YEAR IN REVIEW

GUT–BRAIN AXIS IN 2016 which raises the question: would transplanta-

tion of microbiota from a patient with depres-
sion have a similar effect if the immune system

Brain–gut–microbiota and brain ­development in the recipient animal

were normal?
To answer this question, Kelly and col-

axis — mood, metabolism leagues7 recruited 34 patients with major

depres­sion and 33 healthy individ­uals matched
for age and sex. Plasma levels of cytokines,

and behaviour C‑reactive protein, salivary cortisol and

plasma lipopolysaccharide-binding protein
were determined by ELISA, and showed alter-
Timothy G. Dinan and John F. Cryan ations supporting a proinflamatory phenotype
associated with depression. Plasma levels of
In 2016, key studies have increased our understanding of the part played tryptophan and kynurenine and composition
by the brain–gut–microbiota axis in disorders as diverse as depression, of faecal microbiota were also determined.
Depression was associated with decreased
obesity and autism spectrum disorder. The data indicate that alterations gut-microbiota richness and diversity. A fae-
in gut-microbial composition can substantially affect central physiology, cal microbiota transplant was prepared from
and that transplantation of the gut microbiota can transfer a behavioural a subgroup of patients with depression or
or physiological phenotype. from healthy individuals and transferred
by oral ­gavage to a microbiota-­deficient rat
model. The model comprised normal rats
The association of alterations in gut–brain In one series of experiments, germ-free mice with a developed immune system and nor-
interactions with functional bowel disorders, (but not conventionally raised animals) were mal brain function that were given a cocktail
chronic abdominal pain syndromes and even protected from depression-like immobil- of antibiotics to eliminate the gut microbiota.
eating disorders has become increasingly ity induced by the forced-swim test as well
clear in the past few years. Modulation of as from anxiety behaviours. In addition,
Mood disorder Functional
gut–brain-axis function is associated with ­faecal samples from 58 Chinese patients with Depression bowel disorder
alterations in the stress response and over- major depression and 63 healthy individ­uals Anxiety IBS
all behaviour in both animal models and in as controls showed distinct differences in
humans1. A high comorbidity exists between microbial composition5. In the patients with
stress-related mental symptoms such as depression, the microbiota had alterations
­anxiety and IBS, a fact that has provided the in species belonging to three bacterial phyla:
greatest impetus for research into the impor- Firmicutes, Actinobacteria and Bacteroidetes.
tance of the gut–brain axis2. Over 50% of Transplantation of faecal ­s amples pooled
patients with IBS have comorbid depression from five patients with d­ epression into germ-
or anxiety. Modulation of the gut–brain axis is free mice resulted in depressive behaviour
increasingly being proposed as an appropriate ­patterns; by contrast, faecal transplantation
target for the development of novel treatments from five healthy individ­uals had no behav-
for a wide variety of disorders that range from ioural effect. Mice receiving microbiota from
depression and anxiety to IBS, obesity and patients with depression showed disturbances
neurodevelopmental disorders3. in hippo­campal gene activation and also in
The gut microbiota interact with the host carbo­hydrate and amino-acid metabolism5.
through immune, neuroendocrine and neural This study provides convincing evidence that
pathways4. These pathways are components the depressive phenotype can be transferred by
of the brain–gut–microbiota axis and preclin­ transplantation of the microbiota. However, Neurodevelopmental disorder
ical evidence suggests that the microbiota can germ-free mice have abnormal immune-­ Autism spectrum disorder
recruit this bidirectional communication net- system development and brain anomalies (such
Figure 1 | The brain–gut–microbiota axis.
work to modulate brain development, func- as decreased levels of 5‑hydroxytryptamine The gut microbiota is altered notNature
only inReviews
tion and even behaviour. Preliminary studies and brain-­derived neurotrophic factor, changes Gastroenterology & Hepatology
functional bowel disorders such as IBS but
have shown differences in the composition in neuro­nal morphology in the amygdala, in mood disorders such as depression,
of the gut microbiota in patients with depres- increased adult hippocampal neurogenesis neurodevelopmental disorders such as autism
sion compared with healthy individuals. and increased prefrontal cortical myelination6), spectrum disorder and in metabolic disorders.

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YEAR IN REVIEW

Key advances
• Transplantation of microbiota from patients
with depression to microbiota-depleted
animals induces behavioural and
physiological features characteristic of
depression in the recipient animals7
• Increased production of acetate by an
altered gut microbiota in mice and rats
leads to activation of the parasympathetic
nervous system, which in turn promotes
increased glucose-stimulated insulin
secretion, increased ghrelin secretion,
hyperphagia and obesity8
• A maternal high-fat diet induces changes
in the social behaviour of offspring and is
linked to gut microbiota alterations and
anomalies in the mesolimbic dopamine
reward system; treatment with the
commensal Lactobacillus reuteri reverses
the deficits in social behaviours10
Transplantation of microbiota from patients
with depression to microbiota-depleted rats
induced behavioural and physiological f­ea-
tures characteristic of depression in the recipi-
ent animals, including anhedonia, anxiety-­like
behaviours and alterations in tryptophan
metabolism7. This study prov­ides further evi-
dence that the gut microbiota have a causal
role in the development of features of depres-
sion and could provide a tract­able target in the
treatment and prevention of this disorder.
Several lines of evidence suggest that brain
observed in HFD-fed rats surprisingly had no
effect on GSIS. To examine the role of the gut
microbiota in acetate-induced hyperinsulin­
aemia, HFD-fed rats were treated with broad-­
spectrum, nonabsorbable oral anti­biotics,
which resulted in a major reduction in GSIS
during a hyperglycaemic clamp. Faecal trans-
plantations transferred the acetate turn­over,
faecal acetate and GSIS associated with the
donor animal to the recipient animal. These
data suggest that the gut microbiota are the
source of most of the increase in endogenous
acetate production in HFD-fed rats. When the
vagus nerve was severed in the rats, infusion
with acetate exhibited a marked reduction in
plasma insulin concentrations throughout a
hyperglycaemic clamp, without any change
in plasma glucagon concentrations, when
compared with rats that had an intact vagus
nerve8. Overall, these data support the view
that increased acetate production resulting
from a nutrient–gut-microbiota interaction
and subsequent parasympathetic activation is
a possible therapeutic target for obesity.
…the microbiota can recruit
this bidirectional communication
network to modulate brain
development, function and
even behaviour
MHFD offspring, failed to ­normalise social
behavioural deficits. These data support pre-
vious evidence suggesting a role of the gut
­microbiota in social behaviour 10.
Understanding the way in which the gut
microbiota influence gut–brain-axis com-
munication (FIG. 1) has been the subject of
considerable research effort in the past few
years. The gut microbiota are now recog-
nized to influence processes such as the stress
response and, consequently, to play a part in
the pathophysio­logy of functional bowel dis-
orders such as IBS2. Whether changes in the
microbiota are central to the pathophysiology
of at least some psychiatric disorders such as
depression has yet to be definitively demon-
strated, although the studies published this
year provide further support for such a view.
Increasingly, evidence is accumulating for a
role of the gut microbiota in autism spectrum
disorder and the negative metabolic conse-
quences in obesity. Future studies must deter-
mine whether exciting new data, which has
largely been obtained from preclinical animal
experiments, translates to humans; only time
will tell.
Timothy G. Dinan is at the APC Microbiome Institute and
the Department of Psychiatry, University College Cork,
Cork IE0000, Ireland.
John F. Cryan is at the APC Microbiome Institute and
the Department of Anatomy and Neuroscience,
University College Cork, Cork IE0000, Ireland.
Correspondence to T.G.D.
t.dinan@ucc.ie

function and behaviour are influenced by
microbial metabolites. Short-chain fatty acids
(SCFAs), such as butyrate, propionate and
acetate, are key products of the gut micro­
biota. Although no direct evidence currently
exists that SCFAs travel via the blood stream
to the brain in humans, findings increasingly
support the indirect actions of SCFAs. For
example, increased production of acetate by an
altered gut microbiota in mice and rats leads
to activation of the parasympathetic nervous
system, which in turn promotes increased
glucose-stimulated insulin secretion (GSIS),
increased ghrelin secretion, hyperphagia,
obesity and related sequelae8. Perry and col-
leagues8 found that, in contrast to propion-
ate and butyrate, whole-body turnover of
acetate, and concentrations of acetate in the
plasma and faeces, were markedly increased
in insulin-­resistant rats after a high-fat diet
(HFD) compared with chow-fed rats8. Acetate
infusion in chow-fed rats strongly replicated
the increases in GSIS measured in HFD-fed
rats, implicating heightened acetate turnover
in driving the increases in GSIS in HFD-fed
rats. By contrast, supplementing butyrate in
chow-fed rats to match the turnover rates
Maternal obesity has been linked with
neurodevelopmental disorders in offspring,
including autism spectrum disorder 9. Now,
Buffington and colleagues10 have shown that
obesity in mice induced by a maternal high-
fat diet (MHFD) is associated with social
behavioural deficits, which are mediated by
alterations in the offspring gut microbiota.
The diversity of the microbiota in MHFD
offspring was reduced compared with
­animals on a regular diet, with an especially
notable reduction in Lactobacillus spp. The
MHFD-induced changes in the offspring gut
microbiota were associated with major alter-
ations in the mesolimbic dopamine reward
system within the ventral tegmental area.
Furthermore, treatment with a commensal
bacterial ­species Lactobacillus reuteri increased
levels of oxytocin (known to increase social
behaviour), ameliorated synaptic dysfunction
in the ventral tegmental area and selectively
reversed social deficits in MHFD offspring.
This amelioration of the deficient social
behaviour was entirely speci­fic to L.  reu-
teri, as treatment with another Lactobacillus
­species, Lactobacillus johnsonii, whose abun-
dance is also reduced in the gut microbiota of
doi:10.1038/nrgastro.2016.200
Published online 5 Jan 2017
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challenges for translation in psychiatry.
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depressive-like behaviors through a pathway mediated
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6. Clarke, G. et al. The microbiome–gut–brain
axis during early life regulates the hippocampal
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7. Kelly, J. R. et al. Transferring the blues: depression-
associated gut microbiota induces neurobehavioural
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9. Wang, Y. et al. Maternal body mass index and risk
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deficits in offspring. Cell 165, 1762–1775 (2016).
Competing interests statement
The authors declare no competing interests.

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