrier 
CBT cognitive behavior therapy 
C. difficile Clostridium difficile 
CRF corticotropin releasing factor 
cFos immediate early gene product 
5HT Serotonin 
FOS Fructooligosaccharides 
GABA Gamma-aminobutyric acid 
GOS Galactooligosaccharides 
GPCR G protein coupled receptor 
HDACs histone deacetylases 
HPA Hypothalamic-pituitary-adrenal axis 
IBS Irritable bowels syndrome 
IL Interleukin 
L. rhamnosus Lactobacillus rhamnosus 
SCFAs Short chain fatty acids 
SSRIs Selective serotonin reuptake inhibitors 
WAS water avoidance stress 
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The complexity of psychiatric illnesses cannot be underestimated and despite major advances 
in molecular neurobiology and neuroimaging, there have been no major advances in 
therapeutics. As a discipline psychiatry has had many false dawns and the objective of this 
review is to assess the newly emerging paradigm of the brain-gut-microbiota axis and 
critically assess its value in generating new therapeutic strategies. 
The nineteen fifties were 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 schizophrenia, 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 afterwards imipramine, the first tricyclic antidepressant 
was synthesised and originally considered useful as an antipsychotic. However, it soon 
became clear it has little efficacy in this regard but showed promise in the management of 
depression [4]. 
Since the nineteen fifties there have been no fundamental new advances in 
psychopharmacology. Undoubtedly, the emergence of SSRIs such as fluoxetine in the 
eighties was an advance in the treatment of depression in terms of side-effects. However, the 
SSRIs 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 extrapyramidal side-effects of the earlier compounds, but 
they are no more efficacious (with the exception of clozapine) and 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 psychological interventions such as cognitive behaviour therapy 
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(CBT) and mindfulness. Hundreds of studies have been published on mindfulness in the past 
few years and almost all have reported positive findings[7]. While 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 which exaggerate the effect size of theinterventions [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 CBT trials concludes that control conditions are often less than optimal [11]. 
Despite such reservations, many patients do benefit from these treatments when used 
appropriately. 
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 supports the view that gut microbes have a profound impact on central 
neurochemistry and behaviour, 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 effective 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 centred on gut microbes and mental illness, while 35 
papers focused on psychobiotics. Taking a broader perspective, looking at probiotics and 
mental health there were 50 papers. Of the 142 papers 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. 
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Microbe to brain communication 
The brain-gut-microbiota axis (Figure 1) is a bidirectional communication system which 
enables gut microbes to communicate with the brain, and the brain in turn to communicate 
with the gut [15]. While brain-gut communication has been a subject of investigation for 
decades an exploration of gut microbes as a mediator within this context has only recently 
been addressed. The mechanisms of signal transmission are complex and not fully elucidated, 
but it is clear 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 following 
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 
of certain neurological disorders such as Parkinson’s disease when they enter old age [20]. 
The gut microbiota also regulates central neurotransmitters such as serotonin 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 5HT and the human brain has limited storage capacity, therefore requiring a continual 
replenishment from the intestine. As well as producing precursors many bacteria can 
synthesise and release neurotransmitters e.g. Lactobacillus and Bifidobacterium species can 
produce gamma-aminobutyric acid (GABA): Escheridia, Bacillus and Saccharomyces spp. 
can produce norepinephrine: Candida, Streptococcus, Escheridia and Enterococcus spp. can 
produce 5HT: Bacillus can produce dopamine: and Lactobacillus can produce acetylcholine 
[22, 23]. These microbe-produced neurotransmitters can cross the mucosal layer of the 
intestine, though it is improbable that they directly influence brain physiology. Even if they 
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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 and may exert central 
effects either through GPCRs (G-protein coupled receptors), though 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 
(HDACs)[24]. Immune signalling from gut to 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 (IL)-
1 and IL-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 which frequently have 
psychiatric co-morbidities[27]. 
Psychopathology and gut dysbiosis 
There is increasing evidence that some psychiatric and neurological 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. 
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Depression 
Dinan and his colleagues studied the gut microbiota in a maternal separation model of 
depression in rats [28]. They reported an overactive HPA response in such animals, together 
with an increase in pro-inflammatory cytokines and a decrease in the diversity of gut 
microbes. In a recent study the fecal microbiota was sequenced in a depression study [29]. 
Forty-six patients with depression and 30 healthy controls were recruited. . High-throughput 
pyrosequencing showed that, according to the Shannon index, increased fecal bacterial alpha-
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 profound inter-individual variability, 
levels of several predominant genera were differed between the depressives and controls. 
Most notably, the depressives 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 relationships between gut microbiota and depression and to 
evaluate the suitability of the microbiome as a biomarker. In our study depressed patients 
had elevated cortisol output together with decreased faecal microbial richness and when rats 
were given a humanised microbiota from depressed patients, as opposed to healthy controls, 
they developed a depressive phenotype from a behavioural and immune 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 (OCD) has been most consistently 
associated with infection, especially respiratory tract infection with group A beta-hemolytic 
streptoccus [31]. No studies of probiotics in OCD patientshave been undertaken, though a 
rodent study suggests that L. rhamnosus might be effective [32]. 
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Lyte et al [33] found that oral gavage of the pathogen Campylobacter jejuni, in subclinical 
doses, which did not produce an overt immune response, resulted in anxiety-type behaviour 
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 behavioural responses. 
In a recently published study Bruch interrogated the Medical Expenditure Panel Survey 
(MEPS) to prospectively determine the relationship between intestinal infection and future 
onset of an anxiety disorder [34]. A total of six 2-year panel datasets, which consisted of 5 
consecutive rounds, were amalgamated from 2007 to 2013. This included the data for all 
respondents who were 18 years of age or older and who importantly did not have an anxiety 
disorder at baseline. Within the study population, there were 2577 subjects 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 (Pbeen reported in association with C. difficile infection. Perhaps the 
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association is entirely coincidental, though it has been postulated as mediated by a 
phenylalanine derivative synthetized by the bacteria [50]. C. difficile is also found in some 
babies born by Caesarean section, in whom it does not create obvious difficulties. However, 
there are no published studies available on the long-term outcome of such babies. 
To date no systematic analysis of the gut microbiota in schizophrenia has taken place, though 
it has been argued that any genomic analysis in the disorder should include an analysis of gut 
microbial DNA [51]. 
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 disorders[52]. For example, in Japan traditional dietary 
practice includes fermented soy products and this has been linked to lower rates of 
depression[53]. 
Psychobiotics were first defined as ‘the family of bacteria that, ingested in appropriate 
quantities, had a positive mental health benefit’ [54]. Recently, the definition has been 
expanded to include prebiotics, which are dietary, soluble fibres, for example 
galactooligosaccharides (GOS) or fructooligosaccharides (FOS), that stimulate the growth of 
‘good’ bacteria. 
There is an expanding volume of preclinical data to support the concept of psychobiotics. 
Understandably, clinical data is less abundant but nonetheless is emerging. Given the 
demonstrated efficacy of probiotics in IBS [55] and the high co-morbidity between IBS and 
stress related mental health issues, such as anxiety and depression, it is not surprising that 
certain probiotics might positively impact on mental health. 
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Bifidobacterium longum 1714 in a placebo-controlled study in healthy young volunteers not 
only reduced stress responses but enhanced cognitive activity. Morning cortisol was 
decreased on the psychobiotic relative to that seen with placebo. In marked contrast a 
Lactobacillus rhamnosus (JB1 strain) failed in translation; preclinical studies found 
significant neurochemical and behavioural effects[19], but no impact was found in a placebo-
controlled study in healthy volunteers[56]. 
Mayer’s group at UCLA [57] 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 over 4 weeks. All subjects underwent functional magnetic resonance imaging 
(fMRI) to determine how probiotic ingestion affected brain function. Subjects 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 network 
associated with emotional, somatosensory, and interceptive processing, including the 
somatosensory cortex, the insula, and the periaqueductal grey’. In marked contrast, placebo 
treated subjects 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 as 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 
[58]. Healthy male and female participates consumed either BGOS, FOS, 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 [59]. Participants also completed an emotional dot-probe task measuring 
vigilance, or attention to negative stimuli, which is a marker of anxiety and depression. 
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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 anxiolytic activity. 
Another study of a psychobiotic on stress related parameters was carried out by Takada and 
colleagues[60]. They conducted a placebo controlled trial of Lactobacillus casei strain 
Shirota (LcS) exploring both psychological and physiological parameters. The study group 
was healthy medical students who were participating in an exam. This is a well-established 
stress paradigm. Subjects were randomised to receive either LcS-fermented milk or placebo 
daily for 8 weeks followed by the exam. All subjects completed anxiety scores and provided 
saliva samples for cortisol measurement. Any side effects were carefully documented. 
Academic stress resulted in increases in salivary cortisol and an increase in physical 
symptoms, both of which were significantly suppressed in the LcS group. No significant side 
effects were reported. 
In a parallel animal study, rats were fed a regular diet with or without LcS for 14 days. They 
were then subjected to a water avoidance stress (WAS) test. Blood was drawn from a tail vein 
for corticosterone measurement and the expression of cFos and corticotropin releasing factor 
(CRF) in the paraventricular nucleus (PVN) were determined after the WAS test. In animals 
treated with LcS, WAS-induced elevations in corticosterone were attenuated, and the number 
of CRF-expressing neurons in the PVN was decreased. A mechanistic understanding of these 
findings is provided by the fact that intra-gastric 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 [61]. Seven hundred and ten young adults completed measures of dietary 
intake and personality traits. Controlling for relevant variables it was shown that exercise, 
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neuroticism, and fermented food consumption were a significantly predictor of social anxiety. 
The data indicate that fermented food intake interacts with the personality trait of neuroticism 
in predicting social anxiety. Those subjects with high neuroticism scores but a high frequency 
of fermented food intake had lower symptoms of social anxiety. The data support the view 
that fermented foods containing psychobiotics have a preventive effects against social anxiety 
in those at high genetic risk. 
Sternbergen et al [62] tested a polybiotic (multi-strain probiotic)containing Bifidobacterium 
bifidum, Bifidobacterium lactis, Lactobacillus acidophilus, Lactobacillus brevis, 
Lactobacillus casei, Lactobacillus salivarius, and Lactococcus lactis in normonthymic (non-
depressed) individuals using a triple-blind, placebo-controlled, randomized, design, Twenty 
healthy participants received 28 days of polybiotic treatment while 20 controls received an 
inert placebo. Subjects who received the probiotics showed a statistically significant 
reduction in cognitive reactivity to sad mood. The results provide evidence that probiotics 
may help reduce negative mood responses at least in healthy subjects. 
Romijn and Rucklidge in their systematic review [63] add a note of caution to the above 
optimistic findings concludingthat more well conducted studies are required before any 
definitive conclusions can be drawn about the efficacy of probiotics in mental illness. 
Further studies of a translational nature are certainly required. 
 
Defining dysbiosis 
What is a ‘normal’ gut microbiota? We still cannot say with certainty what the ideal 
composition of the gut microbiota is for optimal wellbeing. With the decreasing costs of 
sequencing and the large scale studies currently underway this issue is likely to be resolved in 
the not too distant future. At this point we have small scale studies in clinical populations, 
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that at best can be described as preliminary and from a bioinformatics perspective are 
worryingly under-powered. We urgently require a profiling of the microbiota 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 documented. 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 acquired from rodent studies is 
frequently lost in translation. There have been numerous false positive studies of compounds 
which 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 influence a 
wide range of bacteria may be more impacting than administering 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. Bifidobacterium infantis 35624 which is effective in treating irritable 
bowel syndrome 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 GABA to varying extents. Are bacteria capable of improving gut barrier 
function likely to have positive mental health benefits? 
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If psychobiotics for treating depression are to emerge the protection 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 developing a psychobiotic, 
only to find that a dietary supplement company market related bacteria with no efficacy data, 
is unlikely to be attractive to big pharmaceutical companies. Appropriate regulation in this 
area is of paramount importance to attract investment. 
Perhaps the main attraction to industry is the potential for rapidly developing psychobiotics in 
a manner not possible with small molecules. Bacteria which have GRAS status (generally 
regarded as safe) do not need time consuming and expensive toxicological analysis. This 
conceivably means that the average 10 year development programme for an antidepressant 
can be significantly shortened. 
As we documented in this review and elsewhere [64], 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 nineteen 
fifties was in terms of antidepressant and antipsychotic development? Only time will tell if 
the new paradigm is a fruitful one or a false dawn. However, what is certain is that this 
paradigm is currently at an embryonic level of development, requiring major financial 
investment if it is to progress. 
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89. http://dx.doi.org/10.1016/j.gtc.2016.09.007 
 
 
 
 
 
 
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Figure Legend 
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, altered levels of short chain fatty acids and tryptophan, 
together with aberrant signalling through the vagus nerve. Psychobiotics have the potential to 
normalize such processes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 1 
 
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