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November 2017 | Volume 8 | Article 14521
REVIEW
published: 02 November 2017
doi: 10.3389/fimmu.2017.01452
Frontiers in Immunology | www.frontiersin.org
Edited by:
Valentin A. Pavlov,
Northwell Health, United States
Reviewed by:
Benjamin Ethan Steinberg,
University of Toronto, Canada
Colin Reardon,
University of California, Davis,
United States
*Correspondence:
Bruno Bonaz
bbonaz@chu-grenoble.fr
Specialty section:
This article was submitted
to Inflammation,
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Frontiers in Immunology
Received: 09July2017
Accepted: 17October2017
Published: 02November2017
Citation:
BonazB, SinnigerV and PellissierS
(2017) The Vagus Nerve
in the Neuro-Immune Axis:
Implications in the Pathology
of the Gastrointestinal Tract.
Front. Immunol. 8:1452.
doi: 10.3389/fimmu.2017.01452
The Vagus Nerve in the
Neuro-Immune Axis: Implications
in the Pathology of the
Gastrointestinal Tract
Bruno Bonaz1,2*, Valérie Sinniger1,2 and Sonia Pellissier3
1 Division of Hepato-Gastroenterology, Grenoble University Hospital, Grenoble, Alpes, France, 2 U1216, INSERM, GIN, Grenoble
Institute of Neurosciences, University Grenoble Alpes, Grenoble, France, 3 Laboratoire Inter-Universitaire de Psychologie,
Personnalité, Cognition et Changement Social LIP/PC2S-EA4145, University Savoie Mont Blanc, Chambéry, France
The vagus nerve (VN) is the longest nerve of the organism and a major component of
the parasympathetic nervous system which constitutes the autonomic nervous system
(ANS), with the sympathetic nervous system. There is classically an equilibrium between
the sympathetic and parasympathetic nervous systems which is responsible for the
maintenance of homeostasis. An imbalance of the ANS is observed in various pathologic
conditions. The VN, a mixed nerve with 4/5 afferent and 1/5 efferent fibers, is a key com-
ponent of the neuro-immune and brain-gut axes through a bidirectional communication
between the brain and the gastrointestinal (GI) tract. A dual anti-inflammatory role of the
VN is observed using either vagal afferents, targeting the hypothalamic–pituitary–adrenal
axis, or vagal efferents, targeting the cholinergic anti-inflammatory pathway. The sympa-
thetic nervous system and the VN act in synergy, through the splenic nerve, to inhibit the
release of tumor necrosis factor-alpha (TNFα) by macrophages of the peripheral tissues
and the spleen. Because of its anti-inflammatory effect, the VN is a therapeutic target
in the treatment of chronic inflammatory disorders where TNFα is a key component.
In this review, we will focus on the anti-inflammatory role of the VN in inflammatory
bowel diseases (IBD). The anti-inflammatory properties of the VN could be targeted
pharmacologically, with enteral nutrition, by VN stimulation (VNS), with complementary
medicines or by physical exercise. VNS is one of the alternative treatments for drug
resistant epilepsy and depression and one might think that VNS could be used as a non-
drug therapy to treat inflammatory disorders of the GI tract, such as IBD, irritable bowel
syndrome, and postoperative ileus, which are all characterized by a blunted autonomic
balance with a decreased vagal tone.
Keywords: vagus nerve, vagus nerve stimulation, cholinergic anti-inflammatory pathway, neuro-immune axis,
splenic nerve
INTRODUCTION
e vagus nerve (VN), the longest nerve of the organism, makes the link between the central nervous
system and the body by innervating major visceral organs such as the heart, the lungs, and the
gastrointestinal (GI) tract. e VN is a mixed nerve with 20% eerent and 80% aerent bers (1), and
a major component of the parasympathetic nervous system which composes, with the sympathetic
nervous system, the autonomic nervous system (ANS). e sympathetic and parasympathetic nervous
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Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1452
systems are classically balanced for maintaining homeostasis. is
balance of the ANS is disrupted in various pathologies such as
irritable bowel syndrome (IBS), inammatory bowel diseases
(IBD), rheumatoid arthritis (RA), and others, and such an imbal-
ance could also be a predictor of various neuro-immune disorders
(2, 3). In particular, an autonomic dysfunction, as represented
by a low parasympathetic activity, precedes the development of
chronic inammatory disorders such as RA (4). Consequently, an
autonomic dysfunction could be involved in the etiopathogenesis
of inammatory disorders rather than being the consequence of
chronic inammation. e modulation of the ANS, in particular
by targeting the VN, is able to improve various pathological
conditions such as inammatory disorders, including IBD, RA,
obesity, and pain (5). Such a modulation of the VN is possible
through pharmacological manipulation, VN stimulation (VNS),
nutritional therapies, physical exercise, and complementary
medicines. e VN classically does not innervate lymphoid
organs; this role is dedicated to the sympathetic nervous system
(6). However, the VN is involved in the neuro-immune axis both
through its aerent and eerent bers. Indeed, the VN stimulates
the hypothalamic–pituitary–adrenal (HPA) axis through its
aerent bers to release glucocorticoids by the adrenal glands
(7). e VN is also involved in the cholinergic anti-inammatory
pathway (CAP) through a vago-vagal reex involving a brainstem
integrated communication between vagal aerent and eerent
bers i.e., the inammatory reex (8, 9). e sympathetic nerv-
ous system and the VN interact both through a vago-sympathetic
pathway involving vagal aerent bers (10) and a vago-splenic
pathway through vagal eerent bers (11). Consequently, the VN
is at the crossroad of neuro-immune interactions and by stimulat-
ing the VN, it is possible to treat various inammatory disorders
of the organism.
In the present manuscript, we will rst, describe the anatomy
of the VN, second, characterize the interactions of the VN with
the HPA axis and the CAP and the sympathetic nervous system,
third, explore the interest of therapeutic manipulation of the
VN for anti-inammatory properties through pharmacologi-
cal activation, VNS, complementary medicines (acupuncture,
hypnosis, mindfulness), enteral nutrition, physical exercise, and
fourth, focus on the role of VNS in the modulation of inamma-
tory disorder conditions and particularly of the GI tract, such as
IBS, IBD, and postoperative ileus (POI).
ANATOMY OF THE VN
e VN innervates all the GI tract of the rat, except for the
rectum (12). In contrast, in human, the GI tract innervation by
the VN is debated. For some authors, the VN innervates the
digestive tract until the splenic exure of the colon (13) and the
sacral parasympathetic nucleus innervates the rest of the gut
through the pelvic nerves; the densest innervation is provided to
the stomach. However, the VN could innervate all the digestive
tract in human (14). e VN is composed of 80% aerent b-
ers conveying taste, visceral and somatic information and 20%
eerent bers involved in the control of motility and secretion
of the GI as well as cardiac parasympathetic tone (15) and the
CAP (8).
Preganglionic neurons of vagal eerents originate in the dorsal
motor nucleus of the vagus (DMNV), below the nucleus tractus
solitarius (NTS) where vagal aerents project to. A viscerotopic
distribution has been described in the rat DMNV such that lateral
neurons innervate the stomach while medial neurons innervate
the colon (16). Preganglionic neurons are connected with post-
ganglionic neurons of the enteric nervous system in the GI tract.
Acetylcholine (ACh) is the neuromediator released at both ends of
these pre- and post-ganglionic neurons which binds to nicotinic
receptors and nicotinic or muscarinic receptors, respectively. e
VN is not in direct contact with the intestinal lamina propria (16)
but through these enteric neurons (17) which are the eectors of
the VN to regulate gut immunity (18).
Vagal aerent bers originate from the dierent intestinal
layers with their cell bodies located in the nodose ganglia.
ey end in the NTS according to a rostro-caudal viscerotopic
representation (19), and then to the area postrema. e DMNV
forms, with the NTS and area postrema, the dorsal vagal com-
plex of the brainstem, a major reex center of the ANS. Indeed,
the activation of vagal aerents generates several coordinated
responses (autonomic, endocrine, and behavioral) via central
pathways involving the dorsal vagal complex. Viscero-sensory
informations coming from the NTS to the DMNV inuence
vagal eerents at the origin of vago-vagal reexes (20). In
addition, the NTS is a relay for these peripheral informations
to reach numerous brain areas (21) which compose the central
autonomic network (CAN) (22) such as the locus coeruleus
(LC), the parabrachial (PB) nucleus the periventricular nucleus
of the thalamus, the central nucleus of the amygdala, the
paraventricular nucleus of the hypothalamus (PVH), the medial
preoptic area, the arcuate nucleus of the hypothalamus, and the
ventrolateral medulla (A1-C1 catecholaminergic nuclei) at the
origin of an autonomic, behavioral, and endocrine response.
e NTS also directly modulates the LC and its projections (23).
e rostroventrolateral medulla is one of the two major sources
of projections to the LC (24). e latter project to numerous
areas of the cortex involved in stress reactions but also in emo-
tional disorders (25). e PVH projects to the bed nucleus of
the stria terminalis, the dorsomedial and arcuate hypothalamic
nuclei, the medial preoptic area, the periventricular nucleus of
the thalamus, the PB region, and the nucleus tegmenti dorsalis
lateralis (26). e PB nucleus in return projects to the central
nucleus of the amygdala, the bed nucleus of the stria terminalis,
and the PVH (27). e PVH projects directly to the NTS (26),
thus creating a feedback loop with the forebrain. Consequently,
visceral information (e.g., nutrient sensing) driven by the VN is
integrated in the CAN involved in the functioning of the ANS
and the HPA axis response. e VN is involved in the interocep-
tive awareness where the insula cortex plays a central role (28).
A perturbation of this interoception is observed in diseases of
the digestive tract such as IBS but also IBD. Indeed, alexithymia
(29) is observed in both of them (30–32).
THE VN AND THE NEURO-IMMUNE AXIS
e VN is a key component of the neuro-immune axis both
through its aerent and eerent bers. e role of vagal aerents
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was rst described by Harris (7) in the regulation of the HPA
axis. Indeed, peripheral administration of lipopolysaccharides
(LPS), classically used as an experimental model of septic shock,
induces the release of interleukin (IL)-1β, a pro-inammatory
cytokine, and nally activates vagal aerents through IL-1 recep-
tors (33). is eect is prevented by vagotomy (34) and works
in a dose and receptor-dependent fashion (35). Vagal aerents
activate NTS neurons from the A2 noradrenergic group which
project to corticotrophin-releasing factor (CRF) neurons of the
parvo-cellular PVH. CRF then induces the release of adreno-
corticotropic hormone by the pituitary to stimulate the release
of glucocorticoids by the adrenal glands to inhibit peripheral
inammation, i.e., the HPA axis.
In addition to this vagal aerent anti-inammatory pathway,
a second one, described in 2000 by the group of Tracey, involves
vagal eerents (36). is group showed that stimulation of the
distal end of the VN, i.e., vagal eerents, prevented a LPS-septic
shock in rats. VNS had an anti-TNFα eect since liver and blood
tumor necrosis factor-alpha (TNFα) levels were dampened. e
release of pro-inammatory cytokines such as TNFα, IL-1β, IL-6,
and IL-18 in LPS-stimulated human macrophages was decreased
by the release of ACh by the VN. ese authors called this path-
way “e CAP” (8) (Figure1) assimilated to an “inammatory
reex,” i.e., a vago-vagal reex where the activation of vagal aer-
ents by LPS-stimulated vagal eerents aer central integration
in the dorsal vagal complex. is group has also identied the
α7 nicotinic ACh receptors (α7nAChR) of macrophages involved
in this eect (37). de Jonge etal. (38) characterized the cellular
mechanistic of this pathway involving α7 subunit-mediated Jak2-
STAT3 activation of macrophages and Sun etal. (39) showed that
microRNA-124 is responsible of the CAP action by the inhibition
of pro-inammatory cytokines production. e VN is not directly
connected with gut resident macrophages but interacts with
enteric neurons expressing nNOS, VIP, and ChAT and located
within the muscularis next to these macrophages expressing the
α7nAChR (40, 41).
e VN has thus a dual anti-inammatory action both via
its aerent and eerent bers activating the HPA axis and the
CAP, respectively. Another anti-inammatory pathway is the
vago-splenic pathway.
THE VAGO-SPLENIC PATHWAY
e group of Tracey also described a vago-splenic pathway, i.e.,
a vago-sympathetic pathway through the spleen (11). Classically
the parasympathetic (i.e., the VN in the present case) and the
sympathetic nervous systems have an opposite eect. However,
in the vago-splenic pathway, this eect is synergistic through
a connection between the VN and the splenic nerve, a sympa-
thetic nerve issued from the celiac ganglion (42), to activate
the splenic nerve through the eect of ACh on α7nAChR. e
nal eect is the inhibition of TNFα release by the spleen (43).
A non-neuronal cholinergic pathway is involved in this eect by
contrast to the vagal neuronal cholinergic pathway. Indeed, nor-
epinephrine, released by the splenic nerve, binds to β2 receptors
of T-lymphocytes of the spleen which release ACh that links to
α7nAChR of macrophages to inhibit the release of TNFα by these
macrophages (44). ese T-lymphocytes are located in the white
pulp of the spleen, particularly the central region receiving a dense
noradrenergic innervation (45). By comparison to the CAP, there
is an intermediate step with a neuro-immune connection involv-
ing the splenic nerve and T-lymphocytes. However, the existence
of this pathway is still controversial (46) since some authors argue
in favor of a direct sympathetic mechanism (47) (see Figure1).
In contrast, the group of Ghia showed that intracerebroventricular
injection of a M1 muscarinic ACh receptor agonist activated the
CAP; this eect was reversed by vagotomy or splenic neurectomy
(48). e same group showed that administration of galantamine,
a central ACh-esterase inhibitor activated the CAP and this eect
was suppressed by vagotomy, splenic neurectomy, or splenectomy
(49). However, a lack of evidence for cholinergic innervation
of the rat spleen was reported by Bellinger etal. (50). Martelli
etal. (51) argue that the eerent mediator of the CAP is not the
VN but the sympathetic nerve, i.e., the splenic nerve. Indeed,
they showed that vagotomy has no eect on the LPS-induced
TNFα response while both splenic and splanchnic nerves were
LPS-activated and suppressed by splanchnicectomy, increasing
TNFα levels (46). ey evoked a splanchnic anti-inammatory
pathway. In both works of the group of Tracey and Martelli, the
model used to activate the CAP and/or the splanchnic pathway
was a septic shock induced by LPS which is rather dierent than
other inammatory conditions in experimental models of IBD
and RA. However, both the role of a CAP and a splenic anti-
inammatory pathway are not incompatible when considering
a vago-sympathetic pathway involving vagal aerents to the
CAN and then descending pathways from the CAN to activate
sympathetic nerves.
e sympathetic innervation of the spleen modulates the
cellular and humoral immune responses of this lymphoid organ
(52–56). Actually, the noradrenergic bers innervating the
spleen (42, 57) are in close contact with immune cells of the
white pulp expressing adrenergic receptors (58, 59). e splenic
preganglionic neurons located in the thoracic and rostral lumbar
spinal cord (60) are controlled by a specic supra-spinal complex
circuitry involved in the regulation of neural–immune interac-
tions in the spleen. e VN is able to modulate the sympathetic
nervous system aer central integration of its aerents in the
CAN which is then able to modulate the sympathetic nerves,
such as the splenic nerve, through descending pathways from the
CAN, i.e., a vago-sympathetic pathway.
THE VAGO-SYMPATHETIC PATHWAY
As described above, vagal aerents end in the NTS and from
there activate the CAN which in return is able to modulate the
ANS through descending pathways targeting the DMNV and
the tractus intermediolateralis in the spinal cord at the origin of
vagal and sympathetic eerents respectively. Five brain nuclei
of the CAN (i.e., PVH, the A5 noradrenergic group, the caudal
raphe region, the rostral ventrolateral medulla, and the ventro-
medial medulla) modulate the sympathetic outow (61–63) by
innervating preganglionic sympathetic neurons of the interme-
diolateral cell column in the spinal cord. Hence, the VN could
induce a non-direct anti-inammatory reex by enhancing the
FIGURE 1 | Different pathways of the anti-inflammatory properties of the VN: activation of the HPA axis (blue) through vagal afferents, the cholinergic anti-
inflammatory pathway through vago-parasympathetic (red) and sympathetic (purple) reflexes. Targeting the VN for its anti-inflammatory properties (orange) in chronic
inflammatory diseases such as inflammatory bowel disease appears as potentially effective therapeutics. Ach, acetylcholine; CAN, central autonomic network; CCK,
cholecystokinin; DMNV, dorsal motor nucleus of the vagus nerve; EPI, epinephrine; HPA, hypothalamic–pituitary–adrenal; NE, norepinephrine; NTS, nucleus tractus
solitarius; TNFα, tumor necrosis factor-alpha; VN, vagus nerve; α7nAChR, alpha7nicotinic acetylcholine receptor.
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sympathetic outow. Among these brain structures, the role of
the C1 adrenergic group has been recently highlighted by Abe
etal. (64) who showed that these adrenergic neurons are involved
in the stress protective eect in renal ischemia-reperfusion
injury through a sympathetic rather than a vagal pathway. is
group had previously shown that activation of vagal aerents
or eerents in mice 24h before injury markedly reduced acute
kidney inammation and TNFα plasma level. is eect was sup-
pressed by splenectomy and was mediated by α7nAChR-positive
splenocytes (65). e PVH, through its eerent projections to
the DMNV and the spinal sympathetic preganglionic neurons
is also able to modulate the ANS. For example, stress through
CRF of the PVH, is able to inhibit the DMNV, i.e., vagal eerents,
and activate the sympathetic nervous system, i.e., sympathetic
eerents (66). Deng etal. (67) have recently shown that chemical
stimulation of the hypothalamus protects against colitis in rats
through a key role of PVN, NTS and VN. e A5 noradrenergic
nucleus of the ventrolateral pons targets almost exclusively the
spinal intermediolateral column (68) and is involved in the regu-
lation of visceral sympathetic tone in rodents (69). A5 receives
inputs from the C1 neurons (70). e eect of a stimulus on
the activity of sympathetic nerves depends on their type bers
composition (71). e relative importance of each of these ve
regions in the control of the sympathetic outow may dier. For
example, for the spleen, A5>rostroventrolateral medulla>PVH
(71). Aer pseudorabies injection into the spleen, the A5 region
is among the rst areas to become infected. Consequently, this
region is involved in the response of all sympathetic-innervated
organs. A5 neurons must be connected to multiple sympathetic
targets. Additional areas may selectively innervate sympathetic
preganglionic neurons such as (i) the Barrington’s nucleus exclu-
sively involved in the control of the parasympathetic outow,
(ii) the LC involved in stress and contributing to the generalized
sympatho-adrenal activation in response to stressful stimuli,
(iii) the periaqueductal gray, lateral hypothalamus, A7 region,
NTS, Edinger-Westphal nucleus, pedunculopontine tegmental
nucleus, C3 group, caudal ventrolateral medulla, and area pos-
trema (72). Neurons in the rostral ventrolateral medulla increase
their activity in association with increases in sympathetic vaso-
motor reactions (73). All these observations reveal that sympa-
thetic outow is dierentially regulated by supra-spinal areas,
without a clearly identied mechanism. Moreover, some areas
coordinate global visceral responses (74) thus making it dicult
to target specic circuits.
HOW TO TARGET THE VN FOR
ANTI-INFLAMMATORY PROPERTIES
e anti-inammatory properties of the VN could be targeted
pharmacologically, with enteral nutrition, by VNS, with comple-
mentary medicines or by physical exercise.
Pharmacological Stimulation of the CAP
Pharmacological stimulation can be obtained by targeting the
CAP either centrally or peripherally.
Galantamine, a cholinesterase blocker and a nicotinic recep-
tor agonist, including α7nAChR, is able to cross the blood–brain
barrier and activates the central cholinergic pathway thus
stimulating VN eerents (75). is drug is used in the treatment
of Alzheimer’s disease. Galantamine dramatically decreases
circulating TNFα and IL-6 and improves survival in a murine
endotoxemia model (75). us, galantamine could be used as
an immune suppressive drug. To our knowledge, galantamine
has only been used in experimental inammation but not in
clinical research. In the same way, CNI-1493 inhibits the p38
MAPK pathway of the TNFα release (76, 77). Central injection
of CNI-1493 during endotoxemia signicantly reduced serum
TNFα levels and this eect is mediated through the VN (9). In a
clinical trial, Crohn’s disease (CD) patients who were treated with
two doses of CNI-1493 for 2weeks presented a clinical remis-
sion and an endoscopic improvement up to 45% of the patients
included (78).
Peripheral α7nAChR can be targeted by agonists such as
GTS-21 that was used in a double-blind placebo control trial
in experimental human endotoxemia. Healthy volunteers aer
either GTS-21 or placebo received a low dose of LPS. GTS-21-
treated group exhibited lower plasma TNFα, IL-6, and IL-1ra
levels compared to placebo (79). In an experimental pancreatitis
in mice, pretreatment with GTS-21 signicantly decreased pan-
creatitis severity (80). AR-R17779, another α7nAChR agonist,
prevented a mouse model of POI (81).
Nutritional Stimulation of the CAP
In a model of hemorrhagic shock, enteral nutrition with a high-
fat diet induces the release of cholecystokinin (CCK), known
to activate CCK1 receptors of vagal aerents, and dampens the
inammatory response (TNFα, IL-6) through a vago-vagal anti-
inammatory reex (82). In the same study, CCK, vagotomy and
nicotinic receptor antagonists prevented the protective eect of
high-fat enteral nutrition on intestinal permeability (82). Mucosal
mast cells are targets of the nutritional anti-inammatory vagal
reex since mucosal mast cell degranulation was prevented by
lipid-rich enteral feeding (83). Consequently, high-fat enteral
nutrition could be used in the treatment of IBD where TNFα and
intestinal barrier dysfunction are prominent. Enteral feeding,
classically used in the treatment of a are of IBD, has shown its
ecacy to induce clinical remission in CD (84).
Complementary Medicines
Inammatory bowel diseases are chronic debilitating diseases
with an impact on quality of life and treatments are not always
ecient and not devoid of side eects. Consequently, patients
oen use complementary medicines. Recently, Cramer etal. (85)
assessed the ecacy and safety of yoga performed 90min per
week for 12weeks for improving quality of life in UC patients in
clinical remission. By comparison to the written self-care advice
group (controls, n=38), the yoga group (n=39) had signicantly
higher disease-specic quality of life at 12 and 24weeks of follow-
up and disease activity was lower at 24 weeks. Gut-directed
hypnotherapy is well known to improve IBS patients (86). Keefer
etal. (87) performed seven sessions of gut-directed hypnosis in
26 UC patients in clinical remission vs 29 patients with attention
control; the patients were follow-up for 1year. Patients in the
hypnosis group stayed signicantly longer in remission at one
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Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
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year than the control group (68 vs 40%). No signicant eect
has been observed for other psychological factors (quality of life,
medication adherence, perceived stress). One mechanism through
which complementary medicines may improve IBD could be
the activation of the CAP. Acupuncture and meditation reduce
both heart rate and inammatory cytokine release. is eect is
mediated by the increase of vagal tone (88). Acupuncture is able
to decrease TNFα release following LPS administration in mouse
(89). Acupuncture is associated with a down regulation of TNFα
synthesis in the spleen that was reversed by splenic neurectomy
and vagotomy. Hypnosis modies heart rate variability (HRV)
by enhancing parasympathetic activity and reducing sympathetic
tone (90). Yoga (91) and mindfulness meditation (92) increase
vagal activity. Consequently, these complementary medicines
may be of interest in the treatment of IBD patients via the CAP.
VN Stimulation
In 1880s, Corning JL (93) was the rst to use VNS for the treat-
ment of seizures. e technique was then forgotten but reintro-
duced in 1938 by Bailey and Bremer (94). In 1990, the rst VNS
for the treatment of pharmacoresistant epilepsy was introduced
in human (95) and VNS was approved by the US Food and Drug
Administration (FDA) for this indication in 1994 and in 1997
for Europe. In 2005, the FDA approved VNS for the treatment
of pharmacoresistant depression (96, 97). Presently, ~100,000
patients have been treated by VNS for epilepsy and ~5,000 for
depression (Livanova, Houston, TX, USA).
e antiepileptic and antidepressive eects of VNS can be
easily explained by the widespread projections of the VN in the
brain from its rst relay in the NTS. e mechanism of action
of VNS is still not well understood but data argue for a role of
the LC, thalamus, hippocampus, periaqueductal gray, and the
neocortex (98). If the role of vagal aerent C-bers was evoked
in the antiepileptic eect of VNS, their alteration by capsaicin did
not suppress the eect, arguing for a role of vagal A- and B-bers
(99). Five parameters of VNS are classically used: intensity
(0.5–3.5mA), frequency (20–30Hz), pulse width (250–500µs),
and duty cycle of 30 s ON and 5 min OFF. Frequencies of
2–300 Hz induced electroencephalographic desynchronization
of the “encéphale isolé” cat that was dampened by a ligature of
the cervical end of the VN (100) thus in favor for a role of vagal
aerent bers. VNS eectiveness is frequency-dependent (101)
up to the maximum threshold of 50Hz beyond which a damage
of the VN is induced (102). In rats, VNS (stimulation parameters
used for epilepsy) induces neuronal activation in brain area
involved in seizures initiation (103). In human, brain imaging
studies reported modications in regions receiving VN aerent
supra-medullar projections (104). VNS is a slow-acting therapy
since a seizure reduction appears in 50% of patients aer 2years
(105). Elliott etal. (106) showed in 65 epileptic patients with a
10-year mean duration of VNS a time-dependent reduction in
seizures. Indeed, the positive eect of VNS at 6months and 1,
2, 4, 6, 8, and 10years was 35.7, 52.1, 58.3, 60.4, 65.7, 75.5, and
75.5%, respectively.
Vagus nerve stimulation can be applied invasively or non-
invasively through the skin. Invasive VNS is classically performed
under general anesthesia by a neurosurgeon and an electrode
is wrapped around the le cervical VN in the neck connected
subcutaneously by a cable to a pulse generator located in the le
chest wall (107). e implantation lasts ~1h. VNS is classically
performed onto the le VN which innervates the atrioventricular
node of the heart while the right VN innervates the sinoatrial
node thus with a weaker inuence on the heart rate (108). e
VNS device is manufactured by Livanova, a merger of Cyberonics
and Sorin (Houston, TX, USA), and composed of a pair of helical
electrodes (2 or 3mm diameter), a battery-powered generator,
a tunneling tool, soware and programming tools (www.livanova.
com/). e price of the generator pulse (model 102) plus the
electrode (model 302) is ~9,300 €. Safety and tolerability were
demonstrated for implantable VNS (101). e minor adverse
events which are classically reported by the patients are: voice
alteration, cough, dyspnea, paresthesia, nausea, headache and
pain; these adverse events decline over time and are easily con-
trolled by reducing stimulation intensity (109). e battery life
depends on the frequency of stimulation used and is longer for
low frequency (5–10Hz), e.g., ~5–10years, than high frequency
(20–30Hz).
Based on the concept that the CAP involves parasympathetic
outow of the vagal nerve, VNS is performed at the lowest fre-
quencies (1–5–10 Hz) to produce its anti-inammatory eect.
Borovikova etal. (36) performed low frequency (1Hz) VNS in
rats with cervical vagotomy and stimulated the distal end cut
of the VN thus stimulating vagal eerents. Bernik et al. (110),
who performed VNS of the le or right VN in anesthetized rats,
demonstrated that a 20min-stimulation prevented endotoxin-
induced hypotension.
Non-invasive VNS (n-VNS) does not need surgical
implantation and improves the safety and tolerability of VNS.
Transcutaneous auricular VNS (ta-VNS) is one of these tech-
niques. Indeed, the VN includes a sensory “auricular” branch
that innervates exclusively the cymba concha of the external ear
(111) and projects to the NTS in cats (112) and humans (113).
ta-VNS produces the same cognitive and behavioral eects than
VNS (114). When performed at 25Hz in healthy adults, it aects
the vagal central projections, compared to a control stimulation
in the earlobe (113). e close anatomical connection between
auricular concha, VN, NTS, and DMNV can thus explain the
auricular-vagal reex. Consequently, ta-VNS could activate the
anti-inammatory pathway. In agreement with this neuroana-
tomical concept, ta-VNS suppresses LPS-induced inammatory
responses via α7nAChR in rats (115) and this eect was sup-
pressed aer vagotomy or with α7nAChR antagonist injection.
Presently, there are two n-VNS devices that are used for epi-
lepsy, depression, and headache but which could also be used in
inammatory disorders of the GI tract such as IBD, IBS, and POI
as well as others. e Cerbomed device called NEMOS (Erlangen,
Germany) uses an intra-auricular electrode (like an earpiece)
to stimulate the vagal auricular branch (116) and has received
the European clearance in 2011 for the indication epilepsy. is
device is available in Austria, Germany, Italy, Switzerland, and
UK. e optimal stimulation is chosen by the patients based on
the intensity to feel a non-painful stinging with a recommended
stimulation duration of 4 h per day. A 70% reduction seizure
frequency was observed aer 9 months of ta-VNS (116) and
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Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1452
a 43% reduction has been observed aer 8weeks in another study
(117). ta-VNS was shown to increase HRV and reduce sympa-
thetic outow in controls (118). e second device is referred as
GammaCore (electroCore LLC, Basking Ridge, NJ, USA) and
comprises a portable stimulator and two stainless steel round
disks functioning as skin contact surfaces that deliver a locked,
low-voltage electrical signal to the cervical vagal nerve; each
stimulation cycle lasts 120s. An improvement of headache was
reported in 48% of patients (119). In another study, mean pain
scores were signicantly reduced at 2h from baseline in patients
with chronic migraine (120). GammaCore is presently evaluated
in controlled trials in North America and EU in patients with
primary headache disorders. n-VNS with the Gammacore
system decreases whole blood culture-derived cytokines and
chemokines in healthy volunteers (121). No signicant serious
device-related adverse events have been reported with NEMOS
and Gammacore. By comparison to invasive VNS, n-VNS has the
disadvantage of its compliance which is an important problem in
the treatment of chronic inammatory diseases.
Physical Exercise
An imbalance of the ANS, with low vagal and high sympathetic
activities, correlates with numerous pathological conditions such
as arrhythmia, heart failure, and hypertension and ischemia/
reperfusion injury. Cardiovascular morbidity and mortality and
inammation are all decreased by high levels of cardiorespiratory
trainings (122, 123). ere is a negative correlation between car-
diorespiratory tness and cardiovascular events, partly mediated
by inammatory factors (124). e ANS is known to aect the
relation between cardiorespiratory tness and inammation in
middle-aged men. en, physical activity and exercise training
may exert a stimulatory eect on the CAP since RR variability is
inversely related to inammatory markers (125). Regular physi-
cal exercise induces an increase in resting vagal tone (126) and
increases central 5-HT synthesis and central 5-HT increases vagal
modulation in conscious rats (127).
VN IN THE MODULATION OF
INFLAMMATORY DISORDER CONDITIONS
Based on its activation of the HPA axis and the CAP, the VN has
the ability to modulate inammatory conditions. Experimental
and more recently clinical data involving pilot studies are avail-
able for this eect in the domain of IBD, RA, and POI. In the next
lines, we will focus on GI inammatory disorders such as IBD,
IBS, and POI.
Chronic Inflammatory Bowel Disorders
Inammatory bowel diseases are classically represented by CD
and ulcerative colitis (UC). CD involves all the digestive tract
and ano-perineal region while UC involves the recto-colon. IBD
begin between 15 and 30years and are characterized by alterna-
tion of ares and remissions. During ares, patients have several
intestinal and extra-intestinal symptoms such as abdominal pain,
diarrhea, skin, eyes, or joints inammation thus explaining their
signicant impact on the quality of life of IBD patients. Both CD
and UC are heterogeneous in their natural history (128). About
1.5 million Americans and 2.2 million Europeans are aected
by IBD (129) and there is an increase of the incidence and
prevalence of IBD due to the “Westernization” of our lifestyle.
Immunologic, genetic, and environmental factors are involved
in the pathophysiology of IBD (130). Experimental and clinical
data seem to show a role of stress in the pathophysiology of IBD
(131). Classically, stress increases intestinal permeability, modify
intestinal microbiota and immunity which are factors involved
in the pathophysiology of IBD. e VN is involved in the stress
eects on the digestive tract. Indeed, stress classically inhibits the
VN and stimulates the sympathetic nervous system (66). Chronic
stress instead of acute stress is more involved in the pathophysiol-
ogy of IBD as well as others GI disorders such as IBS (132). Stress
induces an imbalanced ANS as reported in IBD with a blunted
sympathetic activity in CD (133) and a vagal dysfunction in UC
(134). We previously reported a relationship, in IBD patients,
between an imbalanced ANS, psychological adjustment (3) and
pro-inammatory proles (135). Presently, standard treatment
of IBD patients is represented by steroids, immunosuppressants
(thiopurines, methotrexate), biologicals (anti-TNFα, anti-adhe-
sion molecule, anti-IL12/23). e therapeutic goal is not just to
relieve IBD-related symptoms but also to favor mucosal healing
because it has been involved in a superior long-term prognosis
including a lower surgical risk, hospitalizations, and need for
systemic steroids (136). Anti-TNFα therapies have changed the
prognostic of IBD but 10%-40% of patients lose response within
12months (137) and a further 10–20% annually thereaer (138).
In addition, these treatments are not devoid of side eects (139)
and adherence to medications is a challenge in IBD patients (140).
Surgery for IBD occurs for 70% of CD patients and 35% of UC
patients (141). Surgical operation is performed in case of failure of
medical treatment or complications and patients are re-operated
because surgery, but also medical treatment, is not curative but
only suspensive. e diagnosis of IBD is oen done late at a time
where lesions are evolved such as stenosis, stula, abscesses in
CD, and more refractory to medical treatment. Consequently,
targeting IBD early when the disease is purely inammatory is
of interest. ese patients have also a risk of recto-colonic cancer
due to chronic inammation and mucosal healing is presently a
gold standard in the treatment of IBD.
Experimental
e VN anti-inammatory activity potentiating the CAP has
been reported in experimental colitis (142, 143), aer vagotomy
(142), VNS (144, 145), and peripheral or central injection of
AChesterase inhibitors (146). Its anti-inammatory role goes
through a macrophage-dependent mechanism involving nicotinic
receptors. However, other counter-inammatory mechanisms
play also a role when vagal integrity is compromised and does
not play its protective role (147).
Classically, low frequency (5–10Hz) VNS is known to stimulate
vagal eerents, i.e., the CAP. However, we have shown in experi-
mental conditions that even at low frequency stimulation vagal
aerents are also activated in anesthetized rats under VNS in an
fMRI study using dynamic causal modeling to estimate neuronal
connectivity (148). We have also reported that long-term low
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Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1452
frequency (10Hz) VNS was able to induce modications of the
electroencephalogram in a CD patient under VNS (149). In fact,
in the neuroanatomic context of the pathways that are involved
in the anti-inammatory role of the VN both stimulation of vagal
aerent and eerent bers is of interest.
Using VNS in a rat model of TNBS colitis classically used for
CD, we have shown that low frequency (5Hz) chronic VNS per-
formed for ve consecutive days with parameters classically used
for epilepsy improved colitis (144). Indeed, a multiparametric
index of colitis taking into account clinical, biological, macro-
scopic and histological damage, as well as pro-inammatory
cytokines, was improved in rats under VNS. We observed that
VNS was more ecient on the area of lesion with less inam-
mation located immediately above the principal inammatory
lesion. In the same experimental colitis model, Sun etal. (145),
have also evaluated the chronic VNS eect but with a higher
frequency stimulation (20 Hz) on colonic inammation using
clinical, histological, and biochemical parameters. ey also
recorded HRV in rats with colitis under VNS. ey observed a
signicant decrease of colitis under VNS and IL-6 and TNF-α
cytokines, and show an improvement of the sympatho-vagal bal-
ance. Ver y recently, in a similar approach, Jin etal(150), using the
same model of TNBS colitis, showed that chronic VNS improved
colonic inammation by inhibiting pro-inammatory cytokines
via the autonomic mechanism; addition of non-invasive elec-
troacupuncture to VNS enhanced the anti-inammatory eect
of VNS.
Clinical
Until recently, only few data were available concerning the
anti-inammatory role of the VN in IBD. However, recording of
vagal tone and the sympatho-vagal balance using HRV, a reliable
non-invasive tool that quanties sympathetic and parasympa-
thetic activities, allows such an approach. e risk for developing
a chronic disease is associated to a dysregulated ANS with a
decreased vagal tone. In the context of brain-viscera interaction,
HRV monitoring is an important tool which allows the sensing
of vagal tone and its impairment and, hence, the CAP deciency.
HRV monitoring is a biomarker which predicts the prognosis of
several chronic inammatory diseases (151). As we know that
a decrease in vagal tone induces a reduction in HRV. We have
shown in IBD patients a correlation between vagal tone and
emotional adjustment (low negative emotions vs high negative
emotions) and the way of how patients coped with their disease.
A positive coping prole was associated with a low vagal tone
in CD and with a high vagal tone in UC (3). Consequently, it
is important to separate IBD patients according to the disease
(CD vs UC) as well as the importance of psychological factors on
vagal tone. In addition, recent data have shown that an autonomic
dysfunction precedes the development of RA (4). We have also
reported that CD patients with a low resting vagal tone presented
higher blood TNFα and salivary cortisol levels than patients with
high vagal tone (135). A low vagal tone is thus associated with a
pro-inammatory state. In addition, based on the fact that stress
inhibits the VN and thus favors a pro-inammatory state, this
may explain, at least in part, that stress could favor a relapse in
IBD patients. In this context, monitoring resting vagal tone over
time could be useful (a) for predicting vulnerable state, (b) for
proposing adapted enforcement therapy such as complementary
medicine, known to stimulate the VN, pharmacological manipu-
lation of the CAP, or VNS to restore a normal vagal tone, and (c)
for a follow-up of the therapy ecacy on the parasympathetic
system.
In a translational approach in CD patients, we have performed
a pilot VNS study where 7 patients with active ileo-colonic CD
where implanted with a VNS device. Only two patients out
of seven were on treatment (Azathioprine) on inclusion. We
have recorded clinical (Crohn’s disease activity index, CDAI),
biological (CRP, fecal calprotectin), endoscopic (Crohn’s disease
endoscopic index of severity, CDEIS) markers of activity dur-
ing a 6 months of follow-up. e rst implanted patient was
on April 2012 and the 7th patient on November 2014. All the
patients entered in a follow-up study. VNS induced deep remis-
sion in ve of the seven patients. Two patients were taken o
the study aer a 3months VNS and switched to iniximab and
azathioprine, one was operated (ileo-cecal resection). ese two
patients had the highest CDAI, CRP and CDEIS on inclusion
which suggests that VNS, as a slow-acting therapy, is more
indicated in moderate CD. All the patients have kept the device
in place with the duty cycle still running, except one of the two
patients removed from the study who have a low intensity of
stimulation (0.5mA). VNS was well tolerated with the classical
minor side eect represented essentially by hoarseness. We did
not have any problem of infection either local or systemic and
no VNS device was removed. e data on the rst seven patients
aer a 6-month follow-up were reported for the rst time
recently (152). VNS could also be used to maintain remission
induced by drugs. Surgery is used to cure CD lesions and VNS
as a slow-acting therapy could be an interesting tool to prevent
postoperative recurrence of CD.
Irritable Bowel Syndrome
Abdominal pain, bloating and altered bowel habits without
any organic cause with a higher prevalence in women (153) are
the main characteristics of IBS. IBS prevalence goes from 10
to 15% in industrialized countries (154) and represents up to
12% primary care doctors and 28% gastroenterologist medi-
cal visits (155). Signicant impairment in quality of life, time
o work, and signicant increase in health care costs are the
principal consequences of IBS. Extra-intestinal manifestations
such as headache, arthralgia, urinary problems, insomnia, and
fatigue are classically reported by the patients in association
with digestive symptoms. Fibromyalgia, frequently associated
with IBS, worsens digestive symptoms (156). Psychological
factors as anxiety or major depression, are oen observed in
IBS patients (up to 50%) (157). Stress has a major role in the
pathophysiology of IBS (132). In particular, early life trauma
such as a history of emotional, sexual, or physical abuse is
reported in 30–50% of patients (158) and symptoms are oen
triggered by stress. Intestinal distension–induced visceral
hypersensitivity and characterized by lower pain thresholds
is oen observed in IBS patients and is a classical marker of
the disease (159). Mechanisms of this visceral hypersensitivity
seem to be explained by a low-grade inammation in the GI
9
Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1452
tract (that could favor modications of neuronal plasticity)
(160) and by a mast cells sensitization of intestinal aerent ter-
minals (161). Bacterial gastroenteritis is associated with 4–30%
of post-infectious IBS (162). However, anxiety, high levels of
perceived stress, somatization and negative illness beliefs at
the time of infection were also predictors of post-infectious
IBS (163), arguing for a cognitive-behavioral model of IBS. IBS
has been compared to an IBD “a minima” since an increased
number of gut mucosal T-lymphocytes and mast cells as well as
an increased of blood level pro-inammatory cytokines (IL-10
and IL-12, suggesting 1 polarization) have been described
(164). Globally, IBS is described as a biopsychosocial model due
to a blunted brain–gut axis consistent with an up-regulation in
neural processing between gut and brain. Patients are hypervigi-
lant toward their symptoms explaining visceral hypersensitivity.
Central sensory processes are modied in IBS patients (165) and
this is assimilated to a central sensitization syndrome (166, 167).
Dysautonomia, a marker of brain-gut dysfunction, has been
described with a high sympathetic and a low parasympathetic
tone, irrespective to the positive or negative aective adjust-
ment (3). Because of the multifactorial pathophysiology of IBS,
its medical treatment is disappointing and essentially based to
alleviate symptoms. Psychotherapy, like cognitive-behavioral
therapy and complementary medicine like hypnosis, are known
to improve vagal tone (90, 168, 169), and could be of interest in
the treatment of IBS symptoms.
From a pathophysiological point of view, targeting both the
GI tract and the central nervous system through the VN is of
interest in IBS. Based on its peripheral anti-inammatory action
through the CAP and on its central eect, as antidepressive, VNS
would be of major interest in IBS treatment. In addition, the VN
is involved in the control of pain and VNS has been shown to
modify central pain processing. Indeed, in visceral pain models
in rats, VNS has been shown to increase the pain threshold (170)
and to modulate visceral pain-related aective memory (171).
Modication of pain by VNS has also been reported in epileptic
patients certainly by modulating peripheral nociceptor function
(172). Deep breathing increases cardiac vagal tone and prevents
the development of acid-induced esophageal hypersensitivity in
healthy volunteers; this eect was abolished by atropine (173).
Somatic pain thresholds are increased in healthy volunteers
with ta-VNS (174). VNS activates vagal aerents that project to
brain nuclei involved in the descending inhibitory modulation
of pain (175).
Presently, there is no published data on the treatment of IBS
by VNS although two studies using n-VNS are registered in
ClinicalTrial.gov. e rst study has been set up by ElectroCore
LLC, with a new n-device called GammaCore. is randomized,
single center, double-blind, parallel, sham-controlled pilot study
relates on the treatment of symptoms caused by functional
dyspepsia or IBS (ClinicalTrials.gov Identier: NCT02388269).
Although completed, no results have been still posted. e
second study, still recruiting, evaluates the eect of a 6-month
transcutaneous VNS on intestinal and systemic inammation,
intestinal transit time mucosal permeability, and quality of life
in IBS patients (ClinicalTrials.gov Identier: NCT02420158). Ten
IBS women, aged between 18 and 60years, will be included.
Postoperative Ileus
Abdominal surgery induces POI whatever the localization of
surgery site. POI is dened by a delayed gastric emptying and a
prolonged intestinal transit (176). Stomach and small intestine
functions turn back to normality within 24–48h while the colon
takes generally more time (up to 72h). e recovery of GI motility
can take longer hospitalization times and thus higher healthcare
costs. e cost of this postoperative complication has been esti-
mated at US$1 billion/year in the US (176). Sympatho-adrenergic
and vagal nonadrenergic noncholinergic inhibitory eerent path-
ways play a role in the POI mechanisms while capsaicin-sensitive
neurons are implicated in the aerent pathway of the reex
(177). Supra-spinal brain nuclei have also been implicated in
POI, in particular, specic hypothalamic and pontine-medullary
neurons involved in the autonomic regulation of GI function
(178). A role for CRF in the PVH is evoked since CRF is a key
mediator in the stress eect on the GI tract. Indeed, stress is
well known to inhibit gastric emptying (179) as shown by the
intracerebroventricular injection of a-helical CRF-(9–41), a CRF
antagonist, which reduces the delay of gastric emptying under
stress conditions (180). is eect is CRF1 receptor-dependent.
More recently, a peripheral pathway, involving the CAP, has been
described in the mechanism of POI. Indeed, abdominal surgery
induces inammation of the muscularis propria (181) and acti-
vation of resident macrophages which release TNFα. Depletion
and inactivation of the muscularis macrophage network prevents
POI. Systemic administration of selective nACh agonists as well
as VNS reduces the inammatory response to manipulation of
the intestine during surgery (81). is anti-inammatory eect,
mediated by a reduction in macrophage activation and cytokine
production is driven by the CAP (48). Gum chewing reduces POI
by stimulating vagal activity (182). Targeting the CAP could thus
improve POI by its anti-inammatory action and VNS could
therefore be a potential treatment to prevent POI.
In a mouse model of intestinal manipulation, de Jonge etal.
(38) have shown that 5min of cervical VNS prior to abdominal
surgery improved GI transit through alpha7 subunit-mediated
Jak2-STAT3 activation in intestinal macrophages, indicating that
VNS may represent a new therapeutic approach to shorten POI.
Stakenborg et al. (183) have recently explored the therapeutic
potential of VNS in patients undergoing abdominal surgery for
colo-rectal cancer, randomized to sham stimulation (n=5), 5Hz
stimulation (n=6), or 20 Hz stimulation (n=7) group. ey
performed 1ms and 2.5mA during 2min of VNS at the begin-
ning and at the end of the surgery. ey showed that abdominal
VNS signicantly reduced LPS-induced IL8 and IL6 production
by whole blood in patients. In the same study, they showed that
abdominal VNS was as potent as that of cervical VNS in a murine
model of POI.
CONCLUSION
rough the HPA axis and the CAP, the VN exerts an anti-
inammatory action. ere is also an anti-inammatory vago-
sympathetic pathway where the VN and the sympathetic system
(i.e., the splenic nerve) act synergistically. is anti-inammatory
eect involves both vagal aerent and eerent bers. Targeting the
10
Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1452
VN opens new therapeutic avenues in GI inammatory diseases
such as IBD, POI, IBS, and other TNFα-mediated diseases such
as RA or psoriasis. Among these therapeutic approaches, VNS,
either invasive or non-invasive, appears as an interesting tool
with no major side eects in the era of Bioelectronic Medicine
(184). Patients with chronic diseases are open to such a non-drug
therapy because they are more and more reluctant to conventional
therapies in particular because of their side eects and the need of
chronic use of these treatments.
AUTHOR CONTRIBUTIONS
BB wrote the rst dra of the manuscript and VS and SP provided
critical feedback to improve it.
FUNDING
Supported by INSERM and DGOS (“Appel à Projet Translationnel
2011”) and the DRCI from the Grenoble Hospital, France.
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