Neuron

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Gut Microbe to Brain Signaling:

What Happens in Vagus.
€ lling,1 Timothy G. Dinan,1,2 and John F. Cryan1,3,*
Christine Fu
1APC Microbiome Ireland, University College Cork, Cork, Ireland
2Department of Psychiatry and Neurobehavioural Science, University College Cork, Ireland
3Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland

*Correspondence: j.cryan@ucc.ie
https://doi.org/10.1016/j.neuron.2019.02.008

The gut microbiota has emerged as a key player in health and disease. Here we discuss the vagus nerve,
which connects the visceral organs and the brain, as an important communication pathway for the gut micro-
biota to influence brain and behavior.

Visceral organs and the central nervous
system constantly communicate to pro-
vide a sense of the body’s physiological
condition and to adapt accordingly to
maintain homeostasis. One of the key
players in this interoceptive feedback
loop is the gut-brain axis, the complex
bidirectional communication between
the gastrointestinal (GI) tract and the cen-
tral nervous system that involves endo-
crine, immune, and neural communica-
tion mechanisms, such as that through
vagus nerve signaling. Although best
studied in the context of food intake and
satiety, it is clear that this axis can play a
role across many aspects of physiology
and behavior. More recently the micro-
biota (the trillions of microorganisms in
and on our body) has been shown to be
a key regulator of the gut-brain axis, and
thus the microbiota-gut-brain axis has
been proposed. However, the regulatory
mechanisms occurring are only now be-
ing unravelled. In this NeuroView, we
focus on one such pathway and describe
how the gut microbiota may hijack vagus
nerve signaling as a means to alter brain
and behavior.
Microbiota
The microbiota describes the consortium
of different microbes, including bacteria,
archaea, fungi, viruses, and parasites
that live on our skin, in our lungs, and in
the urogenital and GI tracts. Over the
preceding decades, the microbiota has
received increased attention for its
involvement in various diseases ranging
from obesity to cancer and has become
one of the most reviewed topics in
biomedical science. Within the different
microbial communities, much attention
has been drawn to the one residing in the
GI tract, which is the largest and most
diverse community of microorganisms.
The initial microbiota is acquired at birth
and develops alongside its host. Although
rather easily perturbed in these early
critical years, the microbiota acquires in-
ternal stability during the first years of
development. This process is regulated
by a combination of host genetics
and environmental factors such as diet,
stress, and exposure to other microbes
or antibiotics. Hence, a well-functioning
microbiota is highly adapted to the host
and the host’s habitat and carries out
metabolic and biochemical processes
that are important for the host’s function.
Although this description is broadly appli-
cable to a stable human gut microbiota,
the presence and abundance of bacterial
species can vary significantly between in-
dividuals. This inter-individual difference
is accounted for by the importance of
the functions carried out by the micro-
biota, rather than the individual species,
thus allowing unique microbiota composi-
tion without losing functionality. The adult
microbiota is relatively stable but main-
tains a certain degree of flexibility to
change in response to intrinsic and envi-
ronmental factors (Figure 1A; Bastiaans-
sen et al., 2019).
Habitat and Function
It is important to stress that the gut mi-
crobiota is not uniform. Diversity and
density of microorganisms increase
along the GI tract according to nutri-
tional, chemical, and immunological
gradients (Figure 1C). Each individual
species is therefore highly adapted to
perform specific functions in defined
environmental niches of the GI tract. As
a whole, the gut microbiota produces
an array of metabolites ranging from
sugars and short chain fatty acids to
neuroactive substances such as seroto-
nin or g-aminobutyric acid. These can
serve as energy sources for the gut mi-
crobiota itself or the host, or can act on
the host’s signaling pathways.
Microbiota and Brain
Some of the most convincing evidence
for the involvement of the microbiota in
host physiology and psychology emerged
from germ-free rodents, which have been
deprived of any kind of microbe-host in-
teractions from birth. The lack of micro-
biota in these animals resulted in a variety
of altered physiological functions ranging
from gut sensory-motor functions and
gastric emptying to blood-brain barrier
integrity and immune functions. Further-
more, germ-free rodents showed drastic
alterations in brain physiology. Changes
in hippocampal levels of the neuro-
transmitter serotonin, brain-derived neu-
rotrophic factor (BDNF), and an altered
level of neurogenesis, as well as structural
changes to neurons in the amygdala, and
variations in the level of myelination in
the prefrontal cortex provide the physio-
logical means to explain the differ-
ences in stress reactivity, anxiety-related,
depressive-like, and social behaviors as
well as cognition observed in germ-free
animals (Figure 1B). While these studies
indicated a relationship between the mi-
crobiota and brain and behavior, incon-
trovertible evidence for this link came

998 Neuron 101, March 20, 2019 ª 2019 Elsevier Inc.

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Figure 1. The Microbiota-Gut-Brain Axis

(A) Factors influencing the composition of the gut microbiota. The initial microbiota is acquired at birth and is shaped by a variety of intrinsic and environmental
factors. Although microbiota stability peaks in adulthood, it maintains flexibility to adjust to environmental or dietary changes.
(B) Evidence for the influence of the gut microbiota on brain physiology has surfaced mostly from studying germ-free animals, which show alterations in various
aspects of neurophysiology.
(C) The microbiota-gut-brain axis encompasses different routes of communication that, depending on their location and function, can be hijacked by specific
species of the gut microbiota to influence brain and behavior. Gradients of pH, oxygen, antimicrobial peptides, and bile salts determine the density and diversity of
microbial species along the GI tract. Metabolites produced by the gut microbiota can either activate enteroendocrine cells to release gut hormones or be
absorbed across the epithelial cell layer to either be taken up by the bloodstream or to activate vagus nerve afferents to communicate with the brain. Different
types of vagal afferents can be found within the GI tract that transmits different signals to the brain. Thus, a combination of the location of the microbiota within the
GI tract and the chemicals produced is likely to determine where and how within the NTS the information is relayed, thereby provoking different behavioral
responses.

from a study where anxiety phenotypes
could be transmitted between strains of
animals solely through the transplantation
of the gut microbiota (Bercik et al., 2011).
To date, a variety of preclinical and clinical
studies have linked the gut microbiota
to health and disease. Drastic changes
in the gut microbiota have been observed
in patients with autism spectrum dis-
order, schizophrenia, major depression,
Alzheimer’s disease, Parkinson’s dis-
ease, and multiple sclerosis. Interestingly,
when transferring the gut microbiota of
patients with these diseases to suscepti-
ble germ-free animals, many of the symp-
toms start to emerge which adds a causal
element to the microbiota-gut-brain axis.
Germ-free animals that had received the
gut microbiota of patients with depression
exhibited increased levels of anxiety-
related and depressive-like behavior.
Similarly, germ-free animals receiving
the gut microbiota from patients with Par-
kinson’s disease or multiple sclerosis
developed motor deficits accompanied
by neuroinflammation and autoimmune
encephalomyelitis, respectively. Strik-
ingly, germ-free mice or antibiotic-treated
transgenic mouse models of Alzheimer’s
disease do not develop plaques. Further-
more, preclinical studies demonstrated
beneficial effects of the supplementation
of specific bacterial strains (probiotics)
or so-called prebiotics, which serve as
an energy source for beneficial bacteria,
on anxiety-related, depressive-like as
well as social behavior (Bastiaanssen
et al., 2019).
Mechanisms of Microbiota-Gut-
Brain Signaling
Despite this large body of evidence from
rodent and human studies supporting
the influence of gut microbiota on physi-
ology and psychology, we do not yet fully
understand the mechanisms utilized by
the gut microbiota to impact brain and
behavior.
What we know is that constant commu-
nication within the gut-brain axis regu-
lates specific aspects of homeostasis,
partly through signals coming from the
gut microbiota. This exchange is bidi-
rectional, thus, not only can the gut

Neuron 101, March 20, 2019 999


microbiota influence the host by changing
aspects of homeostasis, but the opposite
is also true.
The gut-brain axis comprises different
routes of communication including endo-
crine, immune, or neural mechanisms,
through which the gut microbiota is
capable of influencing the central nervous
system. The gut microbiota can stimulate
the release of gut peptides and hormones
from enteroendocrine cells which are
taken up by the bloodstream to affect
centrally mediated events. Similarly, it in-
duces cytokine and chemokine release
that locally regulate bacterial concentra-
tions, but these factors can also infiltrate
the blood and lymphatic systems, ulti-
mately allowing them to have direct or in-
direct central effects.
The Vagus Nerve
Although the gut microbiota can commu-
nicate by endocrine and immune path-
ways, perhaps the fastest and most
direct way for the microbiota to influence
the brain is by hijacking vagus nerve
signaling. The vagus nerve, which is the
10th cranial nerve, links the viscera with
the brain. It is a paired nerve that consists
of sensory (afferent) and motor (efferent)
neurons. The vagus nerve tonically trans-
mits information from the viscera to the
brain and vice versa, and as part of the
parasympathetic branch of the autonomic
nervous system is involved in maintaining
corporeal homeostasis. The vagus nerve
has been extensively studied for its
involvement in hunger, satiety, and stress
response but also for its major role in the
regulation of inflammation via neuronal
motor efferents.
Evidence for the involvement of gut
vagal neurons in mental health and
mood-related disorders surfaced as early
as the beginning of the 20th century when
gastrectomy (the partial or complete
removal of the stomach) was applied to
treat peptic ulcers. As a side effect, this
resulted in the ablation of vagus nerve
activity from the stomach downward,
thereby preventing vagal communication
between the lower GI tract and the brain.
Patients that underwent this treatment
demonstrated increased occurrences of
psychiatric-related disorders. These find-
ings are supported by similar animal
studies that ablated gut-related vagal
communication, resulting in changes in
1000 Neuron 101, March 20, 2019
adult neurogenesis, stress reactivity, anx-
iety- and fear-related behavior, as well as
cognition, which are indicative of brain
changes observed in psychiatric disease.
In contrast, vagus nerve stimulation, orig-
inally used for treating refractory epilepsy,
resulted in mood improvement of patients
and is now approved as a method to treat
patients with refractory depression.
Studies have shown that these vagal-
mediated effects are also influenced by
gut bacteria. Specific bacterial strains
have been demonstrated to utilize vagus
nerve signaling to communicate with the
brain and to alter behavior. For example,
administration of a subclinical dose of
the diarrhea-causing pathogen Campylo-
bacter jejuni resulted in increased levels of
anxiety-related behavior and Fos immu-
noreactivity in cell bodies of vagal affer-
ents as well as in the nucleus tractus sol-
itarius (NTS), the main projection side of
gut-related vagal afferents in the brain
(Goehler et al., 2005). In addition, the
beneficial effects of Lactobacillus rham-
nosus JB1 (L. rhamnosus JB1) on anxi-
ety-related and depressive-like behavior
are blocked following vagotomy (Bravo
et al., 2011), as are the cognitive and elec-
trophysiological effects of a prebiotic
which stimulates the production of bene-
ficial bacteria (Vazquez et al., 2016).
L. reuteri, which improves both social
behavior in animal models of autism and
wound healing, both via oxytocin
signaling, has been shown to be depen-
dent on vagus nerve regulated pathways
(Sgritta et al., 2019).
To understand how specific bacteria
within the gut microbiota utilize the vagus
nerve to communicate with the brain, we
need to understand where and how they
can interact with the vagus nerve and
when and how long they activate it to
exert their effects on the brain. Finally,
we need to be able to determine what cir-
cuits are altered in the brain.
Where.
Within the small and large intestine,
vagal afferents end in the muscle layer
as well as in the mucosa. In the muscle
layer, vagal afferents form intraganglionic
laminar endings and intramuscular arrays,
while some vagal endings synapse onto
neurons from the enteric nervous system.
The connection with the enteric nervous
system, which governs the function of
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the GI tract, widens the scope of signals
that can be transmitted by the vagus
nerve. Different types of mucosal endings
have been described in the small intes-
tine: vagal villi and vagal crypt afferents.
Vagal villi afferents, as the name sug-
gests, terminate mostly in the apical part
of the villus in close proximity to the
epithelial layer. Vagal crypt afferent end-
ings, on the other hand, encircle the
luminal end of intestinal crypts. Although
mucosal vagal afferents were thought to
be free neuronal terminals, a recent study
has demonstrated that at least a specific
type of enteroendocrine cells are able to
form glutamatergic synapses with what
are likely to be vagal villus afferents in
the small intestine (Figure 1C). Similar
connections were also observed in the
distal colon between enteroendocrine
cells in the luminal part of the crypt and
vagal afferents (Kaelberer et al., 2018).
While muscular vagal afferents are
implicated in detecting stretch and
tension, mucosal vagal afferents are
perfectly situated to detect chemicals
absorbed across the epithelial layer or
released by epithelial cells in response
to luminal stimuli and to transmit this infor-
mation within seconds. Electrophysiolog-
ical experiments have demonstrated that
vagal afferents respond to a variety of
such stimuli including cytokines, nutri-
ents, gut peptides, and hormones. There-
fore, the gut microbiota can alter vagus
nerve signaling by directly influencing
the concentration or by inducing the
release of either of these factors from en-
teroendocrine or gastrointestinal immune
cells. Furthermore, some bacterial strains
can produce neurotransmitters such as
serotonin that, when absorbed, can act
directly on vagus nerve endings or
indirectly through activation of enteric
neurons.
Information from the vagus nerve is
relayed in the brainstem, where gut vagal
afferents mostly synapse onto neurons in
the NTS. Gastrointestinal vagal afferents
in the NTS are topographically organized,
with vagal afferents from the stomach
projecting to the medial and gelatinous nu-
cleus and afferents from the intestines syn-
apsing onto neurons in the medial and
commissural nucleus. Although glutamate
is the main neurotransmitter, evidence
suggests that in addition to the topo-
logical organization, vagal afferents utilize
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different neurotransmitters depending on
their origin. For example, the neuropep-
tide cocaine and amphetamine-regulated
transcript, which is involved in satiety
signaling, is mainly expressed in afferents
from the proximal GI tract.
Therefore, it is becoming clear that the
location of the microbiota within the GI
tract and the chemicals produced deter-
mine where and how within the NTS the
information is relayed.
When.
When the equilibrium of the gut micro-
biota is altered with the supplementation
of bacterial species, different incubation
times seem to be needed to exert effects
on brain and behavior. Whereas an acute,
subclinical dose of pathogens can result
in brain effects and altered behavior
within hours, effects of probiotic strains
(e.g., L. reuteri and L. rhamnosus) are
usually described after weeks of chronic
treatment. Nevertheless, electrophysio-
logical studies have shown that direct
infusion of L. rhamnosus into the small in-
testine increases the constitutive firing
frequency of vagal afferents within mi-
nutes after luminal application (Perez-
Burgos et al., 2013).
These observations raise the question
of whether bacterial species affecting
the vagus nerve induce neurobiological
changes by simply activating the vagus
nerve or by slowly altering the properties
of vagus nerve signaling and related
neuronal networks, or both. Changes to
excitability, synapse remodeling, or alter-
ation of the sensitivity for certain chemi-
cals in response to microbiota-derived
metabolites could therefore permanently
affect vagus nerve signaling and in turn,
result in changes to the vagal tone. Vagal
tone describes the strength of vagal
(parasympathetic) activation in the dy-
namic interaction between the parasym-
pathetic and sympathetic branches of
the autonomous nervous system. Cardiac
vagal tone, as measured by heart rate
variability, is often used to measure the
strength of parasympathetic activation.
When homeostasis is challenged in such
instances as stress, changes in cardiac
vagal tone can be observed. Interestingly,
patients with Crohn’s disease or irritable
bowel syndrome, two diseases with
malfunctioning gut-brain communication
and altered visceral interoception, also
show alterations in cardiac vagal tone.
Although it is yet to be determined
whether changes in vagal tone in these
instances are cause or consequence,
these observations highlight the link be-
tween gut-related changes and the auto-
nomic nervous system and suggest that
the gut microbiota might be capable of
influencing homeostasis by changing
the properties of vagus nerve signaling
and related neuronal networks (Bonaz
et al., 2016).
What.
Understanding the neural circuitry under-
lying the effects of vagal stimulation on
brain and behavior is a key goal for the
field. Advances in optogenetic and che-
mogenetic tools are transforming how
we delineate the relative contribution of
these pathways to vagus-dependent be-
haviors. However, most of our knowledge
to date has emerged from lesion and
pharmacological studies coupled with
sophisticated anatomical tracing tech-
niques. From the NTS, information is
relayed to various forebrain regions and
other brainstem nuclei, most of which
are also part of the central autonomic
network. Projections from the NTS to the
forebrain that also receive information
from the GI tract have been identified by
tracing studies. These include, among
others, the parabrachial nucleus, locus
coeruleus, hypothalamus, amygdala,
bed nucleus of the stria terminalis, ventral
tegmental area (VTA), and medial septum
which provide the means to influence
emotionality and motivation. In addition,
multi-synaptic projections ascending
from the NTS can transfer information
from the vagus nerve to most likely any
given structure in the brain. Studies iden-
tifying the specific neuronal networks
involved in vagal gut-brain signaling and
their effect on behavior have started to
emerge.
The paraventricular nucleus (PVN) of
the hypothalamus is an important hub
for relay signals emanating from the vagus
nerve. Its projections to the pituitary and
the VTA provide the means to directly in-
fluence the hypothalamic-pituitary-adre-
nal axis and the mesolimbic dopaminergic
system, respectively allowing the vagus
nerve to interact with stress response
and reward circuitries. In addition, opto-
genetic tools have recently been used
to identify the parabrachial nucleus
(PBN) as a relay structure for vagus nerve
signaling-dependent effects on reward
and avoidance behavior. Gut vagal affer-
ents transmit information from the NTS
to the PBN and from there to the substan-
tia nigra (SN) or the central nucleus of the
amygdala (CeA). Activation of the PBN-
SN pathway results in the induction of
reward-related behavior whereas activa-
tion of the PBN-CeA pathway evokes
avoidance behavior (Han et al., 2018). In
addition, a link between the NTS and the
hippocampus via the medial septum has
been demonstrated. This pathway pro-
vides the means by which information
coming from the vagus nerve can impact
hippocampal-dependent memory pro-
cesses. Indeed, it was shown that lesion-
ing of the vagus nerve or subdiaphrag-
matic deafferentation impaired episodic
memory and altered BDNF concentra-
tions in the hippocampus of rats (Suarez
et al., 2018). Furthermore, vagus nerve
stimulation is thought to at least in part
impact depression by acting on noradren-
ergic neurons in the locus coeruleus (LC)
which in turn can impact the serotonergic
system in the dorsal raphe nucleus (DRN).
The NTS-LC-DRN thereby provides
another neuronal pathway that could be
utilized by the gut microbiota to impact
brain and behavior. Finally, integration of
the NTS into the dorsal vagal complex,
which is critical for interoceptive feed-
back, puts the NTS at a perfect relay
hub for vagus nerve signaling to impact
physiology and psychology.
Proof that gut bacteria utilize these
communication pathways has been un-
covered in mouse models. Using opto-
genetic tools, it was demonstrated that
L. reuteri utilizes the NTS-PVN-VTA
pathway to alter social behavior in mouse
models of autism spectrum disorder.
By activating the vagus nerve, L. reuteri
increased oxytocin levels in the PVN
thereby rescuing social interaction-
evoked long-term potentiation in dopami-
nergic neurons in the VTA, which in turn
results in the normalization of social
behavior (Sgritta et al., 2019). In addition,
direct projections from the NTS to the
amygdala are likely to be involved in the
effects of L. rhamnosus on anxiety-related
behavior as administration decreased
GABAAa2 receptor subunit expression
in the amygdala (Bravo et al., 2011).
Neuron 101, March 20, 2019 1001

Furthermore, the effects on BDNF levels
in the hippocampus following the coloni-
zation of germ-free mice with gut bacteria
(Bercik et al., 2011) might be mediated by
the multi-synaptic pathway between the
NTS and the hippocampus as described
above. The same pathway could be
responsible for changes in GABA recep-
tor expression following L. rhamnosus
administration (Bravo et al., 2011). How-
ever, many studies have also shown
that the gut microbiota influences gene
expression in the cortex but the exact
neuronal pathways by which these
changes are mediated have yet to be
determined.
Conclusion
Studies utilizing germ-free rodents or
administration of specific bacterial strains
have provided ample evidence for the role
of the gut microbiota in physiology and
psychology. Although most studies have
focused on a specific behavioral readout
when investigating the effects of single
or multiple bacterial strains on brain and
behavior, the effect of the gut microbiota
is far more extensive when analyzed in
the context of homeostasis. Thus, with
the ability to impact the vagus nerve and
vagus nerve-related functions, the gut mi-
crobiota offers the possibility to employ
the manipulation of the gut microbiota
as a non-invasive treatment option for
various conditions.
However, we are only starting to under-
stand the means by which the microbiota-
gut-brain axis operates. Various factors
determine the means by which a single
bacterial species, or the gut microbiota
as a whole, can impact brain and
behavior, and a number of exiting ques-
tions still need to be addressed. These
1002 Neuron 101, March 20, 2019
include, the details of species and
habitat-specific communication required,
to the identification of the neuronal net-
works within the brain that link the vagus
nerve to a certain behavior.
Finally, it is important to stress that
there has never been a time where
the nervous system has existed without
microbial signals, and thus perhaps it is
not surprising that the vagus is hardwired
to intercept and conduct such signals
to moderate behavior. Although most
studies to date are in rodents, given the
advances in bioelectronics in respect to
vagus nerve stimulation, future studies in
humans investigating the mechanisms of
microbiota-vagus-brain interactions will
emerge. Although much has yet to be
discovered, it is clear that in the context
of microbiota at least what happens
in vagus doesn’t stay in vagus but af-
fects many aspects of emotionality and
neurobiology.
ACKNOWLEDGMENT
We thank Dr. Kiran Sandhu for assistance in pre-
paring the figure. We would like to acknowledge
all the wonderful scientists who we couldn’t refer-
ence due to reference number restrictions. This
work was supported by the Science Foundation
Ireland (SFI) through the Irish Government’s
National Development Plan (Grant Nos. SFI/12/
RC/2273).
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