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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 component 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 sympathetic 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.
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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,
a section of the journal
Frontiers in Immunology
Received: 09July2017
Accepted: 17October2017
Published: 02November2017
Citation:
BonazB, SinnigerV and PellissierS
(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% eerent and 80% aerent 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), inammatory 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 inammatory disorders such as RA (4). Consequently, an
autonomic dysfunction could be involved in the etiopathogenesis
of inammatory disorders rather than being the consequence of
chronic inammation. e modulation of the ANS, in particular
by targeting the VN, is able to improve various pathological
conditions such as inammatory 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 aerent and eerent bers. Indeed, the VN stimulates
the hypothalamic–pituitary–adrenal (HPA) axis through its
aerent bers to release glucocorticoids by the adrenal glands
(7). e VN is also involved in the cholinergic anti-inammatory
pathway (CAP) through a vago-vagal reex involving a brainstem
integrated communication between vagal aerent and eerent
bers i.e., the inammatory reex (8, 9). e sympathetic nerv-
ous system and the VN interact both through a vago-sympathetic
pathway involving vagal aerent bers (10) and a vago-splenic
pathway through vagal eerent 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 inammatory 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-inammatory 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 inamma-
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% aerent b-
ers conveying taste, visceral and somatic information and 20%
eerent 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 eerents originate in the dorsal
motor nucleus of the vagus (DMNV), below the nucleus tractus
solitarius (NTS) where vagal aerents 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 eectors of
the VN to regulate gut immunity (18).
Vagal aerent bers originate from the dierent 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 reex center of the ANS. Indeed,
the activation of vagal aerents 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 inuence
vagal eerents at the origin of vago-vagal reexes (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 (3032).
THE VN AND THE NEURO-IMMUNE AXIS
e VN is a key component of the neuro-immune axis both
through its aerent and eerent bers. e role of vagal aerents
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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-inammatory
cytokine, and nally activates vagal aerents through IL-1 recep-
tors (33). is eect is prevented by vagotomy (34) and works
in a dose and receptor-dependent fashion (35). Vagal aerents
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
inammation, i.e., the HPA axis.
In addition to this vagal aerent anti-inammatory pathway,
a second one, described in 2000 by the group of Tracey, involves
vagal eerents (36). is group showed that stimulation of the
distal end of the VN, i.e., vagal eerents, prevented a LPS-septic
shock in rats. VNS had an anti-TNFα eect since liver and blood
tumor necrosis factor-alpha (TNFα) levels were dampened. e
release of pro-inammatory 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) (Figure1) assimilated to an “inammatory
reex,” i.e., a vago-vagal reex where the activation of vagal aer-
ents by LPS-stimulated vagal eerents aer central integration
in the dorsal vagal complex. is group has also identied the
α7 nicotinic ACh receptors (α7nAChR) of macrophages involved
in this eect (37). de Jonge etal. (38) characterized the cellular
mechanistic of this pathway involving α7 subunit-mediated Jak2-
STAT3 activation of macrophages and Sun etal. (39) showed that
microRNA-124 is responsible of the CAP action by the inhibition
of pro-inammatory 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-inammatory action both via
its aerent and eerent bers activating the HPA axis and the
CAP, respectively. Another anti-inammatory 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 eect. However,
in the vago-splenic pathway, this eect 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 eect of ACh on α7nAChR. e
nal eect is the inhibition of TNFα release by the spleen (43).
A non-neuronal cholinergic pathway is involved in this eect 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 Figure1).
In contrast, the group of Ghia showed that intracerebroventricular
injection of a M1 muscarinic ACh receptor agonist activated the
CAP; this eect 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 eect
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 etal. (50). Martelli
etal. (51) argue that the eerent mediator of the CAP is not the
VN but the sympathetic nerve, i.e., the splenic nerve. Indeed,
they showed that vagotomy has no eect 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-inammatory
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 dierent than
other inammatory conditions in experimental models of IBD
and RA. However, both the role of a CAP and a splenic anti-
inammatory pathway are not incompatible when considering
a vago-sympathetic pathway involving vagal aerents 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
(5256). 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 specic 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 aer central integration of its aerents 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 aerents 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 eerents 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 outow (6163) by
innervating preganglionic sympathetic neurons of the interme-
diolateral cell column in the spinal cord. Hence, the VN could
induce a non-direct anti-inammatory reex 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 outow. Among these brain structures, the role of
the C1 adrenergic group has been recently highlighted by Abe
etal. (64) who showed that these adrenergic neurons are involved
in the stress protective eect in renal ischemia-reperfusion
injury through a sympathetic rather than a vagal pathway. is
group had previously shown that activation of vagal aerents
or eerents in mice 24h before injury markedly reduced acute
kidney inammation and TNFα plasma level. is eect was sup-
pressed by splenectomy and was mediated by α7nAChR-positive
splenocytes (65). e PVH, through its eerent 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 eerents,
and activate the sympathetic nervous system, i.e., sympathetic
eerents (66). Deng etal. (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 eect 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 outow may dier. For
example, for the spleen, A5>rostroventrolateral medulla>PVH
(71). Aer 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 Barringtons nucleus exclu-
sively involved in the control of the parasympathetic outow,
(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 outow is dierentially regulated by supra-spinal areas,
without a clearly identied mechanism. Moreover, some areas
coordinate global visceral responses (74) thus making it dicult
to target specic circuits.
HOW TO TARGET THE VN FOR
ANTI-INFLAMMATORY PROPERTIES
e anti-inammatory 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 eerents (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 inammation 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 signicantly reduced serum
TNFα levels and this eect is mediated through the VN (9). In a
clinical trial, Crohns disease (CD) patients who were treated with
two doses of CNI-1493 for 2weeks 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 aer
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 signicantly 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 aerents, and dampens the
inammatory response (TNFα, IL-6) through a vago-vagal anti-
inammatory reex (82). In the same study, CCK, vagotomy and
nicotinic receptor antagonists prevented the protective eect of
high-fat enteral nutrition on intestinal permeability (82). Mucosal
mast cells are targets of the nutritional anti-inammatory vagal
reex 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
ecacy to induce clinical remission in CD (84).
Complementary Medicines
Inammatory bowel diseases are chronic debilitating diseases
with an impact on quality of life and treatments are not always
ecient and not devoid of side eects. Consequently, patients
oen use complementary medicines. Recently, Cramer etal. (85)
assessed the ecacy and safety of yoga performed 90min per
week for 12weeks 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 signicantly
higher disease-specic quality of life at 12 and 24weeks of follow-
up and disease activity was lower at 24 weeks. Gut-directed
hypnotherapy is well known to improve IBS patients (86). Keefer
etal. (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 1year. Patients in the
hypnosis group stayed signicantly 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 signicant eect
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 inammatory cytokine release. is eect 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 modies 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 eects 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 aerent C-bers was evoked
in the antiepileptic eect of VNS, their alteration by capsaicin did
not suppress the eect, arguing for a role of vagal A- and B-bers
(99). Five parameters of VNS are classically used: intensity
(0.5–3.5mA), frequency (20–30Hz), pulse width (250–500µs),
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
aerent bers. VNS eectiveness is frequency-dependent (101)
up to the maximum threshold of 50Hz 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 modications in regions receiving VN aerent
supra-medullar projections (104). VNS is a slow-acting therapy
since a seizure reduction appears in 50% of patients aer 2years
(105). Elliott etal. (106) showed in 65 epileptic patients with a
10-year mean duration of VNS a time-dependent reduction in
seizures. Indeed, the positive eect of VNS at 6months and 1,
2, 4, 6, 8, and 10years 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 ~1h. 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 inuence 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 3mm diameter), a battery-powered generator,
a tunneling tool, soware 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 (5–10Hz), e.g., ~5–10years, than high frequency
(20–30Hz).
Based on the concept that the CAP involves parasympathetic
outow of the vagal nerve, VNS is performed at the lowest fre-
quencies (1–5–10 Hz) to produce its anti-inammatory eect.
Borovikova etal. (36) performed low frequency (1Hz) VNS in
rats with cervical vagotomy and stimulated the distal end cut
of the VN thus stimulating vagal eerents. Bernik et al. (110),
who performed VNS of the le or right VN in anesthetized rats,
demonstrated that a 20min-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 eects than
VNS (114). When performed at 25Hz in healthy adults, it aects
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 reex. Consequently, ta-VNS could activate the
anti-inammatory pathway. In agreement with this neuroana-
tomical concept, ta-VNS suppresses LPS-induced inammatory
responses via α7nAChR in rats (115) and this eect was sup-
pressed aer 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
inammatory 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 aer 9 months of ta-VNS (116) and
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a 43% reduction has been observed aer 8weeks in another study
(117). ta-VNS was shown to increase HRV and reduce sympa-
thetic outow 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 120s. An improvement of headache was
reported in 48% of patients (119). In another study, mean pain
scores were signicantly reduced at 2h 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 signicant 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 inammatory 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
inammation 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 inammatory factors (124). e ANS is known to aect the
relation between cardiorespiratory tness and inammation in
middle-aged men. en, physical activity and exercise training
may exert a stimulatory eect on the CAP since RR variability is
inversely related to inammatory 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 inammatory conditions. Experimental
and more recently clinical data involving pilot studies are avail-
able for this eect in the domain of IBD, RA, and POI. In the next
lines, we will focus on GI inammatory disorders such as IBD,
IBS, and POI.
Chronic Inflammatory Bowel Disorders
Inammatory 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 30years 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 inammation thus explaining their
signicant 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 aected
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
eects 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-inammatory proles (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
12months (137) and a further 10–20% annually thereaer (138).
In addition, these treatments are not devoid of side eects (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 oen 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 inammatory is
of interest. ese patients have also a risk of recto-colonic cancer
due to chronic inammation and mucosal healing is presently a
gold standard in the treatment of IBD.
Experimental
e VN anti-inammatory activity potentiating the CAP has
been reported in experimental colitis (142, 143), aer vagotomy
(142), VNS (144, 145), and peripheral or central injection of
AChesterase inhibitors (146). Its anti-inammatory role goes
through a macrophage-dependent mechanism involving nicotinic
receptors. However, other counter-inammatory mechanisms
play also a role when vagal integrity is compromised and does
not play its protective role (147).
Classically, low frequency (5–10Hz) VNS is known to stimulate
vagal eerents, i.e., the CAP. However, we have shown in experi-
mental conditions that even at low frequency stimulation vagal
aerents 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
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frequency (10Hz) VNS was able to induce modications 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-inammatory role of the VN both stimulation of vagal
aerent and eerent bers is of interest.
Using VNS in a rat model of TNBS colitis classically used for
CD, we have shown that low frequency (5Hz) 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-inammatory
cytokines, was improved in rats under VNS. We observed that
VNS was more ecient on the area of lesion with less inam-
mation located immediately above the principal inammatory
lesion. In the same experimental colitis model, Sun etal. (145),
have also evaluated the chronic VNS eect but with a higher
frequency stimulation (20 Hz) on colonic inammation using
clinical, histological, and biochemical parameters. ey also
recorded HRV in rats with colitis under VNS. ey observed a
signicant 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 etal(150), using the
same model of TNBS colitis, showed that chronic VNS improved
colonic inammation by inhibiting pro-inammatory cytokines
via the autonomic mechanism; addition of non-invasive elec-
troacupuncture to VNS enhanced the anti-inammatory eect
of VNS.
Clinical
Until recently, only few data were available concerning the
anti-inammatory role of the VN in IBD. However, recording of
vagal tone and the sympatho-vagal balance using HRV, a reliable
non-invasive tool that quanties 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 deciency.
HRV monitoring is a biomarker which predicts the prognosis of
several chronic inammatory 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 prole 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-inammatory state. In addition, based on the fact that stress
inhibits the VN and thus favors a pro-inammatory 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 ecacy 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 aer a 3months VNS and switched to iniximab 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 (0.5mA). VNS was well tolerated with the classical
minor side eect 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
aer 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). Signicant impairment in quality of life, time
o work, and signicant 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 oen 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 oen
triggered by stress. Intestinal distension–induced visceral
hypersensitivity and characterized by lower pain thresholds
is oen 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 inammation in the GI
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Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
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tract (that could favor modications of neuronal plasticity)
(160) and by a mast cells sensitization of intestinal aerent 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-inammatory 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 modied 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 aective 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-inammatory action
through the CAP and on its central eect, 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 aective memory (171).
Modication 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 eect was abolished by atropine (173).
Somatic pain thresholds are increased in healthy volunteers
with ta-VNS (174). VNS activates vagal aerents 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 Identier: NCT02388269).
Although completed, no results have been still posted. e
second study, still recruiting, evaluates the eect of a 6-month
transcutaneous VNS on intestinal and systemic inammation,
intestinal transit time mucosal permeability, and quality of life
in IBS patients (ClinicalTrials.gov Identier: NCT02420158). Ten
IBS women, aged between 18 and 60years, will be included.
Postoperative Ileus
Abdominal surgery induces POI whatever the localization of
surgery site. POI is dened by a delayed gastric emptying and a
prolonged intestinal transit (176). Stomach and small intestine
functions turn back to normality within 24–48h while the colon
takes generally more time (up to 72h). 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 eerent path-
ways play a role in the POI mechanisms while capsaicin-sensitive
neurons are implicated in the aerent pathway of the reex
(177). Supra-spinal brain nuclei have also been implicated in
POI, in particular, specic 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 eect 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 eect is CRF1 receptor-dependent.
More recently, a peripheral pathway, involving the CAP, has been
described in the mechanism of POI. Indeed, abdominal surgery
induces inammation 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 inammatory response to manipulation of
the intestine during surgery (81). is anti-inammatory eect,
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-inammatory action and VNS could
therefore be a potential treatment to prevent POI.
In a mouse model of intestinal manipulation, de Jonge etal.
(38) have shown that 5min 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), 5Hz
stimulation (n=6), or 20 Hz stimulation (n=7) group. ey
performed 1ms and 2.5mA during 2min of VNS at the begin-
ning and at the end of the surgery. ey showed that abdominal
VNS signicantly 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-
inammatory action. ere is also an anti-inammatory vago-
sympathetic pathway where the VN and the sympathetic system
(i.e., the splenic nerve) act synergistically. is anti-inammatory
eect involves both vagal aerent and eerent 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 inammatory 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 eects 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 eects 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.
REFERENCES
1. Prechtl JC, Powley TL. e ber composition of the abdominal vagus of the
rat. Anat Embryol (Berl) (1990) 181(2):101–15. doi:10.1007/BF00198950
2. Adlan AM, Lip GY, Paton JF, Kitas GD, Fisher JP. Autonomic function and
rheumatoid arthritis: a systematic review. Semin Arthritis Rheum (2014)
44(3):283–304. doi:10.1016/j.semarthrit.2014.06.003
3. Pellissier S, Dantzer C, Canini F, Mathieu N, Bonaz B. Psychological adjust-
ment and autonomic disturbances in inammatory bowel diseases and
irritable bowel syndrome. Psychoneuroendocrinology (2010) 35(5):653–62.
doi:10.1016/j.psyneuen.2009.10.004
4. Koopman FA, Tang MW, Vermeij J, de Hair MJ, Choi IY, Vervoordeldonk MJ,
etal. Autonomic dysfunction precedes development of rheumatoid arthritis:
a prospective cohort study. EBioMedicine (2016) 6:231–7. doi:10.1016/j.
ebiom.2016.02.029
5. Bonaz B, Sinniger V, Pellissier S. Anti-inammatory properties of the vagus
nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol
(2016) 594:5781–90. doi:10.1113/JP271539
6. Bellinger DL, Millar BA, Perez S, Carter J, Wood C, yagaRajan S, et al.
Sympathetic modulation of immunity: relevance to disease. Cell Immunol
(2008) 252(1–2):27–56. doi:10.1016/j.cellimm.2007.09.005
7. Harris GW. e hypothalamus and endocrine glands. Br Med Bull (1950)
6(4):345–50. doi:10.1093/oxfordjournals.bmb.a073628
8. Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. e cholinergic
anti-inammatory pathway: a missing link in neuroimmunomodulation.
Mol Med (2003) 9(5–8):125–34.
9. Tracey KJ. e inammatory reex. Nature (2002) 420(6917):853–9.
doi:10.1038/nature01321
10. Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: a new promis-
ing therapeutic tool in inammatory bowel disease. J Intern Med (2017)
282(1):46–63. doi:10.1111/joim.12611
11. Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM,
et al. Splenic nerve is required for cholinergic antiinammatory pathway
control of TNF in endotoxemia. Proc Natl Acad Sci U S A (2008) 105(31):
11008–13. doi:10.1073/pnas.0803237105
12. Altschuler SM, Escardo J, Lynn RB, Miselis RR. e central organization of
the vagus nerve innervating the colon of the rat. Gastroenterology (1993)
104(2):502–9. doi:10.1016/0016-5085(93)90419-D
13. Netter FH. Atlas of Human Anatomy. Ardsley, USA: Ciba-Geigy Corporation
(1989).
14. Delmas J, Laux G. Anatomie Médico-Chirurgicale du Système Nerveux Végétatif:
(Sympathique & Parasympathique). Paris: Masson (1933).
15. Crick SJ, Wharton J, Sheppard MN, Royston D, Yacoub MH, Anderson RH,
et al. Innervation of the human cardiac conduction system. A quantitative
immunohistochemical and histochemical study. Circulation (1994) 89(4):
1697–708. doi:10.1161/01.CIR.89.4.1697
16. Berthoud HR, Carlson NR, Powley TL. Topography of eerent vagal innerva-
tion of the rat gastrointestinal tract. Am J Physiol (1991) 260(1 Pt 2):R200–7.
17. Sharkey KA, Kroese AB. Consequences of intestinal inammation on the
enteric nervous system: neuronal activation induced by inammatory medi-
ators. Anat Rec (2001) 262(1):79–90. doi:10.1002/1097-0185(20010101)262:
1<79::AID-AR1013>3.0.CO;2-K
18. Margolis KG, Stevanovic K, Karamooz N, Li ZS, Ahuja A, D’Autreaux F, etal.
Enteric neuronal density contributes to the severity of intestinal inammation.
Gastroenterology (2011) 141(2):588–98.e2. doi:10.1053/j.gastro.2011.04.047
19. Altschuler SM, Bao XM, Bieger D, Hopkins DA, Miselis RR. Viscerotopic
representation of the upper alimentary tract in the rat: sensory ganglia and
nuclei of the solitary and spinal trigeminal tracts. J Comp Neurol (1989)
283(2):248–68. doi:10.1002/cne.902830207
20. Rinaman L, Card JP, Schwaber JS, Miselis RR. Ultrastructural demonstration
of a gastric monosynaptic vagal circuit in the nucleus of the solitary tract in
rat. J Neurosci (1989) 9(6):1985–96.
21. Sawchenko PE. Central connections of the sensory and motor nuclei of the vagus
nerve. J Auton Nerv Syst (1983) 9(1):13–26. doi:10.1016/0165-1838(83)90129-7
22. Benarroch EE. e central autonomic network: functional organization,
dysfunction, and perspective. Mayo Clin Proc (1993) 68(10):988–1001.
doi:10.1016/S0025-6196(12)62272-1
23. Van Bockstaele EJ, Peoples J, Telegan P. Eerent projections of the nucleus of
the solitary tract to peri-locus coeruleus dendrites in rat brain: evidence for
a monosynaptic pathway. J Comp Neurol (1999) 412(3):410–28. doi:10.1002/
(SICI)1096-9861(19990927)412:3<410::AID-CNE3>3.0.CO;2-F
24. Aston-Jones G, Ennis M, Pieribone VA, Nickell WT, Shipley MT. e brain
nucleus locus coeruleus: restricted aerent control of a broad eerent network.
Science (1986) 234(4777):734–7. doi:10.1126/science.3775363
25. Zagon A. Does the vagus nerve mediate the sixth sense? Trends Neurosci
(2001) 24(11):671–3. doi:10.1016/S0166-2236(00)01929-9
26. Conrad LC, Pfa DW. Eerents from medial basal forebrain and hypothala-
mus in the rat. II. An autoradiographic study of the anterior hypothalamus.
J Comp Neurol (1976) 169(2):221–61. doi:10.1002/cne.901690206
27. Norgren R. Taste pathways to hypothalamus and amygdala. J Comp Neurol
(1976) 166(1):17–30. doi:10.1002/cne.901660103
28. Craig AD. How do you feel? Interoception: the sense of the physiological
condition of the body. Nat Rev Neurosci (2002) 3(8):655–66. doi:10.1038/
nrn894
29. Sifneos PE. e prevalence of ‘alexithymic’ characteristics in psychoso-
matic patients. Psychother Psychosom (1973) 22(2):255–62. doi:10.1159/
000286529
30. La Barbera D, Bonanno B, Rumeo MV, Alabastro V, Frenda M, Massihnia E,
etal. Alexithymia and personality traits of patients with inammatory bowel
disease. Sci Rep (2017) 7:41786. doi:10.1038/srep41786
31. Muscatello MR, Bruno A, Mento C, Pandolfo G, Zoccali RA. Personality traits
and emotional patterns in irritable bowel syndrome. World J Gastroenterol
(2016) 22(28):6402–15. doi:10.3748/wjg.v22.i28.6402
32. Jordan C, Sin J, Fear NT, Chalder T. A systematic review of the psychological
correlates of adjustment outcomes in adults with inammatory bowel disease.
Clin Psychol Rev (2016) 47:28–40. doi:10.1016/j.cpr.2016.06.001
33. Goehler LE, Relton JK, Dripps D, Kiechle R, Tartaglia N, Maier SF, etal. Vagal
paraganglia bind biotinylated interleukin-1 receptor antagonist: a possible
mechanism for immune-to-brain communication. Brain Res Bull (1997)
43(3):357–64. doi:10.1016/S0361-9230(97)00020-8
34. Watkins LR, Goehler LE, Relton JK, Tartaglia N, Silbert L, Martin D, etal.
Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic
vagotomy: evidence for vagal mediation of immune-brain communication.
Neurosci Lett (1995) 183(1–2):27–31. doi:10.1016/0304-3940(94)11105-R
35. Steinberg B, Silverman H, Robbiati S, Gunasekaran M, Tsaava T, Battinelli E,
etal. Cytokine-specic neurograms in the sensory vagus nerve. Bioelectron
Med (2016) 3:7–17. doi:10.15424/bioelectronmed.2016.00007
36. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, etal.
Vagus nerve stimulation attenuates the systemic inammatory response to
endotoxin. Nature (2000) 405(6785):458–62. doi:10.1038/35013070
11
Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1452
37. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, etal. Nicotinic
acetylcholine receptor alpha7 subunit is an essential regulator of inamma-
tion. Nature (2003) 421(6921):384–8. doi:10.1038/nature01339
38. De Jonge WJ, van der Zanden EP, e FO, Bijlsma MF, van Westerloo DJ,
Bennink RJ, etal. Stimulation of the vagus nerve attenuates macrophage acti-
vation by activating the Jak2-STAT3 signaling pathway. Nat Immunol (2005)
6(8):844–51. doi:10.1038/ni0905-954b
39. Sun Y, Li Q, Gui H, Xu DP, Yang YL, Su DF, et al. MicroRNA-124 mediates
the cholinergic anti-inammatory action through inhibiting the production
of pro-inammatory cytokines. Cell Res (2013) 23(11):1270–83. doi:10.1038/
cr.2013.116
40. Cailotto C, Gomez-Pinilla PJ, Costes LM, van der Vliet J, Di Giovangiulio M,
Nemethova A, etal. Neuro-anatomical evidence indicating indirect modula-
tion of macrophages by vagal eerents in the intestine but not in the spleen.
PLoS One (2014) 9(1):e87785. doi:10.1371/journal.pone.0087785
41. Mikkelsen HB, uneberg L, Rumessen JJ, orball N. Macrophage-like
cells in the muscularis externa of mouse small intestine. Anat Rec (1985)
213(1):77–86. doi:10.1002/ar.1092130111
42. Bellinger DL, Felten SY, Lorton D, Felten DL. Origin of noradrenergic
innervation of the spleen in rats. Brain Behav Immun (1989) 3(4):291–311.
doi:10.1016/0889-1591(89)90029-9
43. Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA,
Reardon C, etal. Acetylcholine-synthesizing Tcells relay neural signals in
a vagus nerve circuit. Science (2011) 334(6052):98–101. doi:10.1126/science.
1209985
44. Olofsson PS, Katz DA, Rosas-Ballina M, Levine YA, Ochani M, Valdes-
Ferrer SI, et al. alpha7 nicotinic acetylcholine receptor (alpha7nAChR)
expression in bone marrow-derived non-T cells is required for the inam-
matory reex. Mol Med (2012) 18:539–43. doi:10.2119/molmed.2011.00405
45. Felten DL, Ackerman KD, Wiegand SJ, Felten SY. Noradrenergic sympathetic
innervation of the spleen: I. Nerve bers associate with lymphocytes and
macrophages in specic compartments of the splenic white pulp. J Neurosci
Res (1987) 18(1):28–36, 118–21. doi:10.1002/jnr.490180107
46. Martelli D, Yao ST, McKinley MJ, McAllen RM. Reex control of inamma-
tion by sympathetic nerves, not the vagus. J Physiol (2014) 592(7):1677–86.
doi:10.1113/jphysiol.2013.268573
47. Gautron L, Rutkowski JM, Burton MD, Wei W, Wan Y, Elmquist JK. Neuronal
and nonneuronal cholinergic structures in the mouse gastrointestinal tract
and spleen. J Comp Neurol (2013) 521(16):3741–67. doi:10.1002/cne.23376
48. Munyaka P, Rabbi MF, Pavlov VA, Tracey KJ, Khapour E, Ghia JE. Central
muscarinic cholinergic activation alters interaction between splenic dendritic
cell and CD4+CD25- Tcells in experimental colitis. PLoS One (2014) 9(10):
e109272. doi:10.1371/journal.pone.0109272
49. Ji H, Rabbi MF, Labis B, Pavlov VA, Tracey KJ, Ghia JE. Central cholinergic
activation of a vagus nerve-to-spleen circuit alleviates experimental colitis.
Mucosal Immunol (2014) 7(2):335–47. doi:10.1038/mi.2013.52
50. Bellinger DL, Lorton D, Hamill RW, Felten SY, Felten DL. Acetylcholines-
terase staining and choline acetyltransferase activity in the young adult rat
spleen: lack of evidence for cholinergic innervation. Brain Behav Immun
(1993) 7(3):191–204. doi:10.1006/brbi.1993.1021
51. Martelli D, Farmer DG, Yao ST. e splanchnic anti-inammatory pathway:
could it be the eerent arm of the inammatory reex? Exp Physiol (2016)
101:1245–52. doi:10.1113/EP085559
52. Williams JM, Peterson RG, Shea PA, Schmedtje JF, Bauer DC, Felten DL.
Sympathetic innervation of murine thymus and spleen: evidence for a func-
tional link between the nervous and immune systems. Brain Res Bull (1981)
6(1):83–94. doi:10.1016/S0361-9230(81)80072-X
53. Wan W, Vriend CY, Wetmore L, Gartner JG, Greenberg AH, Nance DM. e
eects of stress on splenic immune function are mediated by the splenic nerve.
Brain Res Bull (1993) 30(1–2):101–5. doi:10.1016/0361-9230(93)90044-C
54. Madden KS, Moynihan JA, Brenner GJ, Felten SY, Felten DL, Livnat S.
Sympathetic nervous system modulation of the immune system. III.
Alterations in T and B cell proliferation and dierentiation in vitro fol-
lowing chemical sympathectomy. J Neuroimmunol (1994) 49(1–2):77–87.
doi:10.1016/0165-5728(94)90182-1
55. Madden KS, Felten SY, Felten DL, Hardy CA, Livnat S. Sympathetic nervous
system modulation of the immune system. II. Induction of lymphocyte pro-
liferation and migration invivo by chemical sympathectomy. J Neuroimmunol
(1994) 49(1–2):67–75. doi:10.1016/0165-5728(94)90182-1
56. Shimizu N, Kaizuka Y, Hori T, Nakane H. Immobilization increases nor-
epinephrine release and reduces NK cytotoxicity in spleen of conscious rat.
Am J Physiol (1996) 271(3 Pt 2):R537–44.
57. Nance DM, Burns J. Innervation of the spleen in the rat: evidence for
absence of aerent innervation. Brain Behav Immun (1989) 3(4):281–90.
doi:10.1016/0889-1591(89)90028-7
58. Bishopric NH, Cohen HJ, Leowitz RJ. Beta adrenergic receptors in
lymphocyte subpopulations. J Allergy Clin Immunol (1980) 65(1):29–33.
doi:10.1016/0091-6749(80)90173-6
59. Brodde OE, Engel G, Hoyer D, Bock KD, Weber F. e beta-adrenergic
receptor in human lymphocytes: subclassication by the use of a new
radio-ligand, (±)-125 Iodocyanopindolol. Life Sci (1981) 29(21):2189–98.
doi:10.1016/0024-3205(81)90490-2
60. Taylor RB, Weaver LC. Spinal stimulation to locate preganglionic neurons
controlling the kidney, spleen, or intestine. Am J Physiol (1992) 263(4 Pt 2):
H1026–33.
61. Strack AM, Sawyer WB, Hughes JH, Platt KB, Loewy AD. A general pattern
of CNS innervation of the sympathetic outow demonstrated by trans-
neuronal pseudorabies viral infections. Brain Res (1989) 491(1):156–62.
doi:10.1016/0006-8993(89)90098-X
62. Strack AM, Sawyer WB, Platt KB, Loewy AD. CNS cell groups regulating
the sympathetic outow to adrenal gland as revealed by transneuronal cell
body labeling with pseudorabies virus. Brain Res (1989) 491(2):274–96.
doi:10.1016/0006-8993(89)90063-2
63. Sved AF, Ruggiero DA. e autonomic nervous system: structure and func-
tion. In: Yates B, Miller A, editors. Vestibular Autonomic Regulation. Boca
Raton: CRC Press (1996). p. 25–51.
64. Abe C, Inoue T, Inglis MA, Viar KE, Huang L, Ye H, etal. C1 neurons mediate
a stress-induced anti-inammatory reex in mice. Nat Neurosci (2017)
20(5):700–7. doi:10.1038/nn.4526
65. Inoue T, Abe C, Sung SS, Moscalu S, Jankowski J, Huang L, etal. Vagus nerve
stimulation mediates protection from kidney ischemia-reperfusion injury
through alpha7nAChR+ splenocytes. J Clin Invest (2016) 126(5):1939–52.
doi:10.1172/JCI83658
66. Wood SK, Woods JH. Corticotropin-releasing factor receptor-1: a therapeutic
target for cardiac autonomic disturbances. Expert Opin er Targets (2007)
11(11):1401–13. doi:10.1517/14728222.11.11.1401
67. Deng QJ, Deng DJ, Che J, Zhao HR, Yu JJ, Lu YY. Hypothalamic paraventricu-
lar nucleus stimulation reduces intestinal injury in rats with ulcerative colitis.
World J Gastroenterol (2016) 22(14):3769–76. doi:10.3748/wjg.v22.i14.3769
68. Byrum CE, Guyenet PG. Aerent and eerent connections of the A5
noradrenergic cell group in the rat. J Comp Neurol (1987) 261(4):529–42.
doi:10.1002/cne.902610406
69. Kanbar R, Depuy SD, West GH, Stornetta RL, Guyenet PG. Regulation of
visceral sympathetic tone by A5 noradrenergic neurons in rodents. J Physiol
(2011) 589(Pt 4):903–17. doi:10.1113/jphysiol.2010.198374
70. Card JP, Sved JC, Craig B, Raizada M, Vazquez J, Sved AF. Eerent projections
of rat rostroventrolateral medulla C1 catecholamine neurons: implications
for the central control of cardiovascular regulation. J Comp Neurol (2006)
499(5):840–59. doi:10.1002/cne.21140
71. Sved AF, Cano G, Card JP. Neuroanatomical specicity of the circuits con-
trolling sympathetic outow to dierent targets. Clin Exp Pharmacol Physiol
(2001) 28(1–2):115–9. doi:10.1046/j.1440-1681.2001.03403.x
72. Cano G, Sved AF, Rinaman L, Rabin BS, Card JP. Characterization of the
central nervous system innervation of the rat spleen using viral transneuronal
tracing. J Comp Neurol (2001) 439(1):1–18. doi:10.1002/cne.1331
73. Dampney RA. e subretrofacial vasomotor nucleus: anatomical, chemical
and pharmacological properties and role in cardiovascular regulation. Prog
Neurobiol (1994) 42(2):197–227. doi:10.1016/0301-0082(94)90064-7
74. Jansen AS, Nguyen XV, Karpitskiy V, Mettenleiter TC, Loewy AD. Central
command neurons of the sympathetic nervous system: basis of the ght-
or-ight response. Science (1995) 270(5236):644–6. doi:10.1126/science.270.
5236.644
75. Pavlov VA, Parrish WR, Rosas-Ballina M, Ochani M, Puerta M, Ochani K,
et al. Brain acetylcholinesterase activity controls systemic cytokine levels
through the cholinergic anti-inammatory pathway. Brain Behav Immun
(2009) 23(1):41–5. doi:10.1016/j.bbi.2008.06.011
76. Tracey KJ. Suppression of TNF and other proinammatory cytokines by the
tetravalent guanylhydrazone CNI-1493. Prog Clin Biol Res (1998) 397:335–43.
12
Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1452
77. Cohen PS, Schmidtmayerova H, Dennis J, Dubrovsky L, Sherry B, Wang H,
etal. e critical role of p38 MAP kinase in Tcell HIV-1 replication. Mol Med
(1997) 3(5):339–46.
78. Hommes DW, van de Heisteeg BH, van der Spek M, Bartelsman JF,
van Deventer SJ. Iniximab treatment for Crohn’s disease: one-year expe-
rience in a Dutch academic hospital. Inamm Bowel Dis (2002) 8(2):81–6.
doi:10.1097/00054725-200203000-00002
79. Kox M, Pompe JC, Peters E, Vaneker M, van der Laak JW, van der Hoeven JG,
et al. alpha7 nicotinic acetylcholine receptor agonist GTS-21 attenuates
ventilator-induced tumour necrosis factor-alpha production and lung injury.
Br J Anaesth (2011) 107(4):559–66. doi:10.1093/bja/aer202
80. van Westerloo DJ, Giebelen IA, Florquin S, Bruno MJ, Larosa GJ, Ulloa L,
etal. e vagus nerve and nicotinic receptors modulate experimental pancre-
atitis severity in mice. Gastroenterology (2006) 130(6):1822–30. doi:10.1053/
j.gastro.2006.02.022
81. e FO, Boeckxstaens GE, Snoek SA, Cash JL, Bennink R, Larosa GJ, etal.
Activation of the cholinergic anti-inammatory pathway ameliorates postop-
erative ileus in mice. Gastroenterology (2007) 133(4):1219–28. doi:10.1053/
j.gastro.2007.07.022
82. Luyer MD, Greve JW, Hadfoune M, Jacobs JA, Dejong CH, Buurman WA.
Nutritional stimulation of cholecystokinin receptors inhibits inammation
via the vagus nerve. J Exp Med (2005) 202(8):1023–9. doi:10.1084/jem.
20042397
83. de Haan JJ, Hadfoune M, Lubbers T, Hodin C, Lenaerts K, Ito A, et al.
Lipid-rich enteral nutrition regulates mucosal mast cell activation via the
vagal anti-inammatory reex. Am J Physiol Gastrointest Liver Physiol (2013)
305(5):G383–91. doi:10.1152/ajpgi.00333.2012
84. Forbes A, Escher J, Hebuterne X, Klek S, Krznaric Z, Schneider S, et al.
ESPEN guideline: clinical nutrition in inammatory bowel disease. Clin Nutr
(2017) 36(2):321–47. doi:10.1016/j.clnu.2016.12.027
85. Cramer H, Schafer M, Schols M, Kocke J, Elsenbruch S, Lauche R, etal.
Randomised clinical trial: yoga vs written self-care advice for ulcerative
colitis. Aliment Pharmacol er (2017) 45(11):1379–89. doi:10.1111/apt.
14062
86. Whorwell PJ. Review article: the history of hypnotherapy and its role in the
irritable bowel syndrome. Aliment Pharmacol er (2005) 22(11–12):1061–7.
doi:10.1111/j.1365-2036.2005.02697.x
87. Keefer L, Ta TH, Kiebles JL, Martinovich Z, Barrett TA, Palsson OS. Gut-
directed hypnotherapy signicantly augments clinical remission in quiescent
ulcerative colitis. Aliment Pharmacol er (2013) 38(7):761–71. doi:10.1111/
apt.12449
88. Oke SL, Tracey KJ. e inammatory reex and the role of complementary
and alternative medical therapies. Ann N Y Acad Sci (2009) 1172:172–80.
doi:10.1196/annals.1393.013
89. Lim HD, Kim MH, Lee CY, Namgung U. Anti-inammatory eects of acu-
puncture stimulation via the vagus nerve. PLoS One (2016) 11(3):e0151882.
doi:10.1371/journal.pone.0151882
90. Aubert AE, Verheyden B, Beckers F, Tack J, Vandenberghe J. Cardiac auto-
nomic regulation under hypnosis assessed by heart rate variability: spectral
analysis and fractal complexity. Neuropsychobiology (2009) 60(2):104–12.
doi:10.1159/000239686
91. Tyagi A, Cohen M, Reece J, Telles S, Jones L. Heart rate variability, ow,
mood and mental stress during yoga practices in yoga practitioners, non-
yoga practitioners and people with metabolic syndrome. Appl Psychophysiol
Biofeedback (2016) 41(4):381–93. doi:10.1007/s10484-016-9340-2
92. Azam MA, Katz J, Mohabir V, Ritvo P. Individuals with tension and migraine
headaches exhibit increased heart rate variability during post-stress
mindfulness meditation practice but a decrease during a post-stress control
condition – a randomized, controlled experiment. Int J Psychophysiol (2016)
110:66–74. doi:10.1016/j.ijpsycho.2016.10.011
93. Lanska DJ. J.L. Corning and vagal nerve stimulation for seizures in the 1880s.
Neurology (2002) 58(3):452–9. doi:10.1212/WNL.58.3.452
94. Bailey P, Bremer F. A sensory cortical representation of the vagus nerve:
with a note on the eects of low blood pressure on the cortical electrogram.
J Neurophysiol (1938) 1(5):405–12.
95. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent
vagal stimulation in humans: preliminary results. Epilepsia (1990) 31(Suppl 2):
S40–3. doi:10.1111/j.1528-1157.1990.tb05848.x
96. Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM,
et al. Vagus nerve stimulation for treatment-resistant depression: a ran-
domized, controlled acute phase trial. Biol Psychiatry (2005) 58(5):347–54.
doi:10.1016/j.biopsych.2005.05.025
97. Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM,
etal. Eects of 12 months of vagus nerve stimulation in treatment-resistant
depression: a naturalistic study. Biol Psychiatry (2005) 58(5):355–63.
doi:10.1016/j.biopsych.2005.05.025
98. Fanselow EE. Central mechanisms of cranial nerve stimulation for epilepsy.
Surg Neurol Int (2012) 3(Suppl 4):S247–54. doi:10.4103/2152-7806.103014
99. Krahl SE, Senanayake SS, Handforth A. Destruction of peripheral C-bers does
not alter subsequent vagus nerve stimulation-induced seizure suppression
in rats. Epilepsia (2001) 42(5):586–9. doi:10.1046/j.1528-1157.2001.09700.x
100. Zanchetti A, Wang SC, Moruzzi G. [Eect of aerent vagal stimulation on
the electroencephalogram of the cat in cerebral isolation]. Boll Soc Ital Biol
Sper (1952) 28(4):627–8.
101. Panebianco M, Rigby A, Weston J, Marson AG. Vagus nerve stimula-
tion for partial seizures. Cochrane Database Syst Rev (2015) (4):1–40.
doi:10.1002/14651858.CD002896.pub2
102. Groves DA, Brown VJ. Vagal nerve stimulation: a review of its applications
and potential mechanisms that mediate its clinical eects. Neurosci Biobehav
Rev (2005) 29(3):493–500. doi:10.1016/j.neubiorev.2005.01.004
103. Naritoku DK, Terry WJ, Helfert RH. Regional induction of fos immunoreac-
tivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy
Res (1995) 22(1):53–62. doi:10.1016/0920-1211(95)00035-9
104. Chae JH, Nahas Z, Lomarev M, Denslow S, Lorberbaum JP, Bohning DE,
et al. A review of functional neuroimaging studies of vagus nerve stimu-
lation (VNS). J Psychiatr Res (2003) 37(6):443–55. doi:10.1016/S0022-
3956(03)00074-8
105. Morris GL III, Mueller WM. Long-term treatment with vagus nerve stimula-
tion in patients with refractory epilepsy. e Vagus Nerve Stimulation Study
Group E01-E05. Neurology (1999) 53(8):1731–5. doi:10.1212/WNL.53.8.1731
106. Elliott RE, Morsi A, Tanweer O, Grobelny B, Geller E, Carlson C, et al.
Ecacy of vagus nerve stimulation over time: review of 65 consecutive
patients with treatment-resistant epilepsy treated with VNS > 10 years.
Epilepsy Behav (2011) 20(3):478–83. doi:10.1016/j.yebeh.2010.10.017
107. Reid SA. Surgical technique for implantation of the neurocybernetic pros-
thesis. Epilepsia (1990) 31(Suppl 2):S38–9. doi:10.1111/j.1528-1157.1990.
tb05847.x
108. Hamlin RL, Smith CR. Eects of vagal stimulation on S-A and A-V nodes.
Am J Physiol (1968) 215(3):560–8.
109. Ben-Menachem E. Vagus nerve stimulation, side eects, and long-term
safety. J Clin Neurophysiol (2001) 18(5):415–8. doi:10.1097/00004691
200109000-00005
110. Bernik TR, Friedman SG, Ochani M, DiRaimo R, Susarla S, Czura CJ, etal.
Cholinergic antiinammatory pathway inhibition of tumor necrosis factor
during ischemia reperfusion. J Vasc Surg (2002) 36(6):1231–6. doi:10.1067/
mva.2002.129643
111. Peuker ET, Filler TJ. e nerve supply of the human auricle. Clin Anat (2002)
15(1):35–7. doi:10.1002/ca.1089
112. Nomura S, Mizuno N. Central distribution of primary aerent bers in the
Arnold’s nerve (the auricular branch of the vagus nerve): a transganglionic
HRP study in the cat. Brain Res (1984) 292(2):199–205. doi:10.1016/0006-
8993(84)90756-X
113. Frangos E, Ellrich J, Komisaruk BR. Non-invasive access to the vagus
nerve central projections via electrical stimulation of the external ear:
fMRI evidence in humans. Brain Stimul (2015) 8(3):624–36. doi:10.1016/j.
brs.2014.11.018
114. Hein E, Nowak M, Kiess O, Biermann T, Bayerlein K, Kornhuber J, etal.
Auricular transcutaneous electrical nerve stimulation in depressed patients:
a randomized controlled pilot study. J Neural Transm (Vienna) (2013)
120(5):821–7. doi:10.1007/s00702-012-0908-6
115. Zhao YX, He W, Jing XH, Liu JL, Rong PJ, Ben H, etal. Transcutaneous
auricular vagus nerve stimulation protects endotoxemic rat from lipopoly-
saccharide-induced inammation. Evid Based Complement Alternat Med
(2012) 2012:627023. doi:10.1155/2012/627023
116. Stefan H, Kreiselmeyer G, Kerling F, Kurzbuch K, Rauch C, Heers M, etal.
Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant
13
Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1452
epilepsies: a proof of concept trial. Epilepsia (2012) 53(7):e115–8.
doi:10.1111/j.1528-1167.2012.03492.x
117. Rong P, Liu A, Zhang J, Wang Y, He W, Yang A, etal. Transcutaneous vagus
nerve stimulation for refractory epilepsy: a randomized controlled trial.
Clin Sci (Lond) (2014):CS20130518. doi:10.1042/CS20130518
118. Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J.
Non-invasive vagus nerve stimulation in healthy humans reduces sympa-
thetic nerve activity. Brain Stimul (2014) 7(6):871–7. doi:10.1016/j.brs.
2014.07.031
119. Nesbitt AD, Marin JC, Tompkins E, Ruttledge MH, Goadsby PJ. Initial use of
a novel noninvasive vagus nerve stimulator for cluster headache treatment.
Neurology (2015) 84(12):1249–53. doi:10.1212/WNL.0000000000001394
120. Moscato D, Moscato FR, Liebler EJ. Ecacy of noninvasive vagus nerve
stimulation (nVNS) in the treatment of acute migraine attacks. Headache
(2014) 44:1418.
121. Lerman I, Hauger R, Sorkin L, Proudfoot J, Davis B, Huang A, et al.
Noninvasive transcutaneous vagus nerve stimulation decreases whole blood
culture-derived cytokines and chemokines: a randomized, blinded, healthy
control pilot trial. Neuromodulation (2016) 19(3):283–90. doi:10.1111/
ner.12398
122. Laukkanen JA, Lakka TA, Rauramaa R, Kuhanen R, Venalainen JM,
Salonen R, etal. Cardiovascular tness as a predictor of mortality in men.
Arch Intern Med (2001) 161(6):825–31. doi:10.1001/archinte.161.6.825
123. Church TS, Barlow CE, Earnest CP, Kampert JB, Priest EL, Blair SN.
Associations between cardiorespiratory tness and C-reactive protein in
men. Arterioscler romb Vasc Biol (2002) 22(11):1869–76. doi:10.1161/
01.ATV.0000036611.77940.F8
124. Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced
risk of cardiovascular events: potential mediating mechanisms. Circulation
(2007) 116(19):2110–8. doi:10.1161/CIRCULATIONAHA.107.729939
125. Sloan RP, McCreath H, Tracey KJ, Sidney S, Liu K, Seeman T. RR interval
variability is inversely related to inammatory markers: the CARDIA study.
Mol Med (2007) 13(3–4):178–84. doi:10.2119/2006-00112.sloan
126. Carnevali L, Sgoifo A. Vagal modulation of resting heart rate in rats: the role
of stress, psychosocial factors, and physical exercise. Front Physiol (2014)
5:118. doi:10.3389/fphys.2014.00118
127. Ngampramuan S, Baumert M, Beig MI, Kotchabhakdi N, Nalivaiko E. Acti-
vation of 5-HT(1A) receptors attenuates tachycardia induced by restraint
stress in rats. Am J Physiol Regul Integr Comp Physiol (2008) 294(1):R132–41.
doi:10.1152/ajpregu.00464.2007
128. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural
history of inammatory bowel diseases. Gastroenterology (2011) 140(6):
1785–94. doi:10.1053/j.gastro.2011.01.055
129. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Cherno G, etal.
Increasing incidence and prevalence of the inammatory bowel diseases with
time, based on systematic review. Gastroenterology (2012) 142(1):46–54.e42.
doi:10.1053/j.gastro.2011.10.001
130. Danese S, Fiocchi C. Etiopathogenesis of inammatory bowel diseases.
World J Gastroenterol (2006) 12(30):4807–12. doi:10.3748/wjg.v12.i30.4807
131. Bonaz BL, Bernstein CN. Brain-gut interactions in inammatory bowel dis-
ease. Gastroenterology (2013) 144(1):36–49. doi:10.1053/j.gastro.2012.10.003
132. Pellissier S, Bonaz B. e place of stress and emotions in the irritable bowel
syndrome. Vitam Horm (2017) 103:327–54. doi:10.1016/bs.vh.2016.09.005
133. Lindgren S, Lilja B, Rosen I, Sundkvist G. Disturbed autonomic nerve
function in patients with Crohns disease. Scand J Gastroenterol (1991)
26(4):361–6. doi:10.3109/00365529108996495
134. Lindgren S, Stewenius J, Sjolund K, Lilja B, Sundkvist G. Autonomic vagal
nerve dysfunction in patients with ulcerative colitis. Scand J Gastroenterol
(1993) 28(7):638–42. doi:10.3109/00365529309096103
135. Pellissier S, Dantzer C, Mondillon L, Trocme C, Gauchez AS, Ducros V,
etal. Relationship between vagal tone, cortisol, TNF-alpha, epinephrine and
negative aects in Crohn’s disease and irritable bowel syndrome. PLoS One
(2014) 9(9):e105328. doi:10.1371/journal.pone.0105328
136. Peyrin-Biroulet L, Lemann M. Review article: remission rates achievable by
current therapies for inammatory bowel disease. Aliment Pharmacol er
(2011) 33(8):870–9. doi:10.1111/j.1365-2036.2011.04599.x
137. Molnar T, Farkas K, Nyari T, Szepes Z, Nagy F, Wittmann T. Frequency and
predictors of loss of response to iniximab or adalimumab in Crohn’s disease
aer one-year treatment period – a single center experience. J Gastrointestin
Liver Dis (2012) 21(3):265–9.
138. Billioud V, Sandborn WJ, Peyrin-Biroulet L. Loss of response and need for
adalimumab dose intensication in Crohn’s disease: a systematic review.
Am J Gastroenterol (2011) 106(4):674–84. doi:10.1038/ajg.2011.60
139. Bonovas S, Fiorino G, Allocca M, Lytras T, Nikolopoulos GK, Peyrin-
Biroulet L, etal. Biologic therapies and risk of infection and malignancy
in patients with inammatory bowel disease: a systematic review and net-
work meta-analysis. Clin Gastroenterol Hepatol (2016) 14(10):1385–97.e10.
doi:10.1016/j.cgh.2016.04.039
140. Lenti MV, Selinger CP. Medication non-adherence in adult patients aected
by inammatory bowel disease: a critical review and update of the deter-
mining factors, consequences and possible interventions. Expert Rev Gastro-
enterol Hepatol (2017) 11(3):215–26. doi:10.1080/17474124.2017.1284587
141. Maggiori L, Panis Y. Surgical management of IBD – from an open to a
laparoscopic approach. Nat Rev Gastroenterol Hepatol (2013) 10(5):297–306.
doi:10.1038/nrgastro.2013.30
142. Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM.
e vagus nerve: a tonic inhibitory inuence associated with inammatory
bowel disease in a murine model. Gastroenterology (2006) 131(4):1122–30.
doi:10.1053/j.gastro.2006.08.016
143. Bai A, Guo Y, Lu N. e eect of the cholinergic anti-inammatory
pathway on experimental colitis. Scand J Immunol (2007) 66(5):538–45.
doi:10.1111/j.1365-3083.2007.02011.x
144. Meregnani J, Clarencon D, Vivier M, Peinnequin A, Mouret C, Sinniger V,
et al. Anti-inammatory eect of vagus nerve stimulation in a rat model
of inammatory bowel disease. Auton Neurosci (2011) 160(1–2):82–9.
doi:10.1016/j.autneu.2010.10.007
145. Sun P, Zhou K, Wang S, Li P, Chen S, Lin G, etal. Involvement of MAPK/
NF-kappaB signaling in the activation of the cholinergic anti-inammatory
pathway in experimental colitis by chronic vagus nerve stimulation. PLoS
One (2013) 8(8):e69424. doi:10.1371/journal.pone.0069424
146. Miceli PC, Jacobson K. Cholinergic pathways modulate experimental dini-
trobenzene sulfonic acid colitis in rats. Auton Neurosci (2003) 105(1):16–24.
doi:10.1016/S1566-0702(03)00023-7
147. Ghia JE, Blennerhassett P, El-Sharkawy RT, Collins SM. e protective
eect of the vagus nerve in a murine model of chronic relapsing colitis.
Am J Physiol Gastrointest Liver Physiol (2007) 293(4):G711–8. doi:10.1152/
ajpgi.00240.2007
148. Reyt S, Picq C, Sinniger V, Clarencon D, Bonaz B, David O. Dynamic
Causal Modelling and physiological confounds: a functional MRI study of
vagus nerve stimulation. Neuroimage (2010) 52(4):1456–64. doi:10.1016/
j.neuroimage.2010.05.021
149. Clarencon D, Pellissier S, Sinniger V, Kibleur A, Homan D, Vercueil L, etal.
Long term eects of low frequency (10 Hz) vagus nerve stimulation on EEG
and heart rate variability in Crohn’s disease: a case report. Brain Stimul (2014)
7(6):914–6. doi:10.1016/j.brs.2014.08.001
150. Jin H, Guo J, Liu J, Lyu B, Foreman RD, Yin J, etal. Anti-inammatory eects
and mechanisms of vagal nerve stimulation combined with electroacupunc-
ture in a rodent model of Tnbs-induced colitis. Am J Physiol Gastrointest
Liver Physiol (2017) 313:G192–202. doi:10.1152/ajpgi.00254.2016
151. Cygankiewicz I, Zareba W. Heart rate variability. Handb Clin Neurol (2013)
117:379–93. doi:10.1016/B978-0-444-53491-0.00031-6
152. Bonaz B, Sinniger V, Homann D, Clarencon D, Mathieu N, Dantzer C, etal.
Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up
pilot study. Neurogastroenterol Motil (2016) 28(6):948–53. doi:10.1111/
nmo.12792
153. Mulak A, Bonaz B. Irritable bowel syndrome: a model of the brain-gut
interactions. Med Sci Monit (2004) 10(4):RA55–62.
154. Canavan C, West J, Card T. e epidemiology of irritable bowel syndrome.
Clin Epidemiol (2014) 6:71–80. doi:10.2147/CLEP.S40245
155. Camilleri M. Pathophysiology in irritable bowel syndrome. Drug News
Perspect (2001) 14(5):268–78. doi:10.1358/dnp.2001.14.5.704648
156. Chang L. e association of functional gastrointestinal disorders and bro-
myalgia. Eur J Surg Suppl (1998) 583:32–6. doi:10.1080/11024159850191210
157. Garakani A, Win T, Virk S, Gupta S, Kaplan D, Masand PS. Comorbidity
of irritable bowel syndrome in psychiatric patients: a review. Am J er
(2003) 10(1):61–7. doi:10.1097/00045391-200301000-00014
14
Bonaz et al. The Vagus Nerve in the Neuro-Immune Axis
Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1452
158. Bradford K, Shih W, Videlock EJ, Presson AP, Nalibo BD, Mayer EA, etal.
Association between early adverse life events and irritable bowel syndrome.
Clin Gastroenterol Hepatol (2012) 10(4):385–90.e1–3. doi:10.1016/j.cgh.
2011.12.018
159. Ritchie JA. e irritable colon syndrome – an unhappy coincidence? Tijd schr
Gastroenterol (1973) 16(4):243–53.
160. Brierley SM, Linden DR. Neuroplasticity and dysfunction aer gastrointes-
tinal inammation. Nat Rev Gastroenterol Hepatol (2014) 11(10):611–27.
doi:10.1038/nrgastro.2014.103
161. Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D,
et al. Activated mast cells in proximity to colonic nerves correlate with
abdominal pain in irritable bowel syndrome. Gastroenterology (2004) 126(3):
693–702. doi:10.1053/j.gastro.2003.11.055
162. Gwee KA, Graham JC, McKendrick MW, Collins SM, Marshall JS,
Walters SJ, et al. Psychometric scores and persistence of irritable bowel
aer infectious diarrhoea. Lancet (1996) 347(8995):150–3. doi:10.1016/
S0140-6736(96)90341-4
163. Spence MJ, Moss-Morris R. e cognitive behavioural model of irritable
bowel syndrome: a prospective investigation of patients with gastroenteritis.
Gut (2007) 56(8):1066–71. doi:10.1136/gut.2006.108811
164. Catanzaro R, Occhipinti S, Calabrese F, Anzalone MG, Milazzo M, Italia A,
et al. Irritable bowel syndrome: new ndings in pathophysiological and
therapeutic eld. Minerva Gastroenterol Dietol (2014) 60(2):151–63.
165. Bonaz B. Abnormal brain microstructure in patients with chronic pancre-
atitis. Gut (2011) 60(11):1445–6. doi:10.1136/gutjnl-2011-300840
166. Yunus MB. Role of central sensitization in symptoms beyond muscle pain,
and the evaluation of a patient with widespread pain. Best Pract Res Clin
Rheumatol (2007) 21(3):481–97. doi:10.1016/j.berh.2007.03.006
167. Yunus MB. Fibromyalgia and overlapping disorders: the unifying concept of
central sensitivity syndromes. Semin Arthritis Rheum (2007) 36(6):339–56.
doi:10.1016/j.semarthrit.2006.12.009
168. Hinton DE, Hofmann SG, Pollack MH, Otto MW. Mechanisms of ecacy
of CBT for Cambodian refugees with PTSD: improvement in emotion reg-
ulation and orthostatic blood pressure response. CNS Neurosci er (2009)
15(3):255–63. doi:10.1111/j.1755-5949.2009.00100.x
169. Ford AC, Quigley EM, Lacy BE, Lembo AJ, Saito YA, Schiller LR , etal. Eect
of antidepressants and psychological therapies, including hypnotherapy,
in irritable bowel syndrome: systematic review and meta-analysis. Am
J Gastroenterol (2014) 109(9):1350–65; quiz 1366. doi:10.1038/ajg.2014.148
170. Zurowski D, Nowak L, Wordliczek J, Dobrogowski J, or PJ. Eects of
vagus nerve stimulation in visceral pain model. Folia Med Cracov (2012)
52(1–2):57–69.
171. Zhang X, Cao B, Yan N, Liu J, Wang J, Tung VO, etal. Vagus ner ve stimulation
modulates visceral pain-related aective memory. Behav Brain Res (2013)
236(1):8–15. doi:10.1016/j.bbr.2012.08.027
172. Kirchner A, Stefan H, Bastian K, Birklein F. Vagus nerve stimulation sup-
presses pain but has limited eects on neurogenic inammation in humans.
Eur J Pain (2006) 10(5):449–55. doi:10.1016/j.ejpain.2005.06.005
173. Botha C, Farmer AD, Nilsson M, Brock C, Gavrila AD, Drewes AM, etal.
Preliminary report: modulation of parasympathetic nervous system tone
inuences oesophageal pain hypersensitivity. Gut (2015) 64(4):611–7.
doi:10.1136/gutjnl-2013-306698
174. Frokjaer JB, Bergmann S, Brock C, Madzak A, Farmer AD, Ellrich J, etal.
Modulation of vagal tone enhances gastroduodenal motility and reduces
somatic pain sensitivity. Neurogastroenterol Motil (2016) 28(4):592–8.
doi:10.1111/nmo.12760
175. Calvino B, Grilo RM. Central pain control. Joint Bone Spine (2006) 73(1):10–6.
doi:10.1016/j.jbspin.2004.11.006
176. Livingston EH, Passaro EP Jr. Postoperative ileus. Dig Dis Sci (1990)
35(1):121–32. doi:10.1007/BF01537233
177. Holzer P, Lippe IT, Holzer-Petsche U. Inhibition of gastrointestinal transit
due to surgical trauma or peritoneal irritation is reduced in capsaicin-
treated rats. Gastroenterology (1986) 91(2):360–3. doi:10.1016/0016-
5085(86)90569-X
178. Bonaz B, Plourde V, Tache Y. Abdominal surgery induces Fos immunore-
activity in the rat brain. J Comp Neurol (1994) 349(2):212–22. doi:10.1002/
cne.903490205
179. Tache Y, Bonaz B. Corticotropin-releasing factor receptors and stress-
related alterations of gut motor function. J Clin Invest (2007) 117(1):33–40.
doi:10.1172/JCI30085
180. Monnikes H, Schmidt BG, Raybould HE, Tache Y. CRF in the paraventricular
nucleus mediates gastric and colonic motor response to restraint stress.
Am J Physiol (1992) 262(1 Pt 1):G137–43.
181. de Jonge WJ, van den Wijngaard RM, e FO, ter Beek ML, Bennink RJ,
Tytgat GN, etal. Postoperative ileus is maintained by intestinal immune
inltrates that activate inhibitory neural pathways in mice. Gastroenterology
(2003) 125(4):1137–47. doi:10.1016/S0016-5085(03)01197-1
182. Ciardulli A, Saccone G, Di Mascio D, Caissutti C, Berghella V. Chewing
gum improves postoperative recovery of gastrointestinal function aer
cesarean delivery: a systematic review and meta-analysis of randomized
trials. J Matern Fetal Neonatal Med (2017):1–9. doi:10.1080/14767058.2017.
1330883
183. Stakenborg N, Wolthuis AM, Gomez-Pinilla PJ, Farro G, Di Giovangiulio M,
Bosmans G, etal. Abdominal vagus nerve stimulation as a new therapeutic
approach to prevent postoperative ileus. Neurogastroenterol Motil (2017)
29(9):e13075. doi:10.1111/nmo.13075
184. Olofsson PS, Tracey KJ. Bioelectronic medicine: technology targeting molec-
ular mechanisms for therapy. J Intern Med (2017) 282(1):3–4. doi:10.1111/
joim.12624
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ducted in the absence of any commercial or nancial relationships that could be
construed as a potential conict of interest.
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... Projections from the NTS directly connect to the paraventricular nucleus (PVN), which is responsible for modulating corticotrophin-releasing hormone (CRH) as part of the hypothalamus-pituitary-adrenal (HPA) axis (Pavlov et al., 2003). The downstream effect of HPA axis stimulation is stress mediation through increased production of cortisol, a potent inflammatory inhibitor (Bonaz et al., 2017). This link between the NTS and PVN provides the VN a pathway to modulate the neurohormonal anti-inflammatory responses in the body (Pavlov et al., 2003). ...
... Non-invasive VNS devices are being investigated for a wide variety of disorders, such as cluster headaches and migraines, tinnitus, schizophrenia, and ASD (Hasan et al., 2015;Hyvärinen et al., 2015;Nesbitt et al., 2015). Furthermore, the discovery of the inflammatory reflex encouraged new studies to investigate VNS as a possible treatment modality for inflammatory conditions, such as inflammatory bowel disease, rheumatoid arthritis, and Crohn's disease (Bonaz et al., 2017;Koopman et al., 2016). Clinical studies focusing on iVNS showed efficacy in rheumatoid arthritis and Crohn's disease in small cohorts, while transcutaneous methods have shown efficacy in alleviating CNS inflammation by altering microglial response to a neuroprotective phenotype in mouse models in vitro (Bonaz et al., 2017;Koopman et al., 2016;Zhao et al., 2019). ...
... Furthermore, the discovery of the inflammatory reflex encouraged new studies to investigate VNS as a possible treatment modality for inflammatory conditions, such as inflammatory bowel disease, rheumatoid arthritis, and Crohn's disease (Bonaz et al., 2017;Koopman et al., 2016). Clinical studies focusing on iVNS showed efficacy in rheumatoid arthritis and Crohn's disease in small cohorts, while transcutaneous methods have shown efficacy in alleviating CNS inflammation by altering microglial response to a neuroprotective phenotype in mouse models in vitro (Bonaz et al., 2017;Koopman et al., 2016;Zhao et al., 2019). Additionally, both invasive and transcutaneous devices have shown some success in treating inflammatory conditions, like rheumatoid arthritis, by reducing mouse and human serum levels of TNF, IL-6, and IL-1β (Hong et al., 2019;Addorisio et al., 2019). ...
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The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN’s mechanisms and act as a possible treatment modality. In this review we examine the VN’s important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS’s impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN’s potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.
... It is a safe procedure and well tolerated by patients [19]. VNS is currently approved as a treatment for epilepsy, depression, and tinnitus, while it is also being researched as a potential novel treatment for stroke, RA, Crohn's disease, and heart failure [20]. ...
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Background Our understanding of osteoarthritis (OA) has evolved from a degenerative disease to one in which low-grade, chronic inflammation plays a central role. In addition, evidence suggests that OA is accompanied by both peripheral and central nervous system sensitization that can cause pain. It has been demonstrated that transcutaneous vagus nerve stimulation (tVNS) can relieve pain, inflammation, and central sensitization in other conditions including fibromyalgia, pelvic pain, and headaches. We aimed to assess the efficacy and safety of tVNS on nociceptive pain, central sensitization, and physical function in knee OA. Methods In this 12-week study, we stimulated the auricular branch of the vagus nerve with an auricular electrode connected to a transcutaneous electrical nerve stimulation device once a day for 3 days each week for 12 weeks. A total of 68 patients with chronic knee OA were randomly assigned to the active and sham groups (34 patients in each group). We used a variety of outcome measures, including the visual analog scale (VAS), pressure pain threshold (PPT), knee injury and osteoarthritis outcome score (KOOS), PainDETECT (PD-Q) and Douleur Neuropathique 4 (DN4) questionnaires. Outcome measures were recorded at baseline, At the end of the stimulation period, and then after 4 weeks. Results In the active group, compared to baseline, there was a significant improvement in VAS scores between the first and second follow-up visits (P < 0.001). A significant improvement in PPT was seen in the right knee, left knee, and right elbow in active tVNS, and this improvement persisted for four weeks post-intervention. Meanwhile, in the sham group, right knee PPT was improved but not maintained. There were statistically significant improvements in the PD-Q and DN4 scores in the active tVNS group (P < 0.001), whereas in the sham group, DN4 questionnaire did not show any improvement. In terms of functional outcomes, the improvement in KOOS was significant only in the active group (31.44 ± 18.49, P < 0.001). No serious adverse events were observed. Conclusion There is preliminary evidence to support the benefits of tVNS in OA, suggesting that neuromodulation can be used as an adjunct to existing pharmacological and non-pharmacological treatments. Trial registration The study was registered on ClinicalTrials.gov (NCT05387135) on 24/05/2022.
... Recent studies have suggested that the cerebral cortex, particularly regions involved in processing visceral sensations and regulating emotional responses, may play a critical role in modulating gastrointestinal functions through this gut-brain axis (13)(14)(15). Additionally, investigating the associations between cerebral cortical structure and BE pioneers a novel paradigm within this interdisciplinary research frontier (16,17). ...
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Purpose: To investigate the activity of default mode network (DMN), frontoparietal network (FPN) and cerebellar network (CN) in drug-resistant epilepsy (DRE) patients undergoing vagus nerve stimulation (VNS). Methods: Fifteen patients were recruited and underwent resting-state functional magnetic resonance imaging (fMRI) scans. Independent component analysis and paired sample t-tests were used to examine activity changes of DMN, FPN and CN before and after VNS. Results: Compared with preoperative patients, DMN exhibited decreased activity in left cuneus/precuneus, left median cingulate gyrus, left superior/middle occipital gyrus, right superior parietal gyrus, right precentral/postcentral gyrus, right rolandic operculum and right insula, while increased activity was observed in right supramarginal gyrus, left fusiform gyrus, right supplementary motor area, left amygdala, and right inferior frontal gyrus. FPN displayed decreased activity in left cuneus, left anterior cingulate gyrus, right precentral gyrus, left middle/inferior frontal gyrus, right middle frontal gyrus, left superior/middle temporal gyrus, left superior/middle occipital gyrus, and right superior parietal gyrus, but increased activity in right inferior temporal gyrus. CN showed decreased activity in left superior/middle frontal gyrus, right inferior frontal gyrus, left supplementary motor area, left precuneus, left postcentral gyrus, left middle occipital gyrus, right middle temporal gyrus, and left inferior cerebellum, while increased activity was detected in bilateral superior cerebellum and right fusiform gyrus. Conclusions: DMN, FPN and CN exhibited distinct changes in DRE patients following VNS. The suppression or activation of sensorimotor, language, memory and emotion-related regions may represent the underlying neurological mechanisms of VNS. However, the contrasting activity patterns between superior and inferior cerebellum require further investigation.
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The axons of the sensory, or afferent, vagus nerve transmit action potentials to the central nervous system in response to changes in the body's metabolic and physiological status. Recent advances in identifying neural circuits that regulate immune responses to infection, inflammation and injury have revealed that vagus nerve signals regulate the release of cytokines and other factors produced by macrophages. Here we record compound action potentials in the cervical vagus nerve of adult mice and reveal the specific activity that occurs following administration of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin 1β (IL-1β). Importantly, the afferent vagus neurograms generated by TNF exposure are abolished in double knockout mice lacking TNF receptors 1 and 2 (TNF-R1/2KO), whereas IL-1β-specific neurograms are eliminated in knockout mice lacking IL-1β receptor (IL-1RKO). Conversely, TNF neurograms are preserved in IL-1RKO mice, and IL-1β neurograms are unchanged in TNF-R1/2KO mice. Analysis of the temporal dynamics and power spectral characteristics of afferent vagus neurograms for TNF and IL-1β reveals cytokine-selective signals. The nodose ganglion contains the cell bodies of the sensory neurons whose axons run through the vagus nerve. The nodose neurons express receptors for TNF and IL-1β, and we show that exposing them to TNF and IL-1β significantly stimulates their calcium uptake. Together these results indicate that afferent vagus signals in response to cytokines provide a basic model of nervous system sensing of immune responses.
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The purpose of this study was to determine the effects and mechanisms of vagal nerve stimulation (VNS) and additive effects of electroacupuncture (EA) on colonic inflammation in a rodent model of IBD. Chronic inflammation in rats was induced by intrarectal TNBS (2,4,6-trinitrobenzenesulfonic acid). The rats were then treated with sham ES (electrical stimulation), VNS, or VNS + EA for 3 wk. Inflammatory responses were assessed by disease activity index (DAI), macroscopic scores and histological scores of colonic tissues, plasma levels of TNFα, IL-1β, and IL-6, and myeloperoxidase (MPO) activity of colonic tissues. The autonomic function was assessed by the spectral analysis of heart rate variability (HRV) derived from the electrocardiogram. It was found that 1) the area under curve (AUC) of DAI was substantially decreased with VNS + EA and VNS, with VNS + EA being more effective than VNS ( P < 0.001); 2) the macroscopic score was 6.43 ± 0.61 in the sham ES group and reduced to 1.86 ± 0.26 with VNS ( P < 0.001) and 1.29 ± 0.18 with VNS + EA ( P < 0.001); 3) the histological score was 4.05 ± 0.58 in the sham ES group and reduced to 1.93 ± 0.37 with VNS ( P < 0.001) and 1.36 ± 0.20 with VNS + EA ( P < 0.001); 4) the plasma levels of TNFα, IL-1β, IL-6, and MPO were all significantly decreased with VNS and VNS + EA compared with the sham ES group; and 5) autonomically, both VNS + EA and VNS substantially increased vagal activity and decreased sympathetic activity compared with sham EA ( P < 0.001, P < 0.001, respectively). In conclusion, chronic VNS improves inflammation in TNBS-treated rats by inhibiting proinflammatory cytokines via the autonomic mechanism. Addition of noninvasive EA to VNS may enhance the anti-inflammatory effect of VNS. NEW & NOTEWORTHY This is the first study to address and compare the effects of vagal nerve stimulation (VNS), electrical acupuncture (EA) and VNS + EA on TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced colitis in rats. The proposed chronic VNS + EA, VNS, and EA were shown to decrease DAI and ameliorate macroscopic and microscopic damages in rats with TNBS-induced colitis via the autonomic pathway. The addition of EA to VNS provided a significant effect on the behavioral assessment of inflammation (DAI, CMDI, and histological score) but not on cytokines or mechanistic measurements, suggesting an overall systemic effect of EA. View this article’s corresponding video summary at https://youtu.be/-rEz6HMkErM .
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C1 neurons (C1), located in the medulla oblongata, mediate adaptive autonomic responses to physical stressors (e.g. hypotension, hemorrhage, lipopolysaccharide). We describe here a powerful effect of restraint stress mediated by C1: protection against renal ischemia-reperfusion injury (IRI). Restraint stress or optogenetic C1 stimulation (10 min) protected mice from IRI. The protection was reproduced by injecting splenic T-cells pre-incubated with noradrenaline or splenocytes harvested from stressed mice. Stress-induced IRI protection was absent in α7nAChR⁻/⁻ mice and greatly reduced by destroying or transiently inhibiting C1. The protection conferred by C1 stimulation was eliminated by splenectomy, ganglionic blocker administration, or β2-adrenergic receptor blockade. Although C1 stimulation elevated plasma corticosterone and increased both vagal and sympathetic nerve activity, C1-mediated IRI protection persisted after subdiaphragmatic vagotomy or corticosterone receptor blockade. In conclusion, acute stress attenuates IRI by activating a cholinergic, predominantly sympathetic, anti-inflammatory pathway. C1 neurons are necessary and sufficient to mediate this effect.
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Psychological factors, specific lifestyles and environmental stressors may influence etiopathogenesis and evolution of chronic diseases. We investigate the association between Chronic Inflammatory Bowel Diseases (IBD) and psychological dimensions such as personality traits, defence mechanisms, and Alexithymia, i.e. deficits of emotional awareness with inability to give a name to emotional states. We analyzed a survey of 100 patients with IBD and a control group of 66 healthy individuals. The survey involved filling out clinical and anamnestic forms and administering five psychological tests. These were then analyzed by using a network representation of the system by considering it as a bipartite network in which elements of one set are the 166 individuals, while the elements of the other set are the outcome of the survey. We then run an unsupervised community detection algorithm providing a partition of the 166 participants into clusters. That allowed us to determine a statistically significant association between psychological factors and IBD. We find clusters of patients characterized by high neuroticism, alexithymia, impulsivity and severe physical conditions and being of female gender. We therefore hypothesize that in a population of alexithymic patients, females are inclined to develop psychosomatic diseases like IBD while males might eventually develop behavioral disorders.
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Content List – Read more articles from the symposium: 13th Key Symposium – Bioelectronic Medicine: Technology Targeting Molecular Mechanisms.
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Objective: To examine whether chewing gum after cesarean delivery hastens the return of gastrointestinal function. Methods: All randomized controlled trials comparing the use of chewing gum in the immediate postoperative recovery period (i.e. intervention group) with a control group were included in the meta-analysis. The primary outcome was time to first flatus in hours. Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of mean difference (MD) or relative risk (RR) with 95% confidence interval (CI). Results: 17 trials, including 3,041 women, were analyzed. Trials were of moderate to low quality with different inclusion criteria. In most of the included trials chewing gum was given right after delivery, three times a day for 30 minutes each and until the first flatus. Women who were randomized to the chewing gum group had a significantly lower mean time to first flatus (MD -6.49 hours, 95% CI -8.65 to -4.33), to first bowel sounds(MD -8.48 hours, 95% CI - 9.04 to -7.92), less duration of stay (MD -0.39 days, 95% CI -0.78 to -0.18), lower time to first feces (MD -9.57 hours, 95% CI -10.28 to 8.87) and to first feeling of hunger (MD -2.89 hours, 95% CI -4.93 to -0.85), less number of episodes of nausea or vomiting (RR 0.33, 95% CI 0.12 to 0.87), less incidence of ileus (RR 0.39, 95% CI 0.19 to 0.80) and significantly higher satisfaction. Conclusion: Gum chewing starting right after cesarean delivery three times a day for about 30 minutes until the first flatus is associated with early recovery of bowel motility. As simple, generally inexpensive intervention, providers should consider implementing cesarean postoperative care with gum chewing.
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Background: Electrical stimulation of the cervical vagus nerve (VNS) prevents postoperative ileus (POI) in mice. As this approach requires an additional cervical procedure, we explored the possibility of peroperative abdominal VNS in mice and human. Methods: The effect of cervical and abdominal VNS was studied in a murine model of POI and lipopolysaccharide (LPS)-induced sepsis. Postoperative ileus was quantified by assessment of intestinal transit of fluorescent dextran expressed as geometric center (GC). Next, the effect of cervical and abdominal VNS on heart rate was determined in eight Landrace pigs to select the optimal electrode for VNS in human. Finally, the effect of sham or abdominal VNS on LPS-induced cytokine production of whole blood was studied in patients undergoing colorectal surgery. Key results: Similar to cervical VNS, abdominal VNS significantly decreased LPS-induced serum tumor necrosis factor-α (TNFα) levels (abdominal VNS: 366±33 pg/mL vs sham: 822±105 pg/mL; P<.01). In line, in a murine model of POI, abdominal VNS significantly improved intestinal transit (GC: sham 5.1±0.2 vs abdominal VNS: 7.8±0.6; P<.01) and reduced intestinal inflammation (abdominal VNS: 35±7 vs sham: 80±8 myeloperoxidase positive cells/field; P<.05). In pigs, heart rate was reduced by cervical VNS but not by abdominal VNS. In humans, abdominal VNS significantly reduced LPS-induced IL8 and IL6 production by whole blood. Conclusions & inferences: Abdominal VNS is feasible and safe in humans and has anti-inflammatory properties. As abdominal VNS improves POI similar to cervical VNS in mice, our data indicate that peroperative abdominal VNS may represent a novel approach to shorten POI in man.
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Inflammatory bowel disease (IBD), that is Crohn's disease (CD) and ulcerative colitis, affects about 1.5 million persons in the USA and 2.2 million in Europe. The pathophysiology of IBD involves immunological, genetic and environmental factors. The treatment is medico-surgical but suspensive. Anti-TNFα agents have revolutionized the treatment of IBD but have side effects. In addition, a non-negligible percentage of patients with IBD stop or take episodically their treatment. Consequently, a nondrug therapy targeting TNFα through a physiological pathway, devoid of major side effects and with a good cost-effectiveness ratio, would be of interest. The vagus nerve has dual anti-inflammatory properties through its afferent (i.e. hypothalamic–pituitary–adrenal axis) and efferent (i.e. the anti-TNFα effect of the cholinergic anti-inflammatory pathway) fibres. We have shown that there is an inverse relationship between vagal tone and plasma TNFα level in patients with CD, and have reported, for the first time, that chronic vagus nerve stimulation has anti-inflammatory properties in a rat model of colitis and in a pilot study performed in seven patients with moderate CD. Two of these patients failed to improve after 3 months of vagus nerve stimulation but five were in deep remission (clinical, biological and endoscopic) at 6 months of follow-up and vagal tone was restored. No major side effects were observed. Thus, vagus nerve stimulation provides a new therapeutic option in the treatment of CD.
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Background: Perceived stress seems to be a risk factor for exacerbation of ulcerative colitis. Yoga has been shown to reduce perceived stress. Aims: To assess the efficacy and safety of yoga for improving quality of life in patients with ulcerative colitis. Methods: A total of 77 patients (75% women; 45.5 ± 11.9 years) with ulcerative colitis in clinical remission but impaired quality of life were randomly assigned to yoga (12 supervised weekly sessions of 90 min; n = 39) or written self-care advice (n = 38). Primary outcome was disease-specific quality of life (Inflammatory Bowel Disease Questionnaire). Secondary outcomes included disease activity (Rachmilewitz clinical activity index) and safety. Outcomes were assessed at weeks 12 and 24 by blinded outcome assessors. Results: The yoga group had significantly higher disease-specific quality of life compared to the self-care group after 12 weeks (Δ = 14.6; 95% confidence interval=2.6-26.7; P = 0.018) and after 24 weeks (Δ = 16.4; 95% confidence interval=2.5-30.3; P = 0.022). Twenty-one and 12 patients in the yoga group and in the self-care group, respectively, reached a clinical relevant increase in quality of life at week 12 (P = 0.048); and 27 and 17 patients at week 24 (P = 0.030). Disease activity was lower in the yoga group compared to the self-care group after 24 weeks (Δ = -1.2; 95% confidence interval=-0.1-[-2.3]; P = 0.029). Three and one patient in the yoga group and in the self-care group, respectively, experienced serious adverse events (P = 0.317); and seven and eight patients experienced nonserious adverse events (P = 0.731). Conclusions: Yoga can be considered as a safe and effective ancillary intervention for patients with ulcerative colitis and impaired quality of life. Trial registration: ClinicalTrials.gov identifier: NCT02043600.