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The Versatile Role Of The Vagus Nerve In The Gastrointestinal Tract



The vagus nerve, the major nerve of the parasympathetic nervous system, innervates several organs from the neck to the abdomen. The vagal branches contain afferent (i.e. sensory) and efferent (i.e. motor) fibres contributing to a bidirectional communication between the visceral organs and the brain. The extensive vagal innervation of the body indicates that vagus nerve has a multitude of physiological functions. Specifically, the gastrointestinal (GI) tract is densely innervated by the vagus nerve and the latter plays a crucial role in GI functions such as food intake, digestion, and GI barrier function. In addition, the vagus nerve has immunomodulatory properties suggesting that activation of the parasympathetic innervation of the GI tract could act as a new therapeutic tool to treat intestinal immune diseases. This review summarises the anatomical and physiological properties of the vagal innervation of the GI tract.
106 107
Nathalie Stakenborg, Martina Di Giovangiulio, Guy E. Boeckxstaens,
Gianluca Matteoli
Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal
Disorders (TARGID), University of Leuven, Leuven, Belgium
Disclosure: No potential conflict of interest.
Support: Supported by grants from Research Foundation – Flanders (FWO); Odysseus and Hercules pro-
gram to G.E.B., FWO postdoctoral research fellowship to G.M. and by FWO PhD fellowship to M.DG.
Received: 03.09.13 Accepted: 29.11.13
Citation: EMJ Gastroenterol. 2013;1:106-114.
The vagus nerve, the major nerve of the parasympathetic nervous system, innervates several organs
from the neck to the abdomen. The vagal branches contain aerent (i.e. sensory) and eerent
(i.e. motor) fibres contributing to a bidirectional communication between the visceral organs and the
brain. The extensive vagal innervation of the body indicates that vagus nerve has a multitude of
physiological functions. Specifically, the gastrointestinal (GI) tract is densely innervated by the vagus
nerve and the latter plays a crucial role in GI functions such as food intake, digestion, and GI barrier
function. In addition, the vagus nerve has immunomodulatory properties suggesting that activation of
the parasympathetic innervation of the GI tract could act as a new therapeutic tool to treat intestinal
immune diseases. This review summarises the anatomical and physiological properties of the vagal
innervation of the GI tract.
Keywords: Parasympathetic nervous system, vagus nerve, gastrointestinal tract.
The vagus nerve, the main contributor of the
parasympathetic nervous system, is the tenth
cranial nerve originating from the medulla
oblongata in the central nervous system.
Within the medulla, the cell bodies of vagal
preganglionic neurons are found in the nucleus
ambiguous (NA) and the dorsal motor of the
vagus (DMV). These nuclei supply fibres to the
vagus nerve, which emerges from the cranium via
the jugular foramen.1 At the level of the jugular
foramen, the superior jugular ganglion of the
vagus provides cutaneous branches to the
auriculus and external acoustic meatus.2,3 Just
distally, there is a second ganglion, referred to
as the nodose ganglion, collecting sensory
innervation from visceral organs. The cell bodies
of aerent (i.e. sensory) neurons are located in the
latter ganglion and project to the nucleus of the
solitary tract (NTS). This nucleus relays input to
the medulla in order to regulate the cardiovascular,
respiratory and gastrointestinal (GI) functions.4
The cervical vagus descends within the carotid
sheath alongside the carotid artery and internal
jugular vein. Cardiac vagal branches leave the
cervical vagus and join the cardiac plexus. The left
and right recurrent laryngeal nerve, arising at the
level of the aortic arch and subclavian artery
respectively, also contribute to the cardiac
innervation. Besides the heart, both vagi innervate
the lungs through the pulmonary plexus.1
More distally, the left and right vagus run with the
oesophagus through the diaphragmatic hiatus.
Upon entering the abdominal cavity, the left and
right vagus become the anterior and posterior
106 107
vagus, respectively.1,5,6 However, one has to keep
in mind that each trunk receives fibres from
both cervical vagus nerves.5 The number of
posterior and anterior trunks passing through the
diaphragmatic opening is variable, up to two in
the former and three in the latter.5 The anterior
trunk distributes gastric branches to the anterior
aspect of the stomach and gives o a hepatic
branch. Besides innervating the liver, the hepatic
stem gives o branches to the pylorus and the
proximal part of the duodenum and pancreas.
On the other hand, the posterior trunk distributes
one gastric branch to the proximal posterior
aspect of the stomach and another to the coeliac
plexus, which innervates the spleen and GI tract
reaching as far as the left colonic flexure.1,5,6 The
large intestine receives additional parasympathetic
innervation through the pelvic splanchnic nerve
(S2-S4), which terminates in the pelvic plexus and
emerges as the colonic and rectal nerve.7-10
The aerent vagus nerve innervates the GI tract
via vagal terminals both in the lamina propria11,12
and in the muscularis externa.13-15 However, the
eerent vagus nerve fibres only interact with
neurons of the enteric nervous system (ENS). The
ENS consists out of a dense meshwork of nerve
fibres, situated in the submucosal (i.e. submucosal
plexus) and external muscular compartment of
the intestine (i.e. myenteric plexus).16 By means
of electrophysiological and anterograde tracer
studies, it was demonstrated that preganglionic
parasympathetic fibres (i.e. both vagal and
sacral innervation) directly interact with multiple
postganglionic myenteric neurons by formation
of varicosities, whereas few vagal fibres
communicate with submucosal neurons.17-20 The
preganglionic innervation of the GI tract displays
a typical rostro-caudal gradient with the highest
density of innervated myenteric neurons in the
stomach and duodenum followed by a progressive
reduction in the small intestine and colon.17
The fact that gastric myenteric neurons are
activated by vagal input was also demonstrated
immunohistochemically with the detection of
c-Fos and phosphorylated c-AMP response
element binding protein (p-CREB), which are
markers for neuronal activity.21,22 As activation of
neurons within one ganglion is initiated after the
same latency period, Schemann et al.20
suggest that the vagal input to the ENS is
monosynaptic. However, this is not confirmed
by other studies.22 Currently, three distinct
vagal aerent terminals have been described.
The specific location of each terminal has
correlations with its physiological function.
Vagal fibres are projected throughout the GI
tract and interact with the gut to regulate
food intake, digestion, barrier keeping, and
immunity. Food intake leads to satiety through
the activation of several pathways: the release
of various peptides from enteroendocrine cells
(EEC), the direct action of certain nutrients
(e.g. short fatty acids23) (Figure 1A), and
mechanoreceptor stimulation due to gastric
distension (Figure 1B).24 Most aerent vagal
endings in the mucosal lamina propria are thought
to be chemoreceptors sensing the presence
of hormones, peptides and nutrients released
by epithelial and neuroendocrine cells.23,25-27 In
contrast, the terminal vagal structures in the
external muscle layers and the myenteric plexus
are considered to be mechanoreceptors detecting
GI distension.13,14 These sensory signals are relayed
to the NTS, in which the aerent information is
processed. Appropriate vagal eerent output is
transmitted from the DMV.12 The latter has a major
metabolic and dietary function, since electrical
stimulation of DMV leads to an increased secretion
of gastric acid,28,29 insulin28,30 and glucagon.28,31
Moreover, the secretion of gastric acid,32 insulin,32-38
glucagon,35-37 and pancreatic polypeptide39,40 is
also elevated when the peripheral vagus nerve
is stimulated (Figure 1). These responses are
all abolished by vagotomy,41 administration of
atropine,35,40,42 or hexamethonium.31,40 Besides
its dietary and metabolic functions, the vagus
nerve also has eects on the intestinal barrier
function through immune cells (i.e. mast cells43) and
the activation of enteric glial cells via the ENS.
Dietary Intake and Metabolism Regulation
Chemical stimulation
The EECs respond to nutrient sensing in the
lumen by the basolateral secretion of leptin in the
stomach44 and cholecystokinin (CCK) in the small
intestine.45 Tracer studies showed that EECs lie in
close vicinity to mucosal vagal aerent terminals
projecting from the nodose ganglia via the
myenteric plexus.11,46 The close anatomical
position between vagal aerents and EECs enables
CCK and leptin to act as paracrine factors,
which activate CCK-A26 and Ob-R receptors25,27
expressed on aerent fibres, respectively.11
108 109
Electrophysiological studies have confirmed
these anatomical observations, since CCK
stimulates aerent nerve fibres47 and nodose
ganglion cell bodies48 via the CCK-A receptor.
Leptin has also been reported to act in synergism
with CCK through CCK-A receptors and aerent
vagal fibres.27,4 9 This aerent signalling is
further relayed to the NTS.49-51 Synergistic vagal
activation by CCK and leptin leads to inhibition
of food intake.49,52,53 In addition, CCK alone
inhibits gastric emptying54-56 and stimulates
biliary and pancreatic secretion (Figure 1).57-59
Figure 1. Vagal regulation of gastrointestinal (GI) physiology.
(A) Aerent vagal fibres receive information from the internal milieu of the GI tract via mechanical
signalling and chemical (i.e. enteroendocrine hormone release and certain food nutrients) and
immunological stimulation (i.e. proinflammatory cytokines).
(B) This sensory information is transmitted to the nucleus of the solitary tract (NTS) to mount an
appropriate eerent (i.e. motor) response through the dorsal motor nucleus of the vagus (DMV),
such as the secretion of neuroendocrine hormones and variations in GI motility, barrier function, and
modulation of the intestinal immune response.
Vagus Nerve
Vagus Nerve
Barrier function
Vagus Nerve
Barrier function
Vagus Nerve
108 109
Indeed, the administration of specific CCK-A
receptors antagonists (i.e. L364,718) prior to a
meal increases food ingestion54,60 and gastric
emptying, but inhibits pancreatic secretion.57,61,62
These eects of CCK are dependent on an
intact vagal supply, since vagotomy58,63,64 or
destruction of small diameter vagal aerent C
fibres by capsaicin abolish the actions of CCK.54-56,58
Mechanical stimulation
Besides chemosensory signal transduction, the
aerent arch of the vagus is also activated by
gastric distension through the stimulation of
aerent vagal mechanoreceptor in the GI tract.
Two candidate mechanoreceptors of the vagus
nerve have been described: the intraganglionic
laminar ending (IGLE)13 and intramuscular
arrays (IMAs).14
The former terminal consists of aggregates
of terminal puncta associated with myenteric
neurons as well as connective tissue structures
surrounding the myenteric ganglia. IGLEs are the
densest in the stomach and become sparse more
caudally.14,65-67 The close anatomical proximity
between the connective tissue layers and the
ganglia indicates that IGLEs are able to detect
the shearing forces between the orthogonal
muscle layers.67,68 Electrophysiological studies
confirm that IGLE could act as low threshold
tension receptors, since distortion of the
stomach leads to activation of tension-sensitive
vagal mechanoreceptors.46,67,69-71
A second class of prominent vagal
mechanoreceptors are IMAs, which consist of
parallel arrays of neurite terminals coursing
parallel to muscle bundles in the longitudinal
or circular muscle layers14,66,72 and lie in close
vicinity of interstitial cells of Cajal (ICC).1 5,73 IMAs
are mostly located in the upper stomach,
lower oesophageal and pyloric sphincters.14,74-76
Based on the morphological features, IMAs appear
to act as stretch receptors sensitive to
shearing forces in the long axis. However,
electrophysiological studies have not been able
to unambiguously determine the true functionality
of IMAs.15,70,71
The sensory vagal mechanoreceptors stimulated
by gastric distension, are the first trigger of
vago-vagal reflexes, such as gastric
accommodation,77 inhibition of food intake, and
antral peristalsis (Figure 1).78 Distension also
appears to act in synergy with CCK to increase
aerent activity and consequently decrease food
intake.79-83 However, Grundy et al.84 disagree to
the fact that CCK exerts a direct eect on vagal
aerent mechanoreceptors, rather they suggest
that the action of CCK is mediated through the
sensory vagal chemoreceptors in the mucosa.84
The Vagus Nerve as Intestinal Barrier Keeper
Intestinal epithelial cells maintain a strict barrier
between the external and internal environment
via the expression of tight junctions. The tight
junctions consist of a branching network of
interacting transmembrane proteins, such as
claudins and occludins. The loss of epithelial
barrier integrity and thus tight junction expression
enables bacterial translocation across the
intestinal mucosa, which can initiate detrimental
systemic inflammation after severe injuries.85
Coimbra et al.86-90 showed that there is increased
intestinal permeability after haemorrhagic
shock and traumatic brain and burn injuries,
characterised by a decreased tight junction
expression. Pharmacological, nutritional and
electrical stimulation of the vagus nerve prevents
the breakdown of the epithelial barrier via the
stabilisation of tight junction expression
(Figure 1).88,89,91-96 Evidence suggests that VNS
maintains the epithelial barrier integrity after
severe injury by enteric glia activation. Several
groups have demonstrated that the activation
of glial cells leads to the release of
S-nitrosoglutathione (GSNO), which increases
the expression of tight junctions and improves
mucosal integrity. These observations were
confirmed in vivo by intraperitoneal (i.p.) injection
of GNSO in inflammatory models.97-100
Vagus Nerve and Intestinal Immune System:
The Cholinergic Anti-Inflammatory Pathway
For many decades, it has been acknowledged
that a complex interplay exists between the
nervous system and immune cells. The central
nervous system (CNS) receives sensory
information about the presence of inflammation
and responds appropriately via two specific
pathways: neuroendocrine and neural routes.101
Aerent arch of CAIP
In light of an overt infection, circular cytokines
(i.e. IL-1 and TNF-α) or pathogenic components
can be detected by higher brain structures (e.g.
110 111
circumventricular organs [CVO]) that are devoid
of a blood brain barrier. Indeed, administration
of intravenous (IV) endotoxin elicited c-Fos
activation in the CVO and NTS.102-104 These
structures give direct input to motor neurons in
the DMV, which project vagal eerents to the
spleen. In this way, the vagus nerve is able to
modulate the splenic immune response.104-106
The immune system does not only communicate
with the brain via the circulation. In the case
of more localised peripheral inflammation, in
which the amount of proinflammatory cytokines
is not detectable by the CVO, aerent vagal
fibres and adjacent glomus cells are activated
by cytokines/chemokines, such as IL-1 and mast
cells mediators.107-109 Electrophysiological studies
have reported that mast cell mediators and IL-1
activate aerent vagal fibres (Figure 1).108,110,111
Furthermore, both IV and IP administration of
endotoxin induced c-Fos activity in primary
aerent ganglia (i.e. nodose ganglia)112 followed
by increased NTS and splenic activity.104 The
same c-Fos induction was observed in the NTS
in response to intestinal anaphylaxis and
inflammation caused by surgical manipulation of
the gut.113-115 Subdiaphragmatic vagotomy largely
abolishes c-Fos activity in NTS and DMV after
i.p. injection of endotoxin (i.e. LPS and SEB).105,116
Together, these observations strongly indicate
that the brain is able to modulate the splenic
immune response indirectly via the detection
of circulating cytokines and directly via aerent
input from sensory fibres.
Eerent arch of CAIP
The splenic immune response plays an important
role during systemic inflammation, since splenic
macrophages are the major source of TNF-α in
sepsis.117 Therefore, the spleen is considered to be
the perfect target to modulate the immune
response in response to endotoxemia. In light of
this, Borovikova et al.118 showed that vagus nerve
stimulation (VNS) strongly inhibits splenic TNF-α
production in a model of systemic inflammation,
introducing the concept of the cholinergic
anti-inflammatory pathway (CAIP). This anti-
inflammatory response is mediated by the
reduced activation of splenic macrophages
expressing alpha7 nicotinic receptor (α7nAChR).
Acetylcholine (ACh) released by memory T cells,
namely, interacts with α7nAChR and inhibits the
secretion of pro-inflammatory cytokines via the
JAK-STAT pathway.119-122
Over the years, many studies have demonstrated
the beneficial eect of VNS in other inflammatory
models such as haemorrhagic shock,123
pancreatitis124 and collagen-induced arthritis.125
Ourselves and others also extended the concept
of CAIP to the GI tract, since the gut is largely
innervated by the vagus nerve. Indeed, we and
others showed that electrical, nutritional and
pharmacological activation of the vagal pathway
prevents surgical induced inflammation and thus
postoperative ileus (POI).122,126-129 CAIP activation
also reduced intestinal inflammation in other
models: diabetic-induced gastroparesis,130
colitis,131-133 and LPS-induced septic ileus.134-137
In contrast, vagotomised mice have a higher
susceptibility to develop colitis after dextran
sulphate sodium (DSS) administration.132,138,139
Moreover, a more severe colitis is also correlated
with a reduction of mucosal levels of ACh in a
model of depression.132,140,141 Like in the spleen, the
anti-inflammatory response of CAIP is mediated
through α7nAChR macrophages. Deficiency
of α7nAChR in bone marrow-derived cells
significantly abrogated the vagal anti-inflammatory
eect, whereas α7nAChR deficiency in neurons
and other cells did not have a significant eect
in POI, indicating that the beneficial eect of
VNS depends on α7nAChR expression on
immune cells rather on neuronal cells.129,142 As in
the spleen, the CAIP is not mediated by direct
interaction between α7nAChR macrophages and
eerent vagal fibres, but rather via the modulation
of cholinergic enteric neurons in proximity of
intestinal α7nAChR expressing macrophages.113,129
Other mucosal and submucosal immune cells,
such as dendritic cells, mast cells, and T and B
lymphocytes also express nicotinic receptors and
may, therefore, be involved in CAIP.141
To date, electrical stimulation of the vagus nerve
is already used as a therapeutic tool for
intractable epilepsy and treatment-resistant
depression. Currently, the anti-inflammatory
eects of VNS are explored in three clinical
trials in patients with rheumatoid arthritis (RA),
Crohn’s disease and postoperative ileus
(NCT01552941, NCT01569503 and NCT01572155).
Future insight from clinical trials and from basic
research will hopefully oer the cholinergic
anti-inflammatory pathway as a novel and powerful
new therapeutic tool.
110 111
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... The vagus nerve is the major nerve of the parasympathetic nervous system and is largely responsible for the communication between the brain and multiple visceral organs that extend into the lower abdomen [95]. The vagus nerve is the forefront of both sensory and motor integration that plays a role in gastrointestinal (GI) tract function. ...
... Indeed, circulating endotoxins and localized inflammation can suppress the vagus, NTS, and DMV neurons [131][132][133][134]. However, vagotomy prevents these effects following intraperitoneal endotoxin administration, suggesting that this response is vagally-dependent [95]. One important aspect of the anti-inflammatory response mediated by the vagus nerve includes attenuating the inflammatory process associated with aneurysms. ...
... The main mechanism by which the vagus regulates the immune response is by activating the cholinergic anti-inflammatory pathway (CAIP). Vagal afferents release acetylcholine, which binds to α 7 nicotinic receptors expressed in different cell populations, including splenic macrophages, dendritic cells, mast cells, and lymphocytes [95]. There is increasing evidence for the critical role that the gut plays in widespread anti-inflammatory action. ...
Full-text available
Fluoroquinolones (FQs) are a broad class of antibiotics typically prescribed for bacterial infections, including infections for which their use is discouraged. The FDA has proposed the existence of a permanent disability (Fluoroquinolone Associated Disability; FQAD), which is yet to be formally recognized. Previous studies suggest that FQs act as selective GABAA receptor inhibitors, preventing the binding of GABA in the central nervous system. GABA is a key regulator of the vagus nerve, involved in the control of gastrointestinal (GI) function. Indeed, GABA is released from the Nucleus of the Tractus Solitarius (NTS) to the Dorsal Motor Nucleus of the vagus (DMV) to tonically regulate vagal activity. The purpose of this review is to summarize the current knowledge on FQs in the context of the vagus nerve and examine how these drugs could lead to dysregulated signaling to the GI tract. Since there is sufficient evidence to suggest that GABA transmission is hindered by FQs, it is reasonable to postulate that the vagal circuit could be compromised at the NTS-DMV synapse after FQ use, possibly leading to the development of permanent GI disorders in FQAD.
... Nonetheless, FGIDs are notably associated with CNS dysregulation at the vagal level [15]. This cranial nerve emerges from the brainstem medulla oblongata at the level of the dorsal motor nucleus of the vagus (DMV) [16][17][18]. DMV neurons tonically regulate gastrointestinal (GI) motility. In turn, DMV neurons are regulated by the neighboring nucleus of the tractus solitarius (NTS), which mainly releases γ-aminobutyric acid (GABA), and secondarily glutamate and other neurotransmitters onto these parasympathetic cholinergic neurons. ...
Full-text available
Background and Objectives: Fluoroquinolones (FQs) are a broad-spectrum class of antibiotics routinely prescribed for common bacterial infections despite recent recommendations to use them only for life-threatening cases. In addition to their antimicrobial properties, FQs act in the central nervous system as GABAA receptor inhibitors, which could potentially affect functionality of the vagus nerve at the forefront of gastrointestinal (GI) tract function. Alterations in neural control of digestion have been shown to be linked to Functional Gastrointestinal Disorders (FGIDs), which are usually diagnosed based on self-reported symptoms. The aim of this study was to assess the incidence of FGIDs following FQ use. Materials and Methods: Self-reports from the FDA Adverse Event Reporting System were analyzed together with ~300 survey responses from a social network derived sample to the Bowel Disease Questionnaire. Results: The results of this study suggested that six different FQs are associated with a wide range of GI symptoms not currently reported in the drugs’ labels. The responses from the survey suggested that ~70% of FQ users scored positive for FGID, with no positive correlation between drug type, duration of administration, dosage and frequency of administration. Conclusions: This study showed that GI disorders other than nausea, vomiting and diarrhea are more common than currently reported on the drug labels, and that FGIDs are possibly a common consequence of FQ use even after single use.
... Similar to the spleen, the alpha 7 nicotinic acetylcholine receptor (α7nAChR) was identified as the target receptor of the "gastrointestinal CAIP", suggesting that acetylcholine (ACh) released from the vagus nerve inhibits MMϕ (2,3,5,6). To date, electrical stimulation of the cervical vagus nerve is already used as therapeutic tool for refractory epilepsy and treatment-resistant depression (7), while its applicability in inflammatory disorders including rheumatoid arthritis (8) and inflammatory bowel diseases (IBD) (9) is currently under investigation. ...
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Background: We previously showed increased susceptibility to dextran sulfate sodium (DSS)-induced colitis in vagotomized mice. Here, we evaluated whether vagus nerve stimulation (VNS) is able to reduce the severity of DSS colitis and aimed to unravel the mechanism involved. Methods: Colitis was induced in wild type mice by 2.5% DSS administration in drinking water for 5 days. VNS (5 Hz, 1 ms, 1 mA) was applied 1 day prior to and after 4 days of DSS administration to evaluate changes in epithelial integrity and inflammatory response, respectively. Epithelial integrity was assessed using TUNEL and Ki67 staining. Monocytes, immature and mature macrophages were sorted from colonic samples and gene expression levels of pro-inflammatory cytokines were studied. Results: VNS applied prior to DSS administration (i.e., prophylactic VNS) reduced disease activity index (VNS 0.8 ± 0.6 vs. sham 2.8 ± 0.7, p < 0.001, n = 5) and tended to improve histology score. Prophylactic VNS significantly increased epithelial cell proliferation and diminished apoptosis compared to sham stimulation. VNS applied at day 4 during DSS administration (i.e., therapeutic VNS) decreased the influx of monocytes, monocyte-derived macrophages and neutrophils, and significantly reduced pro-inflammatory cytokine expression (i.e., Tnf α and Cxcl1 ) in immature macrophages compared to sham stimulation. Conclusions: A single period of VNS applied prior to DSS exposure reduced DSS-induced colitis by an improvement in epithelial integrity. On the other hand, VNS applied during the inflammatory phase of DSS colitis reduced cytokine expression in immature macrophages. Our data further underscores the potential of VNS as novel therapeutic approach for inflammatory bowel diseases.
... Body wide analyses also located α-syn immunoreactivity in the spinal cord, sympathetic ganglia, sciatic nerve, genitourinary tract, respiratory, and endocrine systems [46,53]. A common highlight of these histopathological findings was the predominant aggregation of α-syn in the myenteric plexus with the notable distinction that this plexus contains more postganglionic vagal fiber than the submucosal plexus [54]. Arguably, the most striking histopathological evidence emerged from human enteroendocrine cells (EECs) in the duodenum and colon which were shown to contain α-syn [55]. ...
... The intestinal vagus nerve comprises anterior and posterior branches. The anterior branch shows prominent innervation at the stomach and the proximal small intestine, whereas the posterior branch joins the ventral celiac branch to innervate the distal duodenum, the jejunum, the ileum, the cecum, and the colon [43]. The vagus nerve delivers inputs that ameliorate inflammation and support intestinal immunity [16]. ...
Full-text available
Intestinal homeostasis encompasses a complex and balanced interplay among a wide array of components that collaborate to maintain gut barrier integrity. The appropriate function of the gut barrier requires the mucus layer, a sticky cushion of mucopolysaccharides that overlays the epithelial cell surface. Mucus plays a critical anti-inflammatory role by preventing direct contact between luminal microbiota and the surface of the epithelial cell monolayer. Moreover, mucus is enriched with pivotal effectors of intestinal immunity, such as immunoglobulin A (IgA). A fragile and delicate equilibrium that supports proper barrier function can be disturbed by stress. The impact of stress upon intestinal homeostasis results from neuroendocrine mediators of the brain-gut axis (BGA), which comprises a nervous branch that includes the enteric nervous system (ENS) and the sympathetic and parasympathetic nervous systems, as well as an endocrine branch of the hypothalamic-pituitary-adrenal axis. This review is the first to discuss the experimental animal models that address the impact of stress on components of intestinal homeostasis, with special emphasis on intestinal mucus and IgA. Basic knowledge from animal models provides the foundations of pharmacologic and immunological interventions to control disturbances associated with conditions that are exacerbated by emotional stress, such as irritable bowel syndrome.
... Integrity of the vagus nerve is of great importance for normal gastrointestinal neuromodulatory and anti-inflammatory functions. Many previous studies have demonstrated high anatomical variability of the vagus nerve at the esophageal hiatus and in the abdomen [2,18]. These variations are highly significant for surgeons to consider during operative procedures at the gastroesophageal junction. ...
Full-text available
Purpose Vagus nerve injuries during gastroesophageal surgery may cause significant symptoms due to loss of vagal anti-inflammatory and neuromodulator function. Many previous studies have shown high anatomical variability of the vagus nerve at the esophageal hiatus, but information on its variability in Uganda specifically and Africa in general is scanty. This study provides a reliable and detailed description of the anatomical variation and distribution of the vagus nerve in the esophageal hiatus region of post-mortem cases in Uganda. Methods This was an analytical cross-sectional survey of 67 unclaimed post-mortem cases. Data collection used a pretested data collection form. Data were entered into Epi-Info version 6.0 data base then exported into STATA software 13.0 for analysis. Results The pattern of the anterior vagal trunk structures at the esophageal hiatus was: single trunk [65.7%]; biplexus [20.9%]; triplexus [8.9%] and double-but-not-connected trunks [4.5%]. The pattern of the posterior trunk structures were: single trunk [85.1%]; biplexus 10.4% and triplexus [4.5%]. There was no statistically significant gender difference in the pattern of vagal fibres. There was no major differences in the pattern from comparable British studies. Conclusion The study confirmed high variability in the distribution of the vagus nerve at the esophageal hiatus, unrelated to gender differences. Surgeons must consider and identify variants of vagal innervation when carrying out surgery at the gastroesophageal junction to avoid accidental vagal injuries. Published surgical techniques for preserving vagal function are valid in Uganda.
... Instead, most VNS preclinical studies are performed in murine, rat, and porcine models. [30][31][32][33] Hence, the main objective of this study was to study the composition of the cervical and abdominal VNs in these species and to compare it with that of the human VN. ...
Full-text available
Background Vagus nerve (VN) stimulation is currently evaluated as a novel approach to treat immune‐mediated disorders. The optimal stimulation parameters, however, largely depend on the VN composition potentially impacting on its clinical translation. Hence, we evaluated whether morphological differences exist between the cervical and abdominal VNs across different species. Materials and methods The cervical and abdominal VNs of mouse, pig, and humans were stained for major basic protein and neurofilament F to identify the percentage and size of myelinated and non‐myelinated fibers. Results The percentage of myelinated fibers was comparable between species, but was higher in the cervical VN compared with the abdominal VN. The cervical VN contained 54 ± 4%, 47 ± 7%, and 54 ± 7% myelinated fibers in mouse, pig, and humans, respectively. The myelinated fibers consisted of small‐diameter (mouse: 71%, pig: 80%, and humans: 63%), medium‐diameter (mouse: 21%, pig: 18%, and humans: 33%), and large‐diameter fibers (mouse: 7%, pig: 2%, and humans: 4%). The abdominal VN predominantly contained unmyelinated fibers (mouse: 93%, pig: 90%, and humans: 94%). The myelinated fibers mainly consisted of small‐diameter fibers (mouse: 99%, pig: 85%, and humans: 74%) and fewer medium‐diameter (mouse: 1%, pig: 13%, and humans: 23%) and large‐diameter fibers (mouse: 0%, pig: 2%, and humans: 3%). Conclusion The VN composition was largely similar with respect to myelinated and unmyelinated fibers in the species studied. Human and porcine VNs had a comparable diameter and similar amounts of fibrous tissue and contained multiple fascicles, implying that the porcine VN may be suitable to optimize stimulation parameters for clinical trials.
... The function of the vagus nerves in the abdomen serves both efferent (motor) functions, including stimulating smooth muscle contraction and glandular secretions, such as gastric acid, and afferent (sensory) functions, transmitting neural information regarding the mechanical, chemical, and immunological milieu of the gastrointestinal tract to the brain. Injury to the vagus nerves in the upper abdomen can result in nausea, dumping syndrome, and diarrhea [Stakenborg 2013]. ...
Full-text available
Many cardiothoracic operations put the nerves of the thorax at risk. In fact, nerve injuries are one of the most common reasons cited in malpractice cases brought against cardiothoracic surgeons. While all physicians learn about the nerves of the thorax during anatomy courses in medical school, little is written about avoiding injury to these important nerves in the cardiothoracic surgical literature. We have, therefore, embarked on an effort to collate information on the anatomy, function, and protection of these nerves, with which every cardiothoracic surgeon should be familiar. We will call this effort “The Nerve Protection Project.” Acknowledging that the material to be covered is considerable, we will break the project into a series of editorials. The first installment in this series will address the anatomy and function of the vagus nerve and the protection of this nerve and its branches during cardiothoracic surgical operations, as they are in harm’s way during many of these procedures.
Objective To investigate the vagus nerve (VN) dimensional changes with Parkinson’s disease (PD), compared with healthy subjects. Additionally, it is important to investigate whether there is any relationships between these changes and patient’s motor and non-motor symptoms (NMS) of PD. Materials and Methods A cohort of 43 patients with PD formed a group that was compared with 44 patients without PD, denoted as the healthy subject (HS) group. The diameter and areas of VN of study groups were measured using ultrasonography (US). The study groups were further divided into <65 and ≥65 subgroups, to evaluate the possible effect of age on the VN and evaluated relationships of VN dimensions, between subgroups. In the PD group, a correlational analysis was conducted between the diameter and area of the VN and the motor and NMS scores. Results There was statistically significant difference in right ( P = .002) and left VN diameters ( P = .007) and in right ( P = .001) and left VN areas ( P = .007), between study groups. There was no significant difference in right and left VN diameters and the right and left VN areas, between subgroups. There was moderately negative correlation between gastrointestinal NMS scores and right VN area ( r = −0.499, P = .002), left VN area ( r = −0.499, P = .002), right VN diameter ( r = −0.378, P = .023), left VN diameter ( r = −0.385, P = .021), respectively. Conclusion The US demonstrated that VN dimensions may possibly reduce in those patients affected by PD. In this cohort, it appears that an increase in gastrointestinal NMS scores may be explained by atrophy of the VN.
Background Gastric accommodation is an essential gastric motor function which occurs following ingestion of a meal. Impaired gastric fundic accommodation (IFA) is associated with dyspeptic symptoms. Gastric accommodation is mediated by the vagal pathway with several important physiologic factors such as duodenal nutrient feedback playing a significant role. IFA has been described as a pathophysiologic factor in several gastrointestinal disorders including functional dyspepsia, diabetic gastropathy, post-Nissen fundoplication, postsurgical gastrectomy, and rumination syndrome. Modalities for gastric accommodation assessment include gastric barostat, intragastric meal distribution via scintigraphy, drinking tests (eg, water load), SPECT, MRI, 2D and 3D ultrasound, and intragastric high-resolution manometry. Several treatment options including sumatriptan, buspirone, tandospirone, ondansetron, and acotiamide may improve symptoms by increasing post-meal gastric volume. Purpose Our aim is to provide an overview of the physiology, diagnostic modalities, and therapies for IFA. A literature search was conducted on PubMed, Google Scholar, and other sources to identify relevant studies available until December 2020. Gastric accommodation is an important gastric motor function which if impaired, is associated with several upper gastrointestinal disorders. There are an increasing number of gastric accommodation testing modalities; however, each has facets which warrant consideration. Evidence regarding potentially effective therapies for IFA is growing.
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The cholinergic anti-inflammatory pathway (CAIP) has been proposed as a key mechanism by which the brain, through the vagus nerve, modulates the immune system in the spleen. Vagus nerve stimulation (VNS) reduces intestinal inflammation and improves postoperative ileus. We investigated the neural pathway involved and the cells mediating the anti-inflammatory effect of VNS in the gut. The effect of VNS on intestinal inflammation and transit was investigated in wild-type, splenic denervated and Rag-1 knockout mice. To define the possible role of α7 nicotinic acetylcholine receptor (α7nAChR), we used knockout and bone marrow chimaera mice. Anterograde tracing of vagal efferents, cell sorting and Ca(2+) imaging were used to reveal the intestinal cells targeted by the vagus nerve. VNS attenuates surgery-induced intestinal inflammation and improves postoperative intestinal transit in wild-type, splenic denervated and T-cell-deficient mice. In contrast, VNS is ineffective in α7nAChR knockout mice and α7nAChR-deficient bone marrow chimaera mice. Anterograde labelling fails to detect vagal efferents contacting resident macrophages, but shows close contacts between cholinergic myenteric neurons and resident macrophages expressing α7nAChR. Finally, α7nAChR activation modulates ATP-induced Ca(2+) response in small intestine resident macrophages. We show that the anti-inflammatory effect of the VNS in the intestine is independent of the spleen and T cells. Instead, the vagus nerve interacts with cholinergic myenteric neurons in close contact with the muscularis macrophages. Our data suggest that intestinal muscularis resident macrophages expressing α7nAChR are most likely the ultimate target of the gastrointestinal CAIP.
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Intestinal barrier failure may lead to systemic inflammation and distant organ injury in patients following severe injury. Enteric glia cells (EGCs) have been shown to play an important role in maintaining gut barrier integrity through secretion of S-Nitrosoglutathione (GSNO). We have recently shown than Vagal Nerve Stimulation (VNS) increases EGC activation, which was associated with improved gut barrier integrity. Thus, we sought to further study the mechanism by which EGCs prevent intestinal barrier breakdown utilizing an in vitro model. We postulated that EGCs, through the secretion of GSNO, would improve intestinal barrier function through improved expression and localization of intestinal tight junction proteins. Epithelial cells were co-cultured with EGCs or incubated with GSNO and exposed to Cytomix (TNF-α, INF-γ, IL-1β) for 24 hours. Barrier function was assessed by permeability to 4kDa FITC-Dextran. Changes in tight junction proteins ZO-1, occludin, and phospho-MLC (P-MLC) were assessed by immunohistochemistry and immunoblot. Co-culture of Cytomix-stimulated epithelial monolayers with EGCs prevented increases in permeability and improved expression and localization of occludin, ZO-1, and P-MLC. Further, treatment of epithelial monolayers with GSNO also prevented Cytomix-induced increases in permeability and exhibited a similar improvement in expression and localization of occludin, ZO-1, and P-MLC. The addition of EGCs, or their secreted mediator GSNO, prevents epithelial barrier failure after injury and improved expression of tight junction proteins. Thus, therapies that increase EGC activation, such as VNS, may be a novel strategy to limit barrier failure in patients following severe injury.
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The central nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. Recently, in animal models of sepsis, the vagus nerve (VN) has been proposed to play a crucial role in the regulation of the immune response, also referred to as the cholinergic anti-inflammatory pathway. The VN, through release of acetylcholine, dampens immune cell activation by interacting with α-7 nicotinic acetylcholine receptors. Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect. In this review, we will discuss the current understanding concerning the mechanisms and effects involved in the cholinergic anti-inflammatory pathway in the gastrointestinal tract. Deeper investigation on this counter-regulatory neuroimmune mechanism will provide new insights in the cross-talk between the nervous and immune system leading to the identification of new therapeutic targets to treat intestinal immune disease.
Background: The severity of postoperative ileus (POI) has been reported to result from decreased contractility of the muscularis inversely related to the number of infiltrating leukocytes. However, we previously observed that the severity of POI is independent of the number of infiltrating leukocytes, indicating that different mechanisms must be involved. Here, we hypothesize that the degree of tissue damage in response to intestinal handling determines the upregulation of local cytokine production and correlates with the severity of POI. Methods: Intestinal transit, the inflammatory response, I-FABP (marker for tissue damage) levels and brain activation were determined after different intensities of intestinal handling. Key results: Intense handling induced a more pronounced ileus compared with gentle intestinal manipulation (IM). No difference in leukocytic infiltrates in the handled and non-handled parts of the gut was observed between the two intensities of intestinal handling. However, intense handling resulted in significantly more tissue damage and was accompanied by a systemic inflammation with increased plasma levels of pro-inflammatory cytokines. In addition, intense but not gentle handling triggered enhanced c-Fos expression in the nucleus of the solitary tract (NTS) and area postrema (AP). In patients, plasma levels of I-FABP and inflammatory cytokines were significantly higher after open compared with laparoscopic surgery, and were associated with more severe POI. Conclusions & inferences: Not the influx of leukocytes, rather the manipulation-induced damage and subsequent inflammatory response determine the severity of POI. The release of tissue damage mediators and pro-inflammatory cytokines into the systemic circulation most likely contribute to the impaired motility of non-manipulated intestine.
Leptin, the product of the ob gene, plays a key role in the regulation of food intake via a cross-talk between hypothalamic leptin receptors and neuropeptides that affect feeding behaviour. Recent studies have shown a synergistic interaction between leptin and cholecystokinin (CCK) leading to suppression of food intake, which involves CCK-1 receptors and capsaicin-sensitive vagal fibres. In this study, we have investigated the presence of leptin receptors in afferent and efferent neurons of the vagus nerve. By using reverse transcription-polymerase chain reaction, mRNAs encoding long (Ob-Rb) and short (Ob-Ra) leptin receptor isoforms were detected in the rat nodose ganglion, which contains the cell bodies of the vagal afferent neurons. Western blot analysis confirmed the presence of leptin receptor-immunoreactive proteins in extracts from the vagal trunk. Immunohistochemistry showed the presence of leptin receptors and the leptin-induced transcription factor STAT3 in the cytoplasm of nodose ganglion cells. In cervical vagal segments, levels of leptin receptor protein displayed physiological regulation, with decreased amounts after feeding and increased levels after food restriction. In addition, leptin receptor and STAT3 immunoreactivities were detected in neurons of the nucleus of tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNX) by immunofluorescence histochemistry. Furthermore, direct double-labelling demonstrated colocalization of Ob-Rb and STAT3 immunoreactivities in cholinergic vagal efferent cell bodies of the DMNX. It is speculated that vagal leptin receptors, apart from being activated by adipocyte-derived leptin, may also be influenced by leptin produced by the stomach. This may explain the synergistic action of leptin and CCK on neuronal activity in the NTS and on food intake.
VNS Therapy: the implantation procedureVagus nerve anatomy and mechanism of action of VNSEfficacy studies in patients with epilepsyEfficacy of VNS in animal models of epilepsyEfficacy in other conditionsSafety and tolerability in patients with epilepsyClinical use of VNS for epilepsySummary
Many gastrointestinal and pancreatic functions are under strong modulatory control by the brain via the vagus nerve. To start identifying location and neurochemical phenotype of the enteric neurons receiving functional vagal efferent input, we activated vagal preganglionic neurons either by electrical or chemical stimulation and examined the expression of phosphorylated CREB (c-AMP response element binding protein) and the immediate early gene c-Fos. There was no spontaneous expression of both markers in the pancreas and considerable spontaneous expression of p-CREB but not Fos in the upper GI-tract. Unilateral electrical vagal stimulation-induced p-CREB was found in 40% of neurons in the head of the pancreas. Fos expression was found in 70–90% of neurons in the esophagus and stomach, in 20–30% of myenteric plexus neurons and 5–15% in submucosal neurons of the proximal duodenum. Double-labeling experiments showed that a majority of pancreatic neurons and about 25–35% of neurons in the stomach and duodenum contain NADPH-diaphorase and that many of these receive functional vagal input. Other neurons that can be vagally activated contain gastrin-releasing peptide or calretinin. Chemical stimulation of the dorsal surface of the caudal brainstem with the stable TRH analog RX77368 resulted in selective activation of vagal efferents with expression of Fos in a small number of gastric myenteric plexus neurons. The results demonstrate the suitability of this method to investigate magnitude and local distribution of vagal input to the enteric nervous system as well as specificity of its neurochemically coded pathways. They represent the first step in the identification of function-specific units of parasympathetic vagal outflow. Anat Rec 262:29–40, 2001. © 2001 Wiley-Liss, Inc.