Vagus Nerve Stimulation at the Interface of Brain Gut ...perspectivesinmedicine.cshlp.org/content/early/2018/09/10/cshpersp… · Vagus Nerve Stimulation at the Interface of Brain–Gut

Vagus Nerve Stimulation at the Interfaceof Brain–Gut Interactions

Bruno Bonaz,1,2 Valérie Sinniger,1,2 and Sonia Pellissier3

1Division of Hepato-Gastroenterology, Grenoble University Hospital, 38043 Grenoble Cedex 09, France2U1216, INSERM, GIN, Grenoble Institute of Neurosciences, University Grenoble Alpes, Grenoble, France3University Grenoble Alpes, University Savoie Mont Blanc, 38000 Grenoble, France

Correspondence: [email protected]

The vagus nerve, a key component of the cross-communication between the gut and thebrain, is a major element of homeostasis sensing the “milieu intérieur” and boosting thenervous and endocrine responses to maintain the gastrointestinal health status. This nervehas anti-inflammatory properties regulating the gut through the activation of the hypothalam-ic–pituitary–adrenal axis and the release of cortisol and through avagovagal reflex,which hasan anti–tumor necrosis factor (TNF) effect called the cholinergic anti-inflammatory pathway.Stimulating this nerve is an interesting tool as a nondrug therapy for the treatment of gastro-intestinal diseases in which brain–gut communication is dysfunctional, such as inflammatorybowel disorders and others. This review presents the rationale of vagal gastrointestinal phys-iologyanddiseases and themost recent advances in vagus nerve stimulation. It also highlightsthe main issues to be addressed in the future to improve this bioelectronic therapy for gas-trointestinal disorders.

The brain and the gut communicate bidirec-tionally through the autonomic nervous sys-

tem (ANS), including (1) the parasympatheticnervous system, that is, the vagus nerve (VN)originating from the cranial parasympatheticnucleus, (2) the pelvic nerves originating fromthe sacral parasympathetic nucleus, (3) and thesympatheticnervoussystem(splanchnicnerves),and the circumventricular organs (Bonaz andBernstein 2013). The VN, a key component ofthese interactions, is a mixed nerve composed of80% and 20% of afferent and efferent fibers, re-spectively (Prechtl and Powley 1990). Conse-quently, the VN is essentially a sensory nerve

that informs the brain on the state of visceralorgans such as the gut. In physiological condi-tions, the VN is implicated in homeostasis be-cause it senses the “milieu intérieur” of the gutthrough the interaction of nutrients and/or gutpeptides with vagal afferents (Berthoud andNeuhuber 2000; Berthoud 2004; Ritter 2004).The information is transmitted to the nucleustractus solitarius (NTS) in the medulla, themain entrance of the VN to the brain, in closecontact with the dorsal motor nucleus of the VN(DMNV) ventrally to the NTS, the origin ofvagal efferents. This creates a vagovagal loopinvolved in the regulation of gastrointestinal

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motility, acid secretion, food intake, and satiety(Fig. 1) (Greenwood and Davison 1987; Ber-thoud 2008a). From the NTS, the VN commu-nicates via interneuron projections with theparabrachial nucleus, locus coeruleus, paraven-tricular nucleus of the hypothalamus (PVH),limbic system (amygdala), and other brain nu-clei of the central autonomic network (CAN)(Benarroch 1993). The CAN integrates this in-formation and thenmodulates the ANS throughdescending projections to the DMNV, thusmodulating vagal efferents, and the tractus in-termediolateralis of the spinal cord at the originof the efferent sympathetic nerves (Fig. 2)(Strack et al. 1989; Abe et al. 2017). An inflam-matory reflex in which vagal afferents activatevagal efferents in response to peripheral inflam-mation was described by Tracey (2002) to in-duce anti-inflammatory properties such as ananti–tumor necrosis factor (TNF) effect. TheVN has an anti-inflammatory effect throughtwo pathways (Fig. 3). One is a neuroendocrinepathway involving the hypothalamic–pituitary–adrenal (HPA) axis through a vago–NTS–PVH

pathway leading to the release of cortisol, ananti-inflammatory hormone (Harris 1950).The other is a neural pathway, the inflammatoryreflex, involving VN efferents, that is, the cho-linergic anti-inflammatory pathway (CAP)(Tracey 2007). Such anti-inflammatory proper-ties could be used to dampen peripheral inflam-mation of the gut, through VN stimulation(VNS), as observed in inflammatory bowel dis-ease (IBD), Crohn’s disease (CD), and ulcerativecolitis (UC), but also irritable bowel syndrome(IBS), an IBD “a minima” (Catanzaro et al.2014). IBS and IBD are observed, respectively,in 10%–20% and 0.5%–1% of the populationand are a real health cost burden. For example,CD and UC were associated with direct and in-direct costs ranging between $14.6 and $31.6billion in 2014 (Mehta 2016).

Usually, there is an equilibrium betweensympathetic and parasympathetic activities re-ferred to as the sympathovagal balance involvedin homeostasis regulation. A disruption of thisequilibrium favors but also reflects pathologicalconditions (Bonaz 2016). More specifically,

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Figure 1. The brain–gut axis. The autonomic nervous system (ANS) is the bidirectional link between the centralnervous system (CNS) and the gut via the enteric nervous system (ENS) and the immune, endocrine, and vascularsystems. NTS, nucleus tractus solitarius; DMNV, dorsal motor nucleus of the vagus nerve.

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stress is able to induce an imbalance of the ANSand proinflammatory conditions. Stress usuallystimulates the sympathetic nervous systemwhileinhibiting the VN and stimulating the sacralparasympathetic nucleus (Tache and Bonaz2007; Wood and Woods 2007). An imbalanceof the ANS was described in IBS and IBD (Pel-lissier et al. 2010; Pellissier and Bonaz 2017).The variability in beat-to-beat intervals of theelectrocardiogram is called heart rate variability(HRV). At rest, HRV variables are the markersof the parasympathetic vagal tone. A low HRV,

marker of a low parasympathetic vagal tone, isobserved in IBS and IBD and in proinflamma-tory conditions. Furthermore, a low HRV is as-sociated specifically with high plasmatic levels ofTNF-α in CD, and high resting plasmatic levelsof epinephrine in IBS (Pellissier et al. 2014).Consequently, stimulating the VN to improvethese diseases should be of interest.

Bioelectronic medicine is an original non-drug therapeutic approach, which relies on neu-romodulation of the nervous system’s electricalactivity to restore organ functions and health

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Figure 2. Brain–gut integrative pathway. The gut afferents from the vagus and splanchnic nerves are transmittedto the nucleus tractus solitarius (NTS), in the medulla in close contact with the dorsal motor nucleus of the vagusnerve (DMNV), the origin of parasympathetic vagal efferents, thus creating an autonomic brainstem loopinvolved in the regulation of gastrointestinal motility, acid secretion, food intake, and satiety. This loop is mod-ulated by an autonomic forebrain loop that includes nuclei in the pons, the hypothalamus, the hippocampus, theamygdala, the anterior cingulate, the insular, and the prefrontal cortices. This forebrain loop, also referred to asthe central autonomic network, coordinates visceral information in an integrative dimension that includesneuroendocrine responses, emotions, cognition, and behavior. These two central loops explain how stress,feelings, and thoughts can influence gut functioning and vice versa. RVLM, rostral ventrolateral medulla;ILM, intermediolateralis nucleus.

Vagus Nerve Stimulation

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Activationof the HPA axis

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Figure 3. Different pathways of the anti-inflammatory properties of the vagus nerve and how to target the vagusnerve for its anti-inflammatory properties. ACh, acetylcholine; CAN, central autonomic network; DMNV, dorsalmotor nucleus of the vagus nerve; EPI, epinephrine; HPA, hypothalamic–pituitary–adrenal; NE, norepineph-rine; NTS, nucleus tractus solitarius; TNF-α, tumor necrosis factor α; VNS, vagus nerve stimulation; α7nAChR,α7 nicotinic acetylcholine receptor (Bonaz et al. 2017).

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without the adverse effects of pharmaceuti-cal drugs, thus preventing compliance issues(Olofsson and Tracey 2017). Stimulating pe-ripheral nerves, such as the VN, through VNSis of interest (Bonaz et al. 2013, 2016a,b,c, 2018).The aim of VNS is to use the anti-inflammatoryproperties of the VN and to restore a normalvagal tone. This is within the scope of bioelec-tronic medicine. In this article, we focus onVNSas a nondrug therapy at the interface of brain–gut interactions in IBD, IBS, and other inflam-matory diseases.

BRAIN–GUT INTERACTIONS:NEUROANATOMICAL FUNDAMENTALS

Brain–gut interactions have been well describedboth at the preclinical and clinical levels. Indeed,proinflammatory cytokines are able to target

circumventricular organs, which send projec-tions to the PVH to activate the HPA axis todampen inflammation through the release ofglucocorticoids (Rivest et al. 2000). Likewise,vagal afferents distributed in the gut wall, in-cluding in the external muscle layers, myentericplexus, and mucosal lamina propria (Fig. 4), aresensitive to distension and to the release ofproinflammatory cytokines, as well as to gutpeptides (CCK, GLP-1, leptin, serotonin) actingon vagal receptors and microbiota (de Lartigueand Diepenbroek 2016; Bonaz et al. 2018). Theinformation is then transmitted to the NTS,which sends projections to the CAN inducingendocrine, autonomic, emotional, and cognitiveresponses (Benarroch 1993). After integratingthis information, the CAN is able to modulatethe efferent limbs of the ANS, that is, the VNand splanchnic nerves. In the same way, “sym-

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Figure 4. Extrinsic (autonomic nervous system [ANS]) and enteric nervous system (ENS) innervation of the gut.The extrinsic innervation includes the vagal parasympathetic and sympathetic systems, with afferent sensory andefferent secretomotor fibers. The ENS is a complex neural network controlling various cell populations, includingsmooth muscle, mucosal secretory, endocrine, and immune/inflammatory cells, as well as microvasculature (forsecretion, absorption, andmotility). The ENS network is organized in several plexuses, located in various levels ofthe gut wall, which provides a partial autonomous control of gastrointestinal functions. The ANS provides theextrinsic innervation of the gut with (1) sensory neurons linked to vagal, thoracolumbar, and lumbosacralpathways that are located at the mucosal, myenteric, muscular, and vascular levels, and (2) vagal, sacral, andsympathetic axons for motor activity.



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pathetic afferent” fibers with cell bodies local-ized in the dorsal root ganglia are essentiallyinvolved in visceral pain but also in gut inflam-mation. They project to the spinal cord andreach the NTS (Gamboa-Esteves et al. 2001)and the amygdala, through a spino–parabra-chial–amygdala pathway (Bernard and Besson1990), the thalamus, and the insula, a centrallocus of interoception, and then project to theanterior cingulate and prefrontal cortices (Fig.2) (Craig 2002). Vagal and “sympathetic affer-ents” reach the central nervous system (CNS)through different pathways, respectively, theNTS and spinal cord; but from these locations,the brain targets are almost the same. Theircommon projections on insula and prefrontalcortex explain how various visceral stimuli con-veyed through autonomic afferents are involvedin interoception and interoceptive awareness(Craig 2002). The central sensitivity syndrome,characterizing an abnormal interoceptive pro-cess, has been described in various chronic dis-eases such as IBS, fibromyalgia, chronic fatiguesyndrome, or posttraumatic stress disorders(Yunus 2007). All these pathways have been wellidentified in rodents using the expression of c-fos, a marker of neuronal activation (Bonaz etal. 2000; Sinniger et al. 2005) and functionalhuman brain imaging both in physiological(Baciu et al. 1999) and pathological conditionssuch as IBS and IBD in which abnormal brainloci of activation, aswell as abnormalmorphom-etry, tractography, or resting state, have beendescribed (Bernstein et al. 2002; Bonaz et al.2002; Rubio et al. 2016; Agostini et al. 2017;Kragel et al. 2018).

There is also an anatomical link between themicrobiota and the brain, that is, the micro-biota–gut–brain axis in which the VN is in-volved. Indeed, the VN is able to sense micro-biota metabolites through its afferents and totransfer this gut information to the CAN, thengenerating an adapted or inappropriate re-sponse from the CAN to the gut and the micro-biota (Bonaz et al. 2018). The VN, via the CAP,could modulate the gut microbiota throughmodifications of intestinal permeability and lo-cal immunity (Bonaz et al. 2018). Thus, the va-gal tone could be an interesting marker of the

microbiota–gut–brain axis, and targeting vagaltone through VNS could have therapeutic im-plications in the modulation of this axis.

ANTI-INFLAMMATORY PROPERTIESOF THE VAGUS NERVE

As mentioned above, the VN has anti-inflam-matory properties both through its afferents,(activating the HPA axis) and efferents (via theCAP), putting the VN at the interface of theneuro–endocrine–immune axis (Bonaz et al.2017). Tracey et al. showed, in a model of septicshock following intravenous lipopolysaccha-rides, that stimulating the distal end of the cutVN, thus activating vagal efferents, was able todampen the shock (Borovikova et al. 2000). Thiseffect is mediated by acetylcholine (ACh), whichbinds to the α7 nicotinic cholinergic receptor(αnAChR) of macrophages, thus inhibiting therelease of TNF-α by these cells (Wang et al.2003). In the gut, the VN does not interact di-rectly with macrophages but with nNOS–VIP–ACh enteric neurons (Cailotto et al. 2014). An-other pathway involving the spleen has beendescribed: an interaction of the VN with thesplenic sympathetic nerve, which releases nor-epinephrine that binds to splenic T-lympho-cytes β2 receptors and leads to the inhibitionof TNF-α release by macrophages, through aninteraction of ACh with α7nAChR (Fig. 3) (Ro-sas-Ballina et al. 2011). Some investigators haveproposed alternative pathways involving thesympathetic nervous system, that is, the greatersplanchnic nerves that are activated in responseto an immune challenge and which, in turn,drive postganglionic sympathetic neurons to in-hibit inflammation through splenic sympathet-ic nerve terminals (Martelli et al. 2014, 2016).Indeed, the thoracolumbar spinal cord at theorigin of the splenic nerve is activated by de-scending pathways from A5, C1, and PVH,which are connected to vagal afferents (Stracket al. 1989; Abe et al. 2017). The central cholin-ergic activation of a VN-to-spleen circuit hasbeen shown to control intestinal inflammationin mice with experimental colitis by suppress-ing splenic immune cell activation and alteredinteraction between dendritic and T cells (Ji

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et al. 2014; Munyaka et al. 2014). Furthermore,the inhibition of brain acetylcholinesterase sup-presses systemic inflammation through a cen-tral muscarinic receptor-mediated and vagal-and α7nAChR-dependent mechanism (Pavlovet al. 2009).

INFLAMMATORY BOWEL DISEASE ANDIRRITABLE BOWEL SYNDROME:DISORDERS OF BRAIN–GUTINTERACTIONS

IBD and IBS are chronic disorders of the diges-tive tract. The symptoms described by the pa-tients can be identical, but IBD is characterizedby lesions of the digestive tract involving therectocolon for UC and all the digestive tractfor CD, while the integrity of the digestive tractis preserved in IBS (Mulak and Bonaz 2004;Cosnes et al. 2011). That is why IBS is called afunctional digestive disorder. However, bothdiseases are considered as bio-psycho-social dis-orders (Mulak and Bonaz 2004; Bitton et al.2008). IBS is a disorder of brain–gut interactionsbut considerable data also argues for an alter-ation of these interactions in IBD (Bonaz andBernstein 2013; Gracie et al. 2018). The role ofstress, especially early life stress, has been shownin IBS, both in the initiation but also in themaintenance of the disease (Pellissier and Bonaz2017), which is characterized by motility disor-ders, visceral hypersensitivity, perturbations ofintestinal barrier, proinflammatory predispos-ing conditions (postinfectious and postinflam-matory IBS), and dysbiosis (Holtmann et al.2017). Stress is also involved in the pathophys-iology of IBD (Bonaz and Bernstein 2013). In-deed, ∼50% of included patients reported sig-nificant stress in any 3-month period, but theprimary types were everyday life stressors morethan health-related stress (Bernstein 2010).There is strong evidence for an association be-tween perceived stress levels and flares; and psy-chological factors contribute to IBD symptomflares (Bernstein et al. 2010). Stressmodifies gas-trointestinal motility and secretion, increasesvisceral sensitivity and intestinal permeability,and modifies immunity and gut blood flow; allthese modifications may play a role in the path-

ophysiology of IBS and IBD (Tache and Perdue2004; Tache and Bonaz 2007; Bonaz and Bern-stein 2013). Maternal deprivation in animals isan experimental model of early life trauma inhumans and is commonly used as a model ofbrain–gut axis dysfunction (O’Mahony et al.2011). After reaching adulthood, these animalspresent with visceral hypersensitivity (Moloneyet al. 2012), as in IBS patients, and a worsenedexperimental colitis (Barreau et al. 2004). Anx-iety and depression are usually observed in∼30%–50% of IBS patients (Pellissier and Bonaz2017). We also reported that IBD patients pre-sented with depression even when in remission(Pellissier et al. 2010, 2014); and depressed IBDpatients or patients who have inadequate copingstrategies to stress are more prone to a flare ofthe disease (Mittermaier et al. 2004; Bitton et al.2008). Because IBS and IBD patients havean imbalance of the ANS with a low vagal toneand an increased sympathetic tone, such condi-tions predispose to inflammation.

VAGUS NERVE STIMULATION ININFLAMMATORY BOWEL DISEASE

VNS was first used in cases of drug-resistantepilepsy not amenable to resection surgery. Itwas validated by the Food and Drug Adminis-tration (FDA) in 1994 and for drug-resistantdepression in 2005. In these indications, theaim is to target the CNS through activation ofvagal afferents at high-frequency stimulation(20 to 30 Hz), although even low-frequencystimulation at 5 Hz produces changes in brainregions, but less than at 20 Hz VNS (Lomarevet al. 2002). We also showed that VNS per-formed at a low frequency of stimulation (5 Hz)in rats activated theNTS and other brain regions(Reyt et al. 2010). Thus, low-frequency VNS ac-tivates both vagal afferent and efferent fibers.Although, the VNS mechanism of action is notcompletely understood, the locus coeruleus,thalamus, hippocampus, periaqueductal gray,and the neocortex are key components of thismechanism (Fanselow 2012).

Activation of both vagal afferents and effer-ents would be of interest in IBD, because of thedual anti-inflammatory role of theVN.TheCAP



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involves vagal efferents; thus, VNS at low fre-quency stimulation of these efferents shouldhave an anti-inflammatory effect (Borovikovaet al. 2000). This explains why, in an experimen-tal study on rats presenting with TNBS colitis tomimic CD, we performed VNS at 5Hz frequen-cy stimulation during 5 consecutive days inawake animals (Meregnani et al. 2011). Weshowed thatVNS improved colitis and this effectwas predominant on tissues that were less dam-aged. This result was confirmed by other inves-tigators (Sun et al. 2013; Jin et al. 2017). Weperformed a pilot study in patients with activeCD in a translational approach. Patients wereselected according to a clinical activity index(moderate-to-severe disease; 220 <Crohn’s dis-ease activity index [CDAI] < 450), biological pa-

rameters of inflammation such as C-reactiveprotein (CRP) (>5mg/L) and/or fecal calprotec-tin (>100 µg/g), and ileocolonoscopy with anindex of activity (Crohn’s disease endoscopicindex of severity [CDEIS], macroscopic indexof mucosal healing) ≥7. Patients were followedup for 1 year. We included nine patients andreported the results of this first pilot study ofVNS in seven CD patients after 6 months offollow-up, giving an overview of the type of pa-tients to be selected in a future randomized con-trol trial (Fig. 5) (Bonaz et al. 2016a). VNS is aslow-acting therapy, as reported in epilepsy,with modifications of neuroplasticity (Biggioet al. 2009; Hays et al. 2013). Consequently, weshould not include patients with severe flare-upsof the disease but only those with a mild-to-

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Figure 5. Effect of vagus nerve stimulation (VNS) during 6 months of follow-up in the seven patients presentingwith an active Crohn’s disease at inclusion on (A) the Crohn’s disease activity index (CDAI); (B) C-reactiveprotein (CRP); (C) the Crohn’s disease endoscopic index of severity (CDEIS); (D) the vagal tone (high frequencyin normalized units [HFnu]) and the sympathovagal balance (low frequency [LF]/high frequency [HF]). CDAI <150, clinical remission. Cut-off level for CRP, 5 mg/L. CDEIS < 6, endoscopic remission. HFnu, homeostaticrange. Balanced ratio of LF/HF (sympathovagal balance) ∼1. (From Bonaz et al. 2016a; modified, with permis-sion, from the author.)

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moderate disease. In this context, using VNS toprevent postoperative recurrence of CD wouldalso be of interest. Indeed, the pathological gut isremoved by surgery but this does not cure IBD,and there is usually a recurrence of CD at orabove the anastomosis (De Cruz et al. 2012).VNS could also be used in a combinationtherapy with immunosuppressants or biolog-ics (anti-TNF, anti-IL12/23, anti-integrins) tobridge the slow-acting effect of VNS and thenlater used as a monotherapy as reported in thefirst top-down study in CD in which anti-TNF(infliximab) was combined with azathioprine(D’Haens et al. 2008). Another study (GD’Haens,Z Cabrijan,M Eberhardson, et al., unpubl.) usedVNS in CD patients with a history of inadequateresponse and/or intolerance failure to oneor more anti-TNF. They also observed a clinical,biological, and endoscopic improvement inthese patients. These two studies are comple-mentary in their indications and strongly sup-port the use of VNS in IBD treatment. Of course,a robust randomized control study versus place-bo is needed in CD. VNS could also be used inpatientswithUC,which predominantly involvesthe rectocolon. The VN is usually considered toinnervate all the digestive tract to the left splenicflexure, the rest of the colon and rectum beinginnervated by the pelvic nerves. But for someinvestigators, theVN innervates the entire diges-tive tract (Delmas and Laux 1933), thus makinguse of VNS compatible in UC treatment.

VAGUS NERVE STIMULATION IN IRRITABLEBOWEL SYNDROME

The VN is usually considered to have no effecton pain, either visceral or somatic, this effectbeing mediated by the sympathetic nervous sys-tem. However, experimental and clinical datashowed that the VN had antinociceptive effects.Indeed, patients treated byVNS for epilepsy pre-sent with less pain (Kirchner et al. 2006). TheVN had antinociceptive effects in experimentalmodels of pain either somatic or visceral (Zu-rowski et al. 2012; Chakravarthy et al. 2016;Frokjaer et al. 2016). Because visceral hypersen-sitivity is a marker of IBS (Ritchie 1973), VNSwould be of interest in IBS patients as an anti-

nociceptive therapy. In addition, based on thefact that ∼30% to 50% of IBS patients presentwith depression (Pellissier and Bonaz 2017), theantidepressive effect of VNS would be of addi-tional interest. There is also evidence that cog-nition andmood improvewith VNS (Chan et al.2018). Considering that IBS is also seen as anIBD “a minima” with significant higher levelof proinflammatory cytokines such as interleu-kin (IL)-1β, IL-6, and TNF-α than controls (Lie-bregts et al. 2007; Bashashati et al. 2014), theanti-inflammatory effect of VNS could dampenthis low-grade inflammation and alleviate pain.VNS appears as a potential therapeutic tool inIBS patients because of its anti-inflammatory,antinociceptive, and antidepressive effects. Nodata has been published yet regarding the useof VNS in IBS patients. However, two clinicaltrials using noninvasive VNS are ongoing(ClinicalTrials.gov identifiers: NCT02388269and NCT02420158). The results are expectedwith interest.

FUTURE OF VAGUS NERVE STIMULATION

VNS has other potential indication in the treat-ment of gastrointestinal diseases, which arecharacterized by a dysfunction of brain–gut in-teractions.

VNS in the Treatment of Postoperative Ileus

Postoperative ileus (POI) is characterized by adelay of gastric emptying and prolonged intes-tinal transit after surgery (Stakenborg et al.2017a). The motility of the stomach and smallintestine is restored within 24 to 48 h and up to72 h for the colon. POI can prolong hospitaliza-tion stay and increase healthcare costs estimatedat U.S. $750 million/year in the United States(Senagore 2007). Sympathoadrenergic, vagal-nonadrenergic noncholinergic-inhibitory, cor-ticotrophin-releasing pathways and capsaicin-sensitive afferent neurons are involved in themechanism of POI (Holzer et al. 1986; Barquistet al. 1996; Bonaz and Tache 1997). A peripheralpathway, involving the CAP, was also describedrevealing the release of TNF-α by resident mac-rophages in themuscularis propria after abdom-



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inal surgery (de Jonge et al. 2003). This inflam-matory response is decreased by pretreatmentwith selective α7nAChR agonists and VNS,thus reducing macrophage activation and re-lease of proinflammatory cytokines (The et al.2007). The gastric POI is prevented in rats bycentral activation of the VN (Yuan and Tache2017). Gum chewing, well known to activate theVN, also reduces POI (Xu et al. 2018). Hence,stimulating the CAP and its anti-inflammatoryaction could improve POI. Another alternativeis abdominal VNS, which appears as effective ascervical VNS (Stakenborg et al. 2017b). It hasthe advantage of avoiding implantation of thedevice and an electrode used in cervical VNS.

VNS in the Treatment of Obesity

The VN is involved in the control of food intakeand satiety (Berthoud 2008b). Gastric vagal af-ferents are involved in induction of satiety andproximal small intestine vagal afferents are in-volved in chemosensitivity-induced satiation(de Lartigue and Diepenbroek 2016). There isan intestinal lumen sensing of the VN throughgastric and enteroendocrine cells (Monteiro andBatterham 2017). Vagal efferents are involved inthe regulation of digestion and absorption (deLartigue and Diepenbroek 2016). In obesity, va-gal afferent signaling is disrupted, inducing anoverconsumption of food and weight gain, andsatiety effects of intestinal nutrients are reduced(Browning et al. 2017). Subdiaphragmatic VNSin lean animals induces weight loss, satiation,decreased food intake and sweet cravings, andincrease in energy expenditure (de Lartigue andDiepenbroek 2016). Subdiaphragmatic VNS inhigh-fat-diet animals reduces excess weightgain, adiposity, and hyperphagia (Browning etal. 2017). Chronic VNS induces a decrease ofweight gain, food consumption, and sweet crav-ings in adult obese mini-pigs (Val-Laillet et al.2010).

Sixty percent of patients treated by VNS forepilepsy lost weight; patients treated with thehighest frequency lost more weight (Burneoet al. 2002). In depression, weight loss was pos-itively correlated with the initial body mass in-dex (BMI) in patients treated by VNS for more

than 2 years; the more severe the obesity, thegreater the weight loss (Pardo et al. 2007). Re-garding the mechanisms of VNS in obesitydescribed above, VNS may increase the respon-siveness of vagal afferent neurons to distensionand/or satiating hormones. As seen above, VNSis a slow-acting therapy, suggesting that thebrain adapts to VNS over time. Thus, the effec-tiveness of VNS in obesity may improve overtime. Indeed, many studies made on rodentswere 4–8 weeks long and weight loss in patientswith VNS was predominantly reported after 6–12 months. The optimal parameters are still un-clear. A frequency-dependent improvement wasreported (Burneo et al. 2002). Clinical trials areongoing on VNS for obesity (ClinicalTrial.Gov:Preoperative treatment with noninvasive intra-auricular VNS pending bariatric surgery [re-cruiting]: NCT02648191; Study of the effect ofVNS on human brown adipose tissue activity[unknown]: NCT01491282; VNS and glucosemetabolism [completed]: NCT01117311). Theresults of these clinical trials should be ofinterest.

VNS in Gastroparesis

Gastroparesis is characterized by a delay of gas-tric emptyingwithout any obstruction caused byan abnormal gastric contractility (Langworthyet al. 2016). The symptoms are nausea, vomit-ing, early satiety, abdominal pain, and bloating.Idiopathic gastroparesis, diabetes mellitus, orVN injury owing to gastric surgery are themain etiologies. The available treatments arerather disappointing and have a significant eco-nomic impact (Navas et al. 2017; Kumar et al.2018). Gastric electrical stimulation with theEnterra device (Medtronic, Minneapolis, MN)is also an option for such patients (Levinthaland Bielefeldt 2017). Based on the role of theVN in nausea, gastric emptying, and nocicep-tion, VNS should be of interest. Paulon et al.(2017), in a pilot study, used noninvasive VNSin patients presenting with drug-resistant gas-troparesis, with the gammaCore (electroCore,Basking Ridge, NJ) device self-administered bythe patient with a 2-min stimulation of the VNat the cervical level. Patients performed two

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stimulations on each side three times daily dur-ing weeks 1 and 2 and then three stimulationson each side three times daily during week 3and after. Thirty-five patients were enrolled, 23(65.7%) complied with the procedures and wereincluded in the analysis. Seven patients contin-ued VNS beyond 3 weeks. 8/23 (35%) patientsresponded at week 3, and 10/23 (43%) at week3–6. VNS was well tolerated. Improvement wasobserved for all the cohort and the 10 respond-ers for nausea/vomiting, postprandial fullness/early satiety, and bloating. This is the only pub-lished study on VNS in gastroparesis. Althoughunderpowered, this study supports the use ofVNS in the treatment of refractory gastroparesis,but this needs to be confirmed. One trial iscurrently ongoing (ClinicalTrials.gov identifier:NCT03120325).

NONINVASIVE OR INVASIVE VNS?

Invasive VNS was validated for epilepsy and de-pression. The device is usually implanted by aneurosurgeon familiar with the technique dur-ing a 1-hour surgery. There are a few adverseeffects with this technique: hoarseness, throatpain, cough, and dyspnea as a result of higherstimulation settings (Cukiert 2015). If necessary,the device can be removed but the electrodewrapped around the VN is usually left in place,its removal being risky because of the close con-tact with the carotid artery and vein. Conse-quently, a noninvasive VNS would be of interestespecially for patients reluctant to undergo sur-gery. The principle is to use external devices tostimulate the VN at the cervical level, along thecarotid axis, or at the cymba concha of the ex-ternal ear, which is innervated by a sensoryauricular branch of the VN projecting to theNTS (Peuker and Filler 2002). Transcutaneousauricular VNS is thus able to stimulate theCAP through a vagovagal reflex as shown in amodel of septic shock in rats (Zhao et al. 2012)and recently in healthy volunteers (Lerman et al.2016).

Two noninvasive VNS devices are available,the NEMOS device (Cerbomed, Erlangen, Ger-many) relying on an intra-auricular electrodeand the gammaCore device (electroCore, Bask-

ing Ridge, NJ), which uses two stainless steelround discs as skin contact surfaces of the VNat the cervical level. They are used for epilepsy,depression, and headache (Stefan et al. 2012;Nesbitt et al. 2015; Fang et al. 2016). These de-vices are safe without any reported serious ad-verse events. No data has yet been published onthe use of noninvasive VNS in inflammatorydisorders of the gastrointestinal tract and onlyone pilot study was performed in gastroparesis(Paulon et al. 2017). The drawback of these de-vices could be a low compliance; ∼30%–40% ofIBD patients did not follow their treatment(Herman and Kane 2015). The reproducibilityof the positioning of the device either at theauricular level or at the cervical level is question-able, in particular, for the gammaCore device.

QUESTIONS—FUTURE OF VNS FORGASTROINTESTINAL DISORDERS

Although VNS is an innovative technique forbrain–gut interactions, many questions remainunanswered. Most of the studies using VNS arepilot studies with few patients included. Conse-quently, more robust randomized controlled tri-als are necessary to confirm the reported resultsand to convince health authorities for regulatoryapproval and reimbursement as well as the com-munity of IBD (and others) physicians and pa-tients who may be tempted by this nondrugtherapeutic approach devoid of major adverseeffects. Most of the studies are not controlled,thus a study on a sham-stimulated group of pa-tients is needed with the possibility of being sec-ondarily stimulated.

What stimulation parameters should beused? In particular, what is the optimal frequen-cy of stimulation: high frequency as for epilepsyand depression to target the brain or low-fre-quency to activate vagal efferents and conse-quently the CAP? A dual activation of vagal af-ferents and efferents in a synergistic effectshould be effective. Consequently, using 10 to20 Hz of frequency stimulation would be of in-terest. The intensity ranges between 0.25 and1.5, usually starting at 0.25 mA with a step-by-step increase to the intensity tolerated by thepatient without throat pain, which was, in our



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study, not more than 1.5 mA (Bonaz et al.2016a). In their POI study, Stakenborg et al.(2017b) used a high intensity (2.5 mA) of stim-ulation in patients that were under anesthesia forabdominal surgery; but, at the level of cervicalVNS, such an intensity would most likely not betolerated by the patients.

What is the optimal duration of stimulation?We used 30 sec ON and 5 min OFF, as for epi-lepsy and depression, but Levine et al. (2014)reported that VNS delivered once daily for 60sec inhibited cytokine production and inducedsignificant protection against synovitis and peri-articular bone erosions. In the same way, Koop-man et al. (2016) used intermittent VNS inrheumatoid arthritis (RA) patients during 60sec up to four times daily. Stakenborg et al.(2017b) used 2 min of VNS at the beginningand at the end of surgery.

Helmers et al. (2012) reported that, based ona computational model, a range of output cur-rent settings between 0.75 and 1.75 mA withpulsewidth settings of 250 or 500 µs could resultin optimal stimulation. The miniaturizationof the VNS device is required. The Setpointcompany elaborated on a device that directlystimulates the VN by clipping it around theVN (see setpointmedical.com; MØ1-ØØ1123),thus avoiding a subclavicular incision to posi-tion the neurostimulator. The neurostimulatorevolved in the domain of epilepsy. The AspireSRcan detect the ictal tachycardia as a proxy to anepileptic seizure and deliver a closed-loop elec-trical current to the VN. Hamilton et al. (2018)recently reported that ∼70% of patients treatedwith an implanted VNS device presented withsignificant additional benefit. In the sameway, itwould be interesting to have a device able tomeasure HRV to assess vagal tone and to stim-ulate the VN in the case of a long-lasting lowvagal tone according to body characteristics(temperature, movements, sleep cycles, inflam-matory markers) so as to restore a normal tone.

The efficacy of VNS ismost likely influencedbymorphometric parameters of theVNbut verylittle data is available. The VN is not completelyencircled by the electrode because it is wrappedaround it for ∼270°. Nerve fibers not covered bythe electrode should require higher stimulation,

whereas fibers located near the perineurium of afascicle are exposed to a stronger electric field(Helmers et al. 2012). The right cervical VN hasa 1.5 times larger effective surface area than theleft cervical and there is a large variation withinindividual nerves (Verlinden et al. 2016). Themean effective surface area at the right cervicallevel is greater than at the level inside the skullbase, implying that the VN receives anastomos-ing branches from areas other than the brain-stem. Tyrosine hydroxylase- and dopamineβ-hydroxylase-nerve fibers have been individu-alized in the VN, indicating a catecholaminergicneurotransmission.

More recently, Hammer et al. (2018) inves-tigated the detailed morphometry, vascularity,and surface topography of the cervical VN forboth invasive and noninvasive VNS. They didnot find any sex-, side,- or branching-relateddifferences. An electrode diameter of 7.5 mmwould suit most patients. It was highly unlikelyto find the nerve below 50 mmof the surface andthe laryngeal eminence. The number of vagalarteries in the sample of this study was muchsmaller than reported previously; 49%were con-firmed in this case by histology.

All these technical points should be takeninto consideration when developing clinical tri-als on VNS in gastrointestinal diseases (and oth-ers) because they may influence the results ofthese studies.

It is currently difficult to predict whichpatients will respond to VNS therapy for thegastrointestinal tract and to what extent; al-though, in epilepsy, Liu et al. (2018) recentlyreported that preoperative assessment of HRVcould help in predicting VNS outcomes inpatients with drug-resistant epilepsy. Patientsresponding to VNS had less impairment ofparasympathetic cardiac control than nonre-sponders. In our pilot study in CD, patientswith a low HRV responded to VNS.

CONCLUSION

VNS is an interesting nondrug therapy in thetreatment of gastrointestinal diseases, whichare related to brain–gut disorders such as IBD,IBS, and others. Robust randomized control tri-

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als are still necessary to confirm this becauseonly pilot studies are available at this time.

ACKNOWLEDGMENTS

Our work is supported by the National Institutefor Health and Medical Research (INSERM)andMinistry of Health, France (DGOS) (“Appelà Projet Translationnel 2011”) and the GrenobleHospital Department of Clinical Research andInnovation (DRCI), France. The authors thank(1) Mr. Nicolas Gonnet, Mr. David Tartry, andMrs. Mélanie Arnaud (Clinical Research Asso-ciates) for their help in the management of ourclinical trial on vagus nerve stimulation in pa-tients with Crohn’s disease, (2) Mrs. FrançoiseBardin who helped with the formatting of themanuscript, and (3) Dr. Pierre-Emmanuel Collefor copy-editing the article.

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published online September 10, 2018Cold Spring Harb Perspect Med Bruno Bonaz, Valérie Sinniger and Sonia Pellissier

Gut Interactions−Vagus Nerve Stimulation at the Interface of Brain

Subject Collection Bioelectronic Medicine

DiseaseMedicine in Treatment of Chronic Inflammatory Neural Control of Inflammation: Bioelectronic

Centa, et al.Michael Eberhardson, Laura Tarnawski, Monica

Disease Diagnosis and Treatmenton the Inflammatory Reflex to New Approaches in Bioelectronic Medicine: From Preclinical Studies

J. TraceyValentin A. Pavlov, Sangeeta S. Chavan and Kevin

Therapeutic ImplicationsPathways Using Ultrasound and Its Current Noninvasive Neuromodulation of Peripheral Nerve

Christopher Puleo and Victoria Cotero

SystemVagus Nerve Stimulation and the Cardiovascular

Lance B. BeckerMichael J. Capilupi, Samantha M. Kerath and

Enteric Neuromodulation for the Gut and BeyondYogi A. Patel and Pankaj J. Pasricha Treatment of Inflammation-Mediated Diseases

Harnessing the Inflammatory Reflex for the

ChernoffYaakov A. Levine, Michael Faltys and David

SystemOptogenetic Control of the Peripheral Nervous

Rui B. Chang and Biomarkers of DiseaseRelated to Changes in Physiological Parameters Recording and Decoding of Vagal Neural Signals

Theodoros P. Zanos

and Translational ResearchClosed-Loop Neuromodulation in Physiological

Stavros Zanos State and Future DirectionsBioelectronic Neural Bypass Approach: Current Restoring Movement in Paralysis with a

Chad E. Bouton

Assessment: An OverviewElectrical Impedance Methods in Neuromuscular

Seward B. Rutkove and Benjamin Sanchez

Ethical Concerns−−Bioelectronic Medicine

HaridatSamuel Packer, Nicholas Mercado and Anita

Solutions Precision-Guided by LightOptogenetic Medicine: Synthetic Therapeutic

Haifeng Ye and Martin Fussenegger

Use of Bioelectronics in the Gastrointestinal TractLarry Miller, Aydin Farajidavar and Anil Vegesna

NanoparticleTechnobiology's Enabler: The Magnetoelectric

Sakhrat KhizroevGut Interactions

−Vagus Nerve Stimulation at the Interface of Brain

Bruno Bonaz, Valérie Sinniger and Sonia Pellissier

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