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Feeding the microbiota-gut-brain axis:
diet, microbiome, and neuropsychiatry
€
KIRANV.SANDHU,EOINSHERWIN,HARRIETSCHELLEKENS,CATHERINESTANTON,
TIMOTHYG.DINAN,andJOHNF.CRYAN
CORK,IRELAND
The microbial population residing within the human gut represents one of the most
densely populated microbial niche in the human body with growing evidence
showing it playing a key role in the regulation of behavior and brain function. The
bidirectional communication between the gut microbiota and the brain, the
microbiota-gut-brain axis, occurs through various pathways including the vagus
nerve, the immune system, neuroendocrine pathways, and bacteria-derived
metabolites. This axis has been shown to influence neurotransmission and the
behavior that are often associated with neuropsychiatric conditions. Therefore,
research targeting the modulation of this gut microbiota as a novel therapy for the
treatment of various neuropsychiatric conditions is gaining interest. Numerous fac-
tors have been highlighted to influence gut microbiota composition, including ge-
netics, health status, mode of birth, and environment. However, it is diet
composition and nutritional status that has repeatedly been shown to be one of
the most critical modifiable factors regulating the gut microbiota at different time
points across the lifespan and under various health conditions. Thus the microbiota
is poised to play a key role in nutritional interventions for maintaining brain health.
(Translational Research 2017;179:223–244)
Abbreviations:ASD¼Autismspectrumdisorder;ADHD¼Attention-deficithyperactivedisorder;
AMPK¼AMP-activatedproteinkinase;ANS¼Autonomicnervoussystem;BDNF¼Brain-derived
neurotrophicfactor;BMI¼Bodymassindex;BCFA¼Branchedchainfattyacid;CCK¼Chole-
cystokinin;CNS¼Centralnervoussystem;CREB¼cAMPresponseelement-bindingprotein;DA
¼Dopamine;EECs¼Enteroendocrinecells;ENS¼Entericnervoussystem;FOS¼Fructo-oligo-
saccharides; FXR ¼ Farnesoid X receptor; GOS ¼ Galacto-oligosaccharides; GF ¼ Germ-free;
GLP1¼Glycogen-likeprotein1;GABA¼Gama-aminobutyricacid;GI¼Gastrointestinaltract;
HPA¼Hypothalamus-Pituitary Axis; IBS ¼ Irritable bowel syndrome; IL ¼ Interleukin; LPS ¼ Lipo-
polysaccharide; LTP ¼ Long-term potentiation; MAMP ¼ Microbes-associated molecular pat-
terns; NOD ¼ Nucleotide-binding-oligomerization domain containing peptide; PYY ¼ Peptide
YY; PUFA ¼ Polyunsaturated fatty acid; Reg3g ¼ Regenerating family member 3 gamma;
SCFA¼Shortchainfattyacid;sp¼Species;SPF¼Specific-pathogen-free;TMAO¼Trimethyl-
amineoxide;TNF¼Tumornecrosisfactor;T-regs¼regulatoryTcells;WHO¼WorldHealthOrga-
nization; ZO ¼ Zonula occludens
From the APC Microbiome institute, University College Cork, Cork, Reprint requests: John F. Cryan, Department of Anatomy and Neuro-
Ireland; Department of Anatomy and Neuroscience, University science, University College Cork, Western Gateway Building, Cork,
College Cork, Cork, Ireland; Department of Psychiatry & Ireland; e-mail: j.cryan@ucc.ie.
Neurobehavioural Science, University College Cork, Cork, Ireland; 1931-5244/$ - see front matter
TeagascMooreparkFoodResearchCentre,Fermoy,Co,Cork,Ireland. 2016Elsevier Inc. All rights reserved.
SubmittedforpublicationMay2,2016;revisionsubmittedSeptember http://dx.doi.org/10.1016/j.trsl.2016.10.002
8, 2016; accepted for publication October 6, 2016.
223
Translational Research
224 Sandhuetal January2017
INTRODUCTION mediated through the autonomic nervous system
(ANS), the enteric nervous system (ENS), the
immune system, and the bacterial metabolites.
‘‘Let food be thy medicine and medicine be thy
food.’’ Neuronal pathways. After ingestion of a meal, the
—Hippocrates presence of nutrients in the GI tract initiates complex
neural and hormonal responses informing the brain of
This oft-quoted adage from Hippocrates from over the ongoing change in the nutritional status. The gut is
two thousand years ago may still be as relevant today innervated with primary visceral afferent nerve fibers
wherethereisagrowingrenaissanceinourappreciation from both sympathetic and parasympathetic branches
of the importance of diet in maintaining health, of the ANS.26 The afferent fibers project information
1
including brain health. In parallel, the importance of from the gut to the subcortical and cortical centers of
diet in regulating the composition of the human gut mi- the brain including the cerebral cortex, cingulate, and
crobiota has gained much attention of late.2 Accumu-
insular regions, whereas effector fibers project to the
lating evidence continues to highlight the importance smooth muscles of the gut.27 In addition, the gut also
of the gut microbiota in maintaining homeostasis and informs the brain about the current nutritional status
contributing to a variety of different physiological pro- by secreting a host of gut peptides from intestinal
cesses including protection from pathogens,3 food
4,5 6 cells including enteroendocrine cells (EECs). Some of
metabolism, host fat storage, and even regulation these hormones communicate with CNS primarily via
of brain physiology and behavior.7-9 More recently
effects on nearby afferent nerve fibers supplying the
researchers have started to address the role of the gut gut, whereas others are secreted from the gut into the
microbiota within multiple different neuropsychiatric circulatory system and whereupon they enter the brain
conditions, including autism,10 depression,11,12 28
13 14 to mediate their central effects.
stroke, and schizophrenia. The gut microbiota is This bidirectional communication helps in main-
influenced by various factors such as host genetics, taining a proper GI homeostasis and cognitive
health status, lifestyle, mode of delivery at birth, anti- 23
biotic usage, and dietary pattern based on different cul- function. The vagus nerve is the major nerve of
tural practices.15-18 the parasympathetic system of the ANS and crucial
Given that diet is a key contributor in shaping the for mediating the effects of gut microbiota on
29
composition of the gut microbiota and that changes different neurophysiological function (Fig 1). For
in dietary patterns show a direct effect on the compo- example, vagotomized mice failed to show any
sition of the gut bacteria.18-22 It is important to improvement in anxiety or depressive-like behaviors
contextualize diet and nutrition effects on the following treatment with a potential probiotic Lacto-
microbiota-gut-brain axis. Therefore, in this review, bacillus rhamnosus indicating that behavioral proper-
we discuss recent advances in the understanding of ties of this bacterial strain are dependent upon
gut-brain signaling via the vagus nerve.32 Similarly,
the critical role diet plays in establishing a link be- a potential probiotic Bifidobacterium longum failed
tween the gut microbiota and host health. Further- to produce an anxiolytic effect in a vagotomized coli-
more, the role of the microbiota in the gut-brain tis mouse model.33
axis in relation to its association with various neuro-
psychiatric disorders will be explored. Thevagusnerveterminatingnearthemucosaconveys
information from the intestine to the brainstem through
nucleisuchasthenucleustractussolitariesandthenodos
BIDIRECTIONAL CROSS-TALK BETWEEN GUT ganglion,whichrepresentanintermediaterelayinbrain-
MICROBIOTAANDTHECNS 34
gut axis bidirectional communication. (Fig 1). The va-
The gut-brain axis acts as an integrative physiolog- gusnervedoesnotprojectdirectlyintothelumen,andits
ical system amalgamating endocrine, immunologic, activation is partly dependent on the secretion of chemi-
nutritional, efferent, and afferent neuronal signals calsignalssuchaspeptidehormones(peptideYY[PYY],
between the gastrointestinal (GI) system and the glucagon-like peptide 1 [GLP-1], cholecystokinin
23
brain. The microbiota is now seen as a key compo- [CCK])byEECs,specializedendocrinecellinintestinal
35
nent of this gut-brain axis, and disturbances in the ho- tract (Fig 1). For instance, PYY , the major circu-
3–36
meostasis or dysregulation of the gut-microbiota-brain lating PYY, binds to the hypothalamic neuropeptide
axis have been implicated in various immunologic, YY receptors and is associated with reduction in food
2
neurologic, and psychiatric conditions.23-25 36
The intake in rodents and humans and vagotomy blocks
complex network of communication between the PYY -induced hypophagia and associated activation
3–36
37
gut microbiota and central nervous system (CNS) is of neurons in the hypothalamic arcuate nucleus.
Translational Research
Volume179 Sandhuetal 225
Fig 1. Cross talk between diet-derived macro- and micronutrients, the microbiota and its metabolites, and the
brain:Thefoodinourdietisbrokendownintocarbohydrates,proteinandlipids,whichcanbefurthermetabolized
bythegutmicrobiota.Theby-productsfromcarbohydratefermentationcanresultinthesynthesisofSCFA,which
havethepossibility to induce epigenetic modulation of the intestinal epithelial cell in addition to direct effects on
30
GPCRs (GPR43/41) on EECs. Bile acids derived from fatty acid metabolism can also have multiple effects
including interacting with GPCR TGR5 (also known as G protein-coupled bile acid receptor 1 [GPBAR1]) and
the nuclear receptor farnesoid X receptor (FXR) on the (EECs).31 Both SCFA and bile acids can thus stimulate
the modulationofguthormonessecretion,includingPYY,GLP-1andCCKaswellashavingimmunomodulatory
responses. The satiety hormones can modulate CNS function and regulate appetite and food intake. Finally, a
myriadofneurotransmitters andneuroactivesubstancesproducedbythegutmicrobiotacanregulateahostofpe-
ripheral and central functions via indirect and direct mechanisms. In addition, some metabolites can pass into the
bloodandthroughthecirculatorysystem,indirectly via receptors on cells or directly through the blood brain bar-
rier, modulate brain function. CCK, Cholecystokinin; EECs, Enteroendocrine cells; FXR, Farnesoid X receptor;
GABA,Gamma-aminobutyricacid;GLR-1,Glycogenlikeprotein;GPCR,Gprotein-coupledreceptor;HAT,His-
tone acetyltransferase; HDAC, Histone deacetylases; PYY, Peptide YY; SCFA, Short chain fatty acid.
Translational Research
226 Sandhuetal January2017
Enteroendocrine cells. EECs are a set of specialized immunoglobulinA(IgA),andantimicrobialpeptides.46
endocrine cells forming 1% epithelial cells of the GI These immune cells have an important role to play as
tract and are capable of sensing luminal content and they keep a check on the homeostatic relationship
producing and releasing signaling molecules or between the microbiota and the host. In addition,
hormones.34 As referred to in the previous section, the mucus produced by goblet cells offer the first
EECs release peptides and these peptides act on the line of protection by limiting the contact between
receptors located along the vagal afferent fibers. the microbiota and host tissue, thus preventing
The information generated by EECs is passed to the microbial translocation.46,47 Further production of the
brain by the vagal nerve and therefore EEC is critical antimicrobial peptides by the intestinal epithelial
for the bidirectional gut-brain communication.38 CCK, cells helps to limit the commensal microbiota to the
a satiety peptide hormone, transmits sensory signals gut. For instance, regenerating family member 3
from the gut lumen through direct EEC-nerve gamma (Reg3g), a mucosal antimicrobial peptide
communication or via paracrine mechanisms, that is, secreted by intestinal epithelial cells has been shown
activation of the vagal pathway.34,39 Exogenous to directly kill gram-positive bacteria and thus
administration of CCK activates CCK1 receptor and regulating the microbiota composition.48 Germ-free
induces reduction of meal size and satiety. However, (GF) mice known to have immunologic deficits49 were
CCK1 receptor null mice fail to show reduction of found to express diminished levels of Reg3g,
meal size or satiation.40 suggesting a potential role of gut microbiota in
EECs are located along the GI tract in direct contact immunity regulation. However, colonization of GF
to the lumen and also in close proximity with the gut mice with the gram-negative bacteria Bacteroides
microbiota, which allows for the bacterial commensal thetaiotaomicron induced expression of Reg3g.
to interact with EECs with metabolites and regulate Conversely, when GF mice were colonized with the
the secretion of various gut peptides.26,34 For instance, gram-positive bacteria, B. longum, Reg3g expression
short chain fatty acids (SCFAs; metabolic products was reduced.50-52 Such results highlight an important
of polysaccharide fermentation) interact with regulatory interaction between the gut microbiota
G-protein–coupled receptor 41 (GPR41) expressed and the immune system. Immunoglobulin A is an
upon EECs in the gut epithelium, which causes a immune regulator that is associated with
reduction in the expression of PYY thereby inhibiting the compartmentalization of intestinal bacteria.
gut motility, increasing intestinal transit rate, and Intestinal dendritic cells together with T and B cells in
reducing nutrient contact time.41,42 Consistent with the Peyer’s patches mediate the production of IgA
this finding, Ffar2-and Ffar3-knockout mice display specific for commensal-derived antigens and regulate
impaired oral glucose tolerance and increased intestinal microbial translocation.52
transit time.42,43 However, further research is required Theimmunesystemisnotonlyinvolvedinmaintain-
to clarify the mechanisms of different metabolites inghomeostasisbetweenthegutmicrobiotaandthegut,
on the EECs or intestinal gut cells and their it may also act as an intermediary between the gut mi-
corresponding role in gut-microbiota-brain cross talk. crobiota and the brain.53 The gut microbiota may
Circulatory system. Microbial-derived metabolites mediate an immune response by releasing certain mol-
present in the intestinal lumen are absorbed into the cir- ecules, which are potent promoters of the innate im-
culatory system by passive or active mechanisms, mune system; for example, lipopolysaccharide (LPS)
whereasmetabolitesstructurallysimilartoaminoacids, or peptidoglycan. When the integrity of the intestinal
sugars,andvitaminsareactivelytransportedviaspecific mucosal barrier is compromised, gram-negative bacte-
transporters. For instance, SCFAs are transported either ria expressing LPS can be translocated from the gut
by monocarboxylate transporters or via diffusion.44 into the circulatory system leading to peripheral im-
Conversely, microbial metabolites may cross the mune activation. Preclinical and clinical studies have
barrier via paracellular (between cells) transport when bothshownthatperipheralimmuneactivationfollowing
the epithelial barrier is breached (‘‘leaky gut’’) which LPS administration can lead to depressive-like behav-
may often result in altered microbiota composition iors.54,55 This highlights how the bacterial
and induction of an inflammatory response.45 Thus, commensals can modulate behavior via the immune
blood circulation not only mediates the flow of system. A recent study in GF mice showed a link
metabolites throughout the host system but also between the brain’s resident immune cells, microglia,
regulates gut microbiota message to the brain. and the gut microbiota.56 The GF mice display defects
Immunesystem. Thebacterial commensals present in in microglia with altered cell proportions and immature
the GI tract are often found at sites enriched with phenotype.56 Moreover, microglial activation was
immune cells including epithelial cells, mucus, diminished in GF mice following LPS administration
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