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

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DOI: 10.1097/PSY.0000000000000519

Received Date: July 29, 2016

Revised Date: Apr 27, 2017

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Psychosomatic Medicine Publish Ahead of Print
DOI: 10.1097/PSY.0000000000000519

Brain-gut-microbiota axis and mental health

Timothy G. Dinan, MD, PhD1,2, and John F. Cryan, PhD1,3

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APC Microbiome Institute, University College Cork, Cork, Ireland

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2
Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork,

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Ireland

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Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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Corresponding author:

Prof. Ted Dinan, Department of Psychiatry, University College Cork, Ireland. t.dinan@ucc.ie
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Conflicts of interest and Source of Funding

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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
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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.

Copyright © 2017 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
 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.

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METHODS: A selective literature review was conducted to evaluate the current knowledge

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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
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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
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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
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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
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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

Copyright © 2017 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
 Abbreviations

BBB Blood brain barrier

CBT cognitive behavior therapy

C. difficile Clostridium difficile

CRF corticotropin releasing factor

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cFos immediate early gene product

5HT Serotonin

FOS

GABA TE
Fructooligosaccharides

Gamma-aminobutyric acid
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GOS Galactooligosaccharides

GPCR G protein coupled receptor

HDACs histone deacetylases

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HPA Hypothalamic-pituitary-adrenal axis

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IBS Irritable bowels syndrome

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IL Interleukin

L. rhamnosus Lactobacillus rhamnosus

SCFAs Short chain fatty acids

SSRIs Selective serotonin reuptake inhibitors

WAS water avoidance stress

Copyright © 2017 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
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

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first effective antipsychotics and antidepressants [1]. The demonstrated efficacy of

chlorpromazine in treating schizophrenia, a molecule synthesized by Charpentier, was

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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

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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
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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
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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

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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

Copyright © 2017 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
(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 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.

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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].

appropriately.

Evidence for novel paradigm

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Despite such reservations, many patients do benefit from these treatments when used
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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
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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
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yield effective therapies for psychiatric illnesses?

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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,

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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

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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
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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
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plasma tryptophan levels and thus influence central 5-HT [21]. Tryptophan is the precursor
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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
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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

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(HDACs)[24]. Immune signalling from gut to brain mediated by cytokine molecules is

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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
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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
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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
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inflammatory bowel disorders and irritable bowel syndrome which frequently have

psychiatric co-morbidities[27].
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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

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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

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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
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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
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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,
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they developed a depressive phenotype from a behavioural and immune perspective[30].

Anxiety disorders
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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 patients have 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

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(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

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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
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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 < 0.01) odds ratio

of an emerging anxiety disorder starting in Round 2, 3, 4, or 5. Does this association apply

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to other infections such as respiratory or urinary tract? Respiratory infection was associated

with a 1.36 (P < 0.01) odds ratio of having an anxiety disorder that began in Round 2, 3, 4, or
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5 but other infections were unrelated. This major epidemiological study provides convincing
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evidence 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 characterised by a failure of language acquisition, obsessional traits and a

lack of sociability and is frequently associated with gastrointestinal symptoms [36], the

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relevance of which has been a longstanding 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 behaviour of mice raised in a germ-free environment

was examined [38, 39]. The mice were tested in a three chamber apparatus which assesses

social interaction. Here, a germ-free animal was put in the middle chamber with a familiar

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mouse in chamber 1 and a novel mouse in chamber 3. The germ-free mouse interacted with

the familiar mouse for a similar amount of time to the novel mouse. This contrasts with the

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behaviour of conventionally colonised mice, who spend less time with the familiar than the

novel mouse. Germ-free mice also interact with objects to the same exact as with other

animals, a very unusual pattern of behaviour for a sociable animal. Conventional

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colonisation of the germ free mice does to some extent normalise their behaviour. The

behavioural anomalies s are related to underlying alterations in neural circuitry.

Work from Mazmanian’s group in an animal model demonstrated that the microbiota

mediates the behavioural and biochemical anomalies associated with neurodevelopmental

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disorders including autism [40]. They made use of the maternal immune activation model
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which they induced by poly-IC injection during pregnancy and found significant changes in

gastrointestinal barrier function as well as microbiota anomalies. Oral treatment with the
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human commensal Bacteroides fragilis was shown to normalise gut permeability and most

interestingly stereotypic and other aberrant behaviours. Even more importantly, a metabolite

found in the abnormal animals was observed to transfer the phenotype to naïve animals and

to be reduced by Bacteroides fragilis.

There is currently a lot of attention focused on oxytocin, the hypothalamic peptide, released

from the posterior pituitary, which is has been demonstrated to increase sociability. The

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oxytocin receptor knockout mouse in behavioural tests has major deficits in social behaviour

[41] and small scale studies in humans have shown that that intra-nasally administered

oxytocin positively impacts social behaviour. Large scale clinical trials of oxytocin in autism

spectrum disorder are currently under way [42]. There is controversy as to whether or not the

preclinical findings translate to the clinical setting and assuming they do which subset of

patients are most likely to respond. A recent study indicates that a probiotic can modulate

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HPA activity and elevate oxytocin levels. If this is replicated in humans it may be that social

behavior patterns can be altered via oxytocin by targeting gut microbes [43, 44].

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The gut microbiota in patients with autism spectrum disorder has been sequenced [45]. In the

most recently published study, Tomova et al studied the microbiota in Slovakian children

with autism. They found a significant decrease in the Bacteroidetes/Firmicutes ratio and
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elevation in Lactobacillus spp numbers. There was a modest elevation in Desulfovibrio spp

and a correlation with the severity of autism. A probiotic in the diet was found to normalise

the Bacteroidetes/Firmicutes ratio and Desulfovibrio spp levels. An analysis by Mayer &
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colleagues concludes that there is a shortage of large comprehensive studies of the

microbiome in autism [12] and one can only agree with this assessment. Furthermore, the
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issue of which comes first is fundamental; are these microbiota changes epiphenomenal,
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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.

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Nutrition is clearly an important variable in any microbiota studies and especially in the

context of autism. This was clearly demonstrated in a microbiome composition study, which

showed an elevation in the low-abundance Cyanobacteria/chloroplast genus in children

diagnosed with ASD (Son et al., 2015). However, due to availability of dietary information it

was found that this was probably due to intake of chia seeds which are often present in

specialized diets.

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Schizophrenia

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It has been argued that our social and cognitive development, in evolutionary terms, has been

aided by our symbiotic relationship with microbes. Disruption in social and cognitive

functioning is central to the pathophysiology of schizophrenia. Given this fact there has been
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recent focus on the microbiota in the disorder, though no large scale studies have yet been

published.
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Toxoplasma gondii, the protozoa, is known to cause major changes to the gut microbiota

[46] and is an established environmental risk factor for schizophrenia [47]. In mice it can
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radically alter behavior patterns resulting in reckless behavior in the presence of predators.
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[48]. 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

neural transmission [49].

In the elderly C. difficile infection can be treatment refractory and a few cases of

schizophrenia have been 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

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microbial DNA [51].

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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
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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
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expanded to include prebiotics, which are dietary, soluble fibres, for example

galactooligosaccharides (GOS) or fructooligosaccharides (FOS), that stimulate the growth of

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‘good’ bacteria.

There is an expanding volume of preclinical data to support the concept of psychobiotics.

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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.

Copyright © 2017 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
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

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fermented dairy drink made from the probiotics (Bifidobacterium animalis Lactis,

Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis Lactis), which

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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
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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
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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

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demonstrate the capacity of probiotics to alter brain physiology.

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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

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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

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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
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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
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(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
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of CRF-expressing neurons in the PVN was decreased. A mechanistic understanding of these

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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

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bifidum, Bifidobacterium lactis, Lactobacillus acidophilus, Lactobacillus brevis,

Lactobacillus casei, Lactobacillus salivarius, and Lactococcus lactis in normonthymic (non-

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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
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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 concluding that more well conducted studies are required before any
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definitive conclusions can be drawn about the efficacy of probiotics in mental illness.

Further studies of a translational nature are certainly required.

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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.

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Lost in translation?

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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
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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.
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One approach might be the use of in vitro assays to detect bacteria showing promising anti-
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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
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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.

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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

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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.

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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
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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
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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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