vagal tone: effects on sensitivity, motility, and inflammation · vn stimulation (vns), either...

MINI-REVIEW

Vagal tone: effects on sensitivity, motility, and

inflammation

B. BONAZ,*,† V. SINNIGER*,† & S. PELLISSIER†,‡

*University Clinic of Hepato-Gastroenterology, University Hospital, Grenoble, France

†Stress and Neuro-Digestive Interactions, Inserm U1216, University Grenoble Alpes, Institute of Neurosciences, Grenoble, France

‡Department of Psychology, LIP/PC2S, Savoie University, Chamb�ery, France

Key Points

• The vagus nerve is involved in the control of gastrointestinal sensitivity, motility and inflammation.

• A low vagal tone, as assessed by heart rate variability, is a marker of autonomic dysfunction that might favor

dysfunction of the gastrointestinal tract.

• Restoration of vagal tone is a therapeutic target in some gastrointestinal diseases. Vagus nerve stimulation,

either invasive or non-invasive, opens therapeutic avenues.

Abstract

The vagus nerve (VN) is a key element of the

autonomic nervous system. As a mixed nerve, the

VN contributes to the bidirectional interactions

between the brain and the gut, i.e., the brain-gut axis.

In particular, after integration in the central auto-

nomic network of peripheral sensations such as

inflammation and pain via vagal and spinal afferents,

an efferent response through modulation of pregan-

glionic parasympathetic neurons of the dorsal motor

nucleus of the vagus and/or preganglionic sympathetic

neurons of the spinal cord is able to modulate

gastrointestinal nociception, motility, and inflamma-

tion. A low vagal tone, as assessed by heart rate

variability, a marker of the sympatho-vagal balance, is

observed in functional digestive disorders and inflam-

matory bowel diseases. To restore a normal vagal tone

appears as a goal in such diseases. Among the

therapeutic tools, such as drugs targeting the cholin-

ergic system and/or complementary medicine (hypno-

sis, meditation. . .), deep breathing, physical exercise,

VN stimulation (VNS), either invasive or non-invasive,

appears as innovative. There is new evidence in the

current issue of this Journal supporting the role of VNS

in the modulation of gastrointestinal functions.

Keywords inflammatory bowel disease, motility,

pain, vagal tone, vagus nerve stimulation.

INTRODUCTION

In the current issue of this journal, Frokjaer et al.1

assessed, in healthy volunteers, the effects of transcu-

taneous vagus nerve stimulation (VNS) and deep slow

breathing on validated cardiometrically derived param-

eters of vagal tone, musculoskeletal pain thresholds,

descending pain modulation and gastroduodenal motil-

ity in a randomized, sham-controlled, single-blind,

crossover trial. They showed that transcutaneous VNS

increased: (i) vagal tone, (ii) thresholds to bone pain,

(iii) frequency of antral contractions, and (iv)

Address for Correspondence

Bruno Bonaz, MD-PhD, Clinique Universitaire d’H�epato-Gastroent�erologie, CHU Grenoble, CS-10217, 38043 GrenobleCedex 09, France.Tel: +33476765597; fax: +33476765297;e-mail: [email protected]: 2 February 2016Accepted for publication: 9 February 2016

© 2016 John Wiley & Sons Ltd 455

Neurogastroenterol Motil (2016) 28, 455–462 doi: 10.1111/nmo.12817

Neurogastroenterology & Motility

gastro-duodenal motility index. These data have poten-

tial therapeutic implications in the domain of chronic

pain and gastrointestinal motility disturbances but also

inflammatory disorders of the gastrointestinal tract as

observed in functional dyspepsia, irritable bowel syn-

drome (IBS), inflammatory bowel disease (IBD), and

others.

The VN is a key part of the autonomic nervous

system (ANS), composed of the parasympathetic and

sympathetic nervous systems. Information regarding

the extent of its involvement in the regulation of the

digestive tract homeostasis is rapidly expanding and

provides new insights from a therapeutic point of view.

The VN is the longer nerve in the body; it is a mixed

nerve containing approximately 80% afferent and 20%

efferent fibers2 supplying mostly visceral organs. Vagal

afferents are activated by gastrointestinal and pancre-

atic hormones, mechanical distortion of the mucosa,

luminal osmolarity and ingested macronutrients, and

are involved in the regulation of food intake, pancreatic

exocrine and endocrine secretion, and cardiac and

respiratory rhythm generation.

In normal resting conditions, there is a balance

between the parasympathetic and sympathetic nervous

systems as indexed by heart rate variability (HRV).3

This balance is modified in acute stress condition

because stress induces a parasympathetic withdrawal

and stimulates the sympathetic nervous system.4 This

balance is restored after acute stress but in chronic

stress conditions it can be disrupted for long periods.

Stress is involved in the pathophysiology of functional

and organic diseases of the gastrointestinal tract such

as functional dyspepsia, IBS, IBD (Crohn’s disease,

ulcerative colitis).5,6 An imbalance between the ANS

and the hypothalamic pituitary adrenal (HPA) axis has

been reported in such diseases.7 This imbalance is

often the consequence of an imbalance between the

prefrontal cortex (PFC) and the amygdala which inner-

vate central autonomic network (CAN) areas.8 Thus,

an abnormal vagal tone could be the cause and/or the

consequence of such an imbalance. Consequently,

restoration of normal vagal tone could be of interest

in the medical management of such diseases either

through drugs targeting the cholinergic system, com-

plementary medicine (hypnosis, meditation. . .), deep

breathing, physical exercise, VNS. This might favor-

ably prevent an individual’s risk profile.

In this mini-review, we highlight the anatomy of the

ANS with a special focus on the VN and the central

ANS and the control/evaluation of vagal tone in

normal and pathological conditions through HRV. We

will focus on the role of vagal tone on sensitivity,

motility, and inflammation of the gastrointestinal

tract. Finally, we will review nonpharmacological

ANS modulation therapies, focusing on VNS, com-

menting on novel technologies and strategies on the

horizon.

THE AUTONOMIC NERVOUS SYSTEMAND THE CENTRAL AUTONOMICNETWORK

Visceral information conveyed by vagal and spinal

afferents are integrated in the CAN containing brain

regions highly interconnected and distributed through-

out the neuraxis involved in the autonomic, endocrine,

motor, immune, and behavioral responses.9 These

regions include: the frontal, insular, and anterior cingu-

late cortices; the amygdala (central nucleus); several

areas of the hypothalamus, in particular the paraven-

tricular nucleus (PVH); the midbrain periaqueductal

gray matter; the parabrachial nucleus in the pons; and,

in themedulla, the nucleus tractus solitarius (NTS), the

first relay station for general visceral afferents, ventro-

lateral reticular formation and raphe nuclei. This brain

network can be divided roughly into structures such as

the frontal cortex, which are involved in higher level

executive functions, and structures such as thehypotha-

lamus and limbic system, which are involved in home-

ostatic functions. These areas receive converging

visceral and nociceptive inputs and, after integration,

generate stimulus-specific patterns of autonomic

responses via projections to preganglionic sympathetic

neurons in the spinal cord and parasympathetic neurons

of the dorsal motor nucleus of the VN to modulate the

ANS and thus the vagal tone. Many of these areas are

also components of pain modulatory circuits and con-

trol nociceptive processing via projections to the spinal

and trigeminal dorsal horns. The CAN is a complex

system including many positive and negative feedback

loops governing both sympathetic and parasympathetic

outputs. Because of this complexity, it is difficult to

predict the final results of activity of this system since

prefrontal activation might induce enhancement of

sympathetic activity in one situation but enhancement

of vagal activity in another.

VAGAL TONE AND THE CENTRALAUTONOMIC NETWORK

Vagal tone could be explored via the cardiac vagal tone

by means of HRV measurement.3 However, correla-

tions between cardiac vagal tone and, for example,

gastrointestinal vagal tone require further study, par-

ticularly under pathophysiological conditions. There is

no a priori reason why vagal output from the nucleus

© 2016 John Wiley & Sons Ltd456

B. Bonaz et al. Neurogastroenterology and Motility

ambiguus to the heart is regulated in concert with

vagal output from the dorsal motor nucleus of the VN

to the stomach. Actually, this method even if not

direct, provides the advantage of being non-invasive,

easy to apply and perform comparisons among different

studies. The cardiac vagal tone and HRV have allowed

the construction of the neurovisceral integration

model that includes the CAN.10 A decreased HRV at

rest reflects a low vagal tone and could be considered as

a marker of stress.11 Decreased vagal function and HRV

are associated with increased fasting glucose level,

increased overnight urinary cortisol, and increased pro-

inflammatory cytokines and acute-phase proteins.12

All of these factors have been associated with increased

allostatic load and poor health. A high level of HRV is

associated with good health and well-being and good

resilience in emotional self-regulation.13,14 A high

level of HRV with low level of cortisol reflects the

inhibitory influence of the PFC on amygdala.12 The

PFC contributes to negative feedback control of the

HPA axis.15 The hypoactivity of the PFC and the

enhancement of amygdala activity are strongly influ-

enced by stress. The PFC regulates peripheral immune

cells through the autonomic and neuroendocrine

pathways and controls vagal tone by modulating the

VN efferent outflow. Increased inflammatory markers,

e.g., C reactive protein and IL-6 are associated with

decreased HRV.16 We have described an imbalance

between the HPA axis and vagal tone in CD and IBS

patients.7 Furthermore, we highlighted the specific

homeostatic link between a low vagal tone and tumor

necrosis factor (TNF)-a in Crohn’s disease and epi-

nephrine in IBS in relation with a strong comorbidity of

negative mood, anxiety, and visceral pain that has been

observed in those diseases.7 These data, underline the

link between brain areas involved in cognition and

mood regulation, visceral perception and conscious-

ness, stress response, and HRV as a marker of vagal

tone in gut diseases.

VAGAL TONE AND SENSITIVITY

Classically, pain arising from the viscera is mediated

exclusively by spinal afferents and there is evidence

that the sympathetic nervous system is involved in

pain generation in chronic pain states.17 There is

growing evidence that the VN modulates nociceptive

processing in the spinal cord and the brain.18 Studies

have shown that vagal afferents respond to nociceptive

mechanical and chemical stimulation and this leads to

brainstem representation of nociceptive signals. The

increase in NTS c-fos expression observed in response

to noxious gastric distention is attenuated by vago-

tomy but persists after spinal cord transection.19 It has

been suggested that nociceptive input through the VN

may contribute to the affective-emotional rather than

to the sensory-discriminative aspect of pain. Thus, the

VN may indirectly modulate abdominal hyperalgesia.

Electrical stimulation of abdominal vagal afferents

inhibits or facilitates somatic nociceptive impulse

transmission in the spinal dorsal horn, and depresses

nociceptive behavior, depending on whether unmyeli-

nated or myelinated vagal afferents are excited.18

Patients with VNS for epilepsy and depression often

report improvement of pain. There is evidence for a

relationship between VN activity and pain, based on

the fact that the VN inhibits factors that are etiologic

to pain such as inflammation, oxidative stress, and

sympathetic activity, activates brain regions that can

oppose the brain ‘pain matrix’, and finally influences

the analgesic effects of opioids.20 Administration of

cholecystokinin (CCK)-8 enhances memory retention

in the mice after aversive training; this effect is

blocked by vagotomy indicating that CCK-8 may

produce its effect on memory retention by activating

vagal afferents.21 Thus, in a number of gastrointestinal

disorders, such as IBS, nutrient content may contribute

to painful visceral perception by enhancing visceral

aversive memory via vagal afferent pathways.22

Activation of vagal afferents is part of themechanism

that not only gives rise to vago-vagal reflex but also can

modulate brain cortex neuronal activity and plays a role

in the behavioral control of nociception and memory

storage processes.23 It is well known that a hot drink or a

nourishing meal are relaxing and help to calm anxiety

suggesting that enhanced sensory vagal inputs originat-

ing fromthegutmodulateattitudeandbehavior.24Vagus

nerve stimulation suppresses experimentally induced

pain through activation of vagal afferents which termi-

nate in the NTS; NTS neurons then innervate the CAN

and the nucleus raphe magnus and locus coeruleus, to

cause subsequent activation of descending inhibitory

painpathways.25Low-intensityVNSthatactivatesvagal

afferent Ad fibers reduces visceral pain suggesting that a

group of vagal afferents innervating viscera may have

functions related to visceral pain inhibition.23

VAGAL TONE AND MOTILITY

The VN innervates classically the digestive tract from

the esophagus to the splenic flexure while the rest of

the digestive tract, i.e., the left colon and rectum, is

innervated by the sacral parasympathetic nucleus.

However, for some anatomists, the VN innervates all

the digestive tract in human.26 The VN is a major

component in the control of upper gastrointestinal


Volume 28, Number 4, April 2016 Mini-review

motility, thus a low vagal tone could favor gastroin-

testinal motility disturbances. Vagal dysfunction is

known to contribute to esophageal hypomotility.27

Physiological vagal input to cholinergic enteric neu-

rons is necessary to maintain a basal gastric tone and

vagal cooling induces a decrease in gastric tone.28 A

very low tonic vagal activity is apparently necessary

and sufficient to produce basic antral motility, while

more sustained vagal activity is necessary for high-

amplitude gastric contractions and significant sus-

tained fundic relaxation; the maximal effect of vagal

stimulation on amplitude and length of gastric con-

traction is already reached at 2–4 Hz, with no further

increase at 8 Hz.29 Chewing gum, via activation of

cephalic stimulation, is an adequate stimulus to

induce vagally mediated normalization of meal-

induced antral motility in functional dyspepsia, sug-

gesting that hypomotility is related to inadequate vagal

stimulation.30 Antral dysmotility is a consistent find-

ing in diabetics with delayed gastric emptying and

impaired gastric autonomic innervation probably con-

tributes to this dysmotility. Patients with Type 1

diabetes mellitus have impaired meal-induced volume

response, possibly as a consequence of reduced vagal

tone.31 Gastric dysmotility in diabetes is thus caused,

at least in part, by vagal neuropathy and the VN is

important for gastric meal accommodation in man.

Stress is well known to delay gastric emptying, alter

intestinal transit and colonic motility and inhibit vagal

tone; this effect is mediated, at least in part, by

corticotrophin-releasing factor.4 Autonomic dysfunc-

tion has been frequently reported in patients with

gastrointestinal motility disorders. By stimulating

gastrointestinal motility via activation of vagal path-

ways,32 gum chewing reduces the duration of postop-

erative ileus in abdominal surgery.33 Nicotine gum

chewing combines the stimulation of the cephalic-

vagal reflex by gum chewing and the activation of the

cholinergic anti-inflammatory pathway by nicotine

administration; it might be beneficial for the preven-

tion of postoperative ileus.34 Improving vagal tone

through gum chewing, deep breathing,1 moderate-

pressure massage therapy, or other exercises that have

a strong effect on heart rate and its variability or

through VNS could have prokinetic effects. Further

investigations are needed to explore the intestinal

component of digestive tract motility under the mod-

ulation of vagal tone re-inforcement.

VAGAL TONE AND INFLAMMATION

TheVNexerts a dual anti-inflammatory role through its

afferents and efferents. Classically, peripheral pro-

inflammatory cytokines, such as IL-1beta, activate

vagal afferents and then the HPA axis through nora-

drenergic projections from the NTS to the PVH.35 More

recently, an anti-inflammatory role of vagal efferents

has been described by Tracey’s group. Indeed, VNS-

induced acetylcholine release from the peripheral ter-

minals of vagal efferents dampens the release of TNF-aby macrophages in a model of endotoxic shock in rats.

This effect is mediated via activation of a7-nicotinicreceptors on macrophages and defined as the inflamma-

tory reflex, i.e., the cholinergic anti-inflammatory

pathway.36 The same group has described a vago-

sympathetic link involving a stimulatory effect of the

VN on the spleen through an interaction with the

splenic sympathetic nerve resulting in the inhibition of

TNF-a release by spleen macrophages36 although this

pathway has been recently revisited.37 We have shown

that vagal tone is significantly blunted in IBD in relation

with negative affect,38 and high TNF-a levels.7 Conse-

quently, low vagal tone has a pro-inflammatory effect.

Low vagal tone is a significant predictor of necrotizing

enterocolitis, an exaggerated inflammatory response

resulting in high levels of pro-inflammatory cytokines,

in preterm infants39 which opens up avenues for its role

as a predictive biomarker of this disease. Stress is

evoked in the pathophysiology of inflammatory disor-

ders such as IBD, at least through an inhibition of vagal

tone either through activation of projections from the

hypothalamus to the dorsal motor nucleus of the VN or

through modifications of the fronto-amygdaloid com-

plex.5 We have shown that low frequency (5 Hz) VNS

improves colitis in rats40 and may exert an anti-

inflammatory effect in Crohn’s disease patients that

exhibit an autonomic imbalance.41 We showed that

VNS induced a clinical, biological, and endoscopic

remission at 6 months in the majority (5/7) of patients

with mild to moderate active Crohn’s disease and

restored autonomic balance toward the homeostatic

values observed in healthy subjects.38 We have also

shown, in a case report, that VNS induced significant

changes in resting EEG.42 In particular, activation was

observed over the mediofrontal electrodes for both low

and high frequency bands with the most important

activation for theta band. Significant correlations were

detected between EEG and high frequency-HRV for

delta, theta, beta, and gamma frequency bands.

THERAPEUTIC IMPLICATIONS:ACTIVATION OF VAGAL AFFERENTS/EFFERENTS

Vagus nerve stimulation can be used to modu-

late gastrointestinal inflammation, motility, and



nociception, in addition to its current use for drug-

resistant epilepsy and depression and open new

avenues in the therapeutic armamentarium. Implan-

table VNS is an invasive technique, which poses a risk

for adverse events from infection, although the risk is

low since the technique is well described and com-

monly used. To avoid potential bradycardia, VNS

electrodes are placed on the left cervical VN which is

easily accessible at the level of the neck. ~100 000

patients have been implanted with invasive VNS for

epilepsy and depression. Depending on the therapeutic

purpose, either anti-inflammatory and/or anti-nocicep-

tive, or prokinetic, one might suggest activating vagal

afferents in case of nociception or vagal efferents in

case of inflammation and for prokinetic effect. How-

ever, classically while low (5–10 Hz) frequency VNS is

supposed to activate vagal efferents and high (20–30 Hz) frequency is supposed to activate vagal affer-

ents, in practice things are not so simple. Indeed, we

have shown that even low frequency (5 Hz) VNS is able

to modulate CNS functions.43 Consequently, it seems

unlikely to selectively activate vagal afferents or

efferents alone. In addition, one may speculate that

activation of both vagal afferents and efferents may be

of interest in the domain of inflammation, pain, and

gastrointestinal motility. The total charge for the

device plus implantation varies from $12 000 to

$25 000. By comparison, the cost of a 1 year treatment

of biosimilar infliximab is ~6000 euros for the treat-

ment alone in IBD.

Newer non-invasive VNS delivery systems do not

require surgery and permit patient-administered stim-

ulation on demand. These non-invasive VNS systems

improve the safety and tolerance of VNS and are easy

to use, making it more accessible and facilitating

further investigations across a wider range of uses. Two

non-invasive VNS devices are currently on the market

(Fig. 1). NEMOS (Cerbomed, Erlangen, Germany) is an

external device that provides transcutaneous auricular

VNS (ta-VNS) by using a dedicated intra-auricular

electrode (like an earphone) which stimulates the

auricular branch of the VN. No clinically relevant

adverse events, either cardiovascular or otherwise,

have been reported with this device. The recom-

ImplantableVNS devices Non-implantable VNS devices

Figure 1 Implantable VNS systems: (top)

VNS Therapy system (Cyberonics, Houston,

TX, USA); (bottom) CardioFit (BioControl

Medical Ltd.). Non-implantable VNS

systems: (top) NEMOS (Cerbomed), (bottom)

gammaCore (electroCore LLC).



mended daily stimulation duration is 4 h and should

be reached daily. Transcutaneous auricular VNS is able

to increase HRV and reduce sympathetic nerve outflow

in healthy controls.44 GammaCore (electroCore LLC,

Basking Ridge, NJ, USA), is a non-invasive VNS device

that uses two stainless steel round discs as skin

contacts to deliver a programmable number of stimu-

lation cycles through a transcutaneous low voltage

electrical signal to the cervical VN, each lasting 120 s

at a frequency of 25 Hz. This device is currently being

tested for headache, epilepsy, and gastrointestinal

disorders.45

Some data is emerging regarding the use of VNS,

either invasive on non-invasive, in fibromyalgia,

pelvic pain, and headaches (see for review 46). Lange

et al.47 examined the safety and tolerability of inva-

sive VNS in treatment resistant fibromyalgia and

determined preliminary measures of efficacy as a

secondary endpoint in this small cohort. Together

with what is already known about VNS and its

antinociceptive and anti-inflammatory effects, find-

ings from preliminary studies are promising in terms

of addressing the hyperalgesia and central sensitiza-

tion associated with chronic pelvic pain and other

chronic pain syndromes.48

Ideally, VNS coupled to the detection of HRV would

be of interest, particularly in patients with vagal

dysautonomia, i.e., vagal hypotony as observed in IBD

and IBS. The neurostimulator itself, for example, could

also be used to measure HRV.38 For example, CardioFit

(BioControl Medical Ltd., Yehud, Israel) is an implan-

table VNS device being investigated in heart failure

that acts through preferential activation of vagal

efferents.49 The system consists of a stimulator, a

sensor lead and a stimulation lead, which are

implanted under the skin of the chest. The sensor lead

is extended from the stimulator to the right ventricle of

the heart, and the stimulation lead is extended from

the stimulator to the VN on the right side of the neck.

Once activated, the stimulator’s electrical pulses are

transferred via the stimulation lead to the VN. The

stimulation is designed to correct the autonomic

imbalance (sustained sympathetic overdrive and

parasympathetic withdrawal) that is maladaptive in

heart failure. Unfortunately, CardioFit is an invasive

system. A VNS device coupled to skin conductance

evaluation, as a marker of sympathetic nervous system

activity, would be of interest as well. In the same way,

a VNS device coupled to circulating TNF-a levels

would be of interest. Indeed, following intraperitoneal

administration of TNF-a, the VN senses changes in

peripheral inflammatory status within 3 min, and

increases vagal tone in response.50 This defines a

mechanism of inflammation sensing by the brain.

Another point, is the improvement of VNS device

through a miniaturization of the device and a multi-

contact electrode that would stimulate ideally all the

fibers components of the VN or selectively afferents or

efferents. However, the exact topographic distribution

of vagal afferents/efferents in the VN needs to be

specified. Although non-implantable devices are attrac-

tive, they raise the problem of compliance as observed

in the medical treatment of chronic diseases with

drugs and which is avoided by the classical invasive

VNS.

CONCLUSION

As a bidirectional link between the brain and the

gastrointestinal tract the VN is involved in maintain-

ing the homeostasis of gut functions such as sensitiv-

ity, motility, and immunity both through its sensing

and modulatory roles. A dysfunction of the vagal tone

is observed in functional and inflammatory digestive

disorders. To restore a normal vagal tone is a thera-

peutic goal in such diseases where VNS appears as an

interesting tool.

FUNDING

No funding obtained for this mini review.

CONFLICTS OF INTEREST

No conflicts of interest exist.

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