Enteric nervous system
David Grundya and Michael Schemannb
Purpose of review
Enteric neurobiology is a rapidly advancing field of
investigation providing insight into the way in which diverse
gastrointestinal functions are controlled, coordinated and
integrated with central mechanisms important for food
intake regulation, illness behaviour and sensory
mechanisms. Our aim was to highlight recent advances.
Recent findings
With such a large number of studies to choose from and
given our emphasis in previous years on developmental
aspects, sensory transmission, and neuro-immune
interactions, we have focused on two themes. One
reflecting the current interest in the way the enteric nervous
system is altered in disease and the second covering the
enormous interest in the contribution of enteric mechanisms
to the control of energy balance.
Summary
The new basic science information gathered during the past
year provides insight into pathophysiological processes and
will pave the way for improved understanding of both
organic and ‘functional’ gastrointestinal disorders.
Keywords
cholecystokinin, enteric glia, neuromodulator, nutrient
signals, vagus
Curr Opin Gastroenterol 23:121–126. ß 2007 Lippincott Williams & Wilkins.
a
Department of Biomedical Science, University of Sheffield, Sheffield, UK and
Human Biology, TU Munich, Freising-Weihenstephan, Germany
b
Correspondence to Professor David Grundy, Department of Biomedical Science,
University of Sheffield, Western Bank, Sheffield S10 2TN, UK
Tel: +44 114 2224657; fax: +44 114 2221090; e-mail: d.grundy@sheffield.ac.uk
Current Opinion in Gastroenterology 2007, 23:121–126
Abbreviations
CCK-1
DRG
EGFP
GABA
MCH
NTS
cholecystokinin-1
dorsal root glanglion
enhanced green fluorescent protein
g-aminobutyric acid
melanin-concentrating hormone
nucleus tractus solitarius
ß 2007 Lippincott Williams & Wilkins
0267-1379
Introduction
Last year the journal Science ran a special issue called ‘the
inner tube of life’ featuring a number of review articles
dealing with diverse topics such as colon cancer and
the gut immune system. The enteric nervous system
received scant mention except for a review by Badman
and Flier [1] that drew attention to the importance of the
enteric innervation and in particular the role of the vagus
nerve in signalling sensory information from the gut to
the brain that helps coordinate digestive activity with
energy intake and expenditure. The past 12 months
have seen a number of important papers that develop
this theme.
Vagal signalling mechanisms
Vagal afferents are becoming increasingly recognized as a
site where diverse gastrointestinal signals that reflect
recent food intake, nutrient content and overall energy
stores are integrated. In the central nervous system
(CNS) these signals serve to regulate food intake and
energy expenditure. In addition to their role in regulating
energy metabolism, however, these afferents contribute
to mechanisms that regulate inflammatory responses, the
so-called ‘vagal anti-inflammatory pathway’ [2] and also
input to brain regions whose output serves to influence
somatic pain transmission in the spinal cord [3]. The
vagus is therefore being recognized as a major player in
homeostasis and interoception, and which may contribute
to overall feelings of well being [4]. Here we consider a
number of papers published this year that address this
topic.
The importance of vagal afferents for meal termination
is well recognized. Cholecystokinin is a peptide that is
released from enteroendocrine cells in the intestinal
mucosa in response to luminal nutrients, principally
lipids, and which mediates effects on gastrointestinal
function that optimize digestion and absorption and
which also cause satiety. Both these actions of cholecystokinin involve interaction with cholecystokinin-1
(CCK-1) receptors on vagal afferents that signal to the
brainstem. The mechanisms that underlie cholecystokinin release in response to luminal nutrients are incompletely understood. On the one hand, preabsorptive
mechanisms are considered to arise from interactions
between luminal nutrients and the apical membrane of
the cholecystokinin-containing enteroendocrine cells.
On the other hand, chylomicron formation is involved
implicating postabsorptive mechanisms particularly for
the inhibitory effect of long chain triglycerides (>C12). A
121
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122 Small intestine
recent study has utilized apolipoprotein A-IV knockout
mice to examine the role of this chylomicron component
in the signalling of intestinal lipid [5]. They found that
gastric emptying was faster in the knockout compared
with wild-type animals. In addition, meal-stimulated
gastric acid secretion was inhibited by intestinal
lipid infusion in wild-type but not the knockout animals.
Finally, they demonstrated that vagal activation of the
nucleus of the solitary tract by intestinal lipid was attenuated in the knockout animals. Neuronal activation
induces transcriptional and translational activity of
the c-fos oncogene which in turn generates intracellular regulatory proteins, Fos, which can be detected
using immunocytochemical methodology. Counting the
number of Fos-positive neurones in the nucleus tractus
solitarius (NTS) is therefore a measure of vagal activity.
These experiments provide a clear demonstration of the
importance of lipid absorption and chylomicron formation for vagal signalling of lipid components within
ingested meals. It is also clear, however, that this is not
the only mechanism involved since the reduction in Fos
expression in the NTS was reduced only by about half in
the knockout animals. It would be interesting to correlate
these effects with cholecystokinin release in order to
determine the extent to which pre and postabsorptive
mechanisms contribute to nutrient signalling. In this
respect, the same group has utilized a CCK-1 receptor
knockout mouse to examine the role of vagal afferent
mechanisms in lipid-induced modulation of gastric motor
and secretory function [6]. Like the apolipoprotein A-IV
knockout, the CCK-1 receptor knockout had increased
gastric emptying and blunted inhibition of gastric acid
secretion following intestinal lipid infusion. Similarly,
brainstem Fos activation by intestinal lipid was also
reduced by about 50% in the CCK-1 knockout, despite
the absence of any response to exogenous cholecystokinin. Thus it is unlikely that CCK-2 receptors contribute
to the vagal activation in response to intestinal lipid but
that other mechanisms independent of cholecystokinin
release are likely involved, possible arising from mealinduced distension or release of other chemical mediators
from the intestinal epithelium by preabsorptive or postabsorptive nutrient stimuli.
While the studies discussed above have focused on the
gastrointestinal consequence of vagal afferent activation
by meal-related stimuli, a recent review by Schwartz [7]
has considered the consequence for food intake regulation. The integration of vagal and nonvagal mechanisms
are discussed, with an important role for the brainstem in
assimilating and processing sensory information and,
through reciprocal interactions with hypothalamic nuclei
and areas of the limbic cortex, influencing food consumption. One important pathway between the NTS and
hypothalamus is mediated by neurones that express
proopiomelancortin. Proopiomelancortin knockout mice
are obese yet little is known about the role of NTS
proopiomelancortin neurones in the processing of vagal
afferent input from the gut. A recent study [8] has started
to address this following development of a transgenic
mouse in which proopiomelancortin is tagged with
enhanced green fluorescent protein (EGFP). This allows
the distribution of EGFP in the subnuclei of the NTS to
be determined and targeted in electrophysiological
experiments designed to examine their synaptic inputs.
Cholecystokinin induced c-fos gene expression in NTS
proopiomelancortin EGFP neurones consistent with
synaptic input from vagal afferents. Moreover, cholecystokinin was shown in patch clamp experiments to
activate these neurones via a presynaptic mechanism
to increase glutamate release. Opiates have an opposing
action consistent with their orexogenic effect when
injected into the NTS. Thus the brainstem melanocortin
system has the potential to integrate signals from the
periphery via incoming afferents carrying short-term
information on satiety with central pathways that can
activate appetite.
Integration may also occur in the periphery on the terminals of sensory vagal afferents. While a pivotal role for
CCK-1 receptors is well established, recent studies have
identified a number of other putative humoral agents that
are considered to act on CCK-1 receptor expressing vagal
neurones. Thus vagal neurones expressing CCK-1 receptors also express receptors for leptin (Ob-R), orexin
(OX-R1), ghrelin (GHS-1R) and endocannabinoids
(CB1). The ligands for these receptors are released in
the periphery during fasting or upon feeding and may
therefore influence sensory signalling from the gastrointestinal tract with consequences for both short-term and
long-term food intake regulation. A recent study adds
another mediator to the list, melanin-concentrating
hormone (MCH) [9]. The receptor, MCH-1R, can be
detected in both rat and human nodose neurones by both
reverse transcriptase PCR and immunocytochemistry.
Moreover, over 90% of neurones expressing MCH-1R
also express CCK-1 receptors. MCH-1R expression is low
in fed animals but high in rats fasted for 24 h. In addition,
re-feeding fasted animals resulted in a decline in MCH1R expression but only after a period of 5 h. This effect
was mimicked by exogenous cholecystokinin and the
effect of re-feeding blocked by pretreatment with the
CCK-1R antagonist, lorglumide. This suggests that in
addition to the effects of cholecystokinin on short-term
food intake regulation, it may have long-term effects that
extend beyond the period of a single meal. Another
striking finding in this study was the observation that
the ligand, MCH, is expressed in the same vagal
neurones as its receptor and regulated in a similar way
by feeding and fasting. MCH in the hypothalamus is
associated with hyperphagia and increased body weight.
The increase of MCH and its receptor in vagal neurones
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Enteric nervous system Grundy and Schemann
during fasting may also be linked to increased appetite
and thus terminated by food intake following release of
cholecystokinin. In other words, changes in orexogenic
signalling by the vagus may contribute to the suppression
of anorexic signals. In contrast, however, a study examining the effect of obestatin, a recently described anorexogenic peptide isolated from the stomach [10], found
no effect on vagal afferent activity or cholecystokininmediated inhibition of food intake or gastric emptying
[11].
Quite a different role for cholecystokinin arises from a
publication by Luyer et al. [12], one which implicates
cholecystokinin in the regulation of inflammation. This
study arose out of the identification of vagal efferent
mechanisms in the inhibition of the systemic inflammatory response to endotoxin [2]. Activation of this ‘cholinergic antiinflammatory pathway’ resulted in reduced
tumour necrosis factor-a levels and blunted nuclear factor
kB activation following haemorrhagic shock. The authors
reasoned that the mechanisms that enable absorption
and utilization of nutrients also represent a defence
liability to dietary antigen and commensal bacteria and
thus the immune system may be downregulated in
response to food intake with a critical role for cholecystokinin in the activation of a vago-vagal antiinflammatory reflex. They demonstrated that rats fed a high-fat
diet had a reduced cytokine response and preserved
intestinal barrier function with reduced bacterial translocation following haemorrhagic shock and that this effect
was lost in vagotomized animals. The combined treatment with CCK-1 and CCK-2 receptor antagonists also
prevented the high-fat meal induced protection against
haemorrhagic shock. The authors argue that a state of
immune hyporesponsiveness occurs upon feeding in
order to limit any unwanted response to dietary
antigens, bacterial toxins and destructive endogenous
lysozymes and so preserve gut barrier function and
homeostasis.
A genome-wide screen of expression levels of receptors
and ion channels expressed by gut projecting nodose
ganglion neurones (the cell bodies of vagal afferent
neurones) in comparison with sensory neurones in the
dorsal root glanglion (DRG) has been performed by
Peeters et al. [13]. The expression of CCK-1 receptors
by nodose neurones is 15-fold higher than in the DRG,
which is perhaps not surprising given the wealth of
functional data demonstrating the role of the vagus in
cholecystokinin’s action on gut function and satiety, as
discussed above. This study, however, identifies many
other genes that are differentially expressed and therefore provides a valuable resource for anyone who is
interested in ion channels and receptors that underlie
sensory signalling in nodose and DRG sensory neurones.
The supplementary data accessible online catalogues
123
expression of a variety of ion channels and receptors
including potassium channels, calcium channels and
g-aminobutyric acid (GABA) receptor. These expression
data fit nicely a functional study which examined the
inhibition of vagal mechanosensitivity by GABA-B receptor activation using baclofen [14]. This inhibition is
associated with a reduction in the triggering of transient
lower oesophageal relaxations that lead to gastrooesophageal reflux and has potential as a theurapeutic target for
treatment of patients with gastrooesophageal reflux disease. The latest study into this mechanism examined the
sensitivity of different subpopulations of vagal afferents
supplying the gastrooesophageal mucosa and muscle to
baclofen in the absence and presence of agents which
blocked certain potassium and calcium channels. The
mucosal afferent response to stroking the receptive field
was inhibited by baclofen, but this effect was lost when
rubidium was added to block the G-protein coupled
inward rectifier potassium channel and similarly blocked
in the presence of the v-conotoxin GVIA, specific for
N-type Ca channels. In contrast, the inhibition of tension
receptors by baclofen was unaffected by either of these
blockers alone or combined. The data suggest that
the inhibitory effect of GABA-B receptor activation is
mediated via different transduction pathways in the
different subpopulations that supply the ferret oesophagus. Mucosal afferent inhibition is N-type Ca channel
and GIRK sensitive while inhibition of tension receptor
involves neither. This suggests that downstream signalling from GABA-B receptors may be different in different
neuronal populations and therefore subjected to differential pharmacological manipulation.
Enteric disorders and disease
The past year has seen some important publications that
advance our understanding of gut diseases in humans and
reveal novel targets to improve symptoms or treat the
disease.
A very elegant study by Wedel et al. [15] reported on
novel smooth muscle markers that reveal abnormalities of
the intestinal musculature in severe colorectal motility
disorders. While smooth muscle a-actin staining was
generally normal, immunoreactivity for smooth muscle
myosin heavy chain, histone deacetylase 8 or smoothelin
was either absent or focally lacking in Hirschsprung’s
disease, idiopathic megacolon and slow-transit constipation. In contrast, diseased specimens showed normal
smooth muscle morphology by conventional haematoxylin/eosin and Masson’s trichrome staining. Noteworthy,
regardless of the type of the underlying colorectal motility disorder and the pattern of altered immunostaining,
intestinal blood vessels and the lamina muscularis mucosae were consistently normally labelled, indicating that
such alterations would have been missed by studying
mucosal biopsies, even those including submucosal
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124 Small intestine
layers. This raises the important issue of whether
progress in pathogenesis of some gut diseases will require
extended histopathology in full thickness biopsies.
The relevance of altered expression of smooth muscle
markers is apparent in mice lacking smoothelin A. The
pathology of these animals is similar to that seen in
patients with chronic intestinal pseudoobstruction
[16]. Extended histopathology has been shown to be
of great value in prediction of recurrence of Crohn’s
disease [17]. The presence of myenteric plexitis diagnosed at the time of ileocolonic resection in Crohn’s
disease patients was a consistent predictor of recurrence
and the degree of myenteric plexitis correlated with the
severity of recurrence.
A recent review covered the emerging roles of hydrogen
sulphide on gut physiology and pathology [18]. Hydrogen sulphide has been suggested as the third gaseous
mediator besides nitric oxide and carbon monoxide [19].
It is a neurotransmitter in the CNS and functions as a
vasodilator [20,21]. Hydrogen sulphide is generated
by endogeneous enzyme systems, mainly cystathionine
g-lyase and cystathionine ß-synthase and is produced in
amounts that can account for physiological responses
[20,21]. In the near future we expect to see a growing
number of papers on the effect of hydrogen sulphide in
the gut. Hydrogen sulphide is synthesized in enteric
neurons and acts as an excitatory neuromodulator in
the enteric nervous system [22]. Its role in inflammation, nociception, motility and secretion may reveal
novel strategies in treating gut disorders that are associated with increased hydrogen sulphide levels. The source
of hydrogen sulphide could be diet, enteric neurons,
blood or intestinal microbiota. Dietary factors such as
red meat, high protein intake, and alcohol are associated
with relapse in ulcerative colitis, possibly mediated via
hydrogen sulphide production [23,24]. Ulcerative colitis
patients have higher luminal hydrogen sulphide concentrations which may compromise use of endogeneously
produced butyrate, a short-chain fatty acid that has been
shown to antagonize some ulcerative colitis pathologies.
It is tempting to speculate whether one rationale to use
probiotics for treatment of inflammatory conditions,
including some irritable bowel syndrome entities, may
be related to prevention of the negative effects of
hydrogen sulphide. The positive effects of butyrate
may be due to its direct action on epithelium but also
to activation of neural pathways that may be protective by
increasing motility. It has been recently shown that in
rats, short-chain fatty acids trigger peristaltic reflex
activity by release of 5-hydroxytryptamine (5-HT)
from mucosal cells and activation of 5-HT4 receptors
on sensory calcitonin gene-related peptide-containing
nerve terminals [25]. Some effects of butyrate are
mediated via G-protein coupled receptors, namely
GPR43 and GPR41. In the rat intestine GPR43 receptors
are expressed on some enteroendocrine cells and mast
cells but not on enterochromaffin cells [26].
Enteric glia receive growing interest which is reflected by
the increased number of publications revealing their
importance for normal gut function. A series of papers
by Neunlist and colleagues described some novel roles
for enteric glia. In a transgenic mouse model of glial cell
disruption they reported changes in enteric neuronal
phenotype, in particular a decreased vasoactive intestinal
peptide and substance P expression in the submucous
plexus and a decreased nitric oxide synthase with concomitant increases in choline acetyltransferase expression in the myenteric plexus [27]. These changes had a
functional correlate in that neurally mediated relaxations
were much less in transgenic animals. In addition, transgenic mice showed higher intestinal permeability. In
another study the same group [28] was able to show that
enteric glia cells have antiproliferative effects involving
secretion of transforming growth factor-b1 by glial cells.
Taken together, these studies suggest that alterations in
glia functions impair the gastrointestinal mucosal barrier
system and in concert with enteric nerves may be
involved in pathologies such as cancer and inflammatory
bowel diseases. Interestingly, and in contradiction to the
findings in transgenic animals, disruption of glial cell
functions with the gliatoxin fluorocitrate caused reduced
small intestinal motility [29]. The reason for this discrepancy remains unknown but one important difference
between the two models is the lack of inflammation in
the fluorocitrate treated animals whereas the transgenic
animals showed CD3 positive T-cell infiltrates in the
myenteric plexus. It is important to investigate possibilities to selectively activate or inhibit glial cell functions
in the tissue in order to provide evidence that this cell
population is a worthwhile drug target. The recent identification of aquaporin 1, dipeptide transporter PEP2 and
a2 receptor expression on enteric glia is only a first step in
this direction [30–32].
The interaction between the enteric nervous and
immune systems remains an important topic and some
progress has been achieved to shed some light on the
neuro-immune axis in the human gut. Importantly, localization of histamine receptors in human tissue has been
studied in detail, although we still do not understand
enough about the role of particular histamine receptors in
the function of the receptor-expressing enteric neurones.
Both histamine H1 and H2 receptors have been localized
in the enteric plexus [33]. Although the title and abstract
of the paper suggest the absence of H3 receptors, the
authors describe in the result section H3 expression in
two specimens. There is the possibility that the lack of
H3 expression in most specimens may be due to the
antibody not cross-reacting with the numerous splice
variants of the human H3 receptor. A detailed mapping
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Enteric nervous system Grundy and Schemann
of constitutively expressed cyclooxygenase-2 protein in
human myenteric and submucous ganglia [34] should be
followed by further studies on the neuromodulatory role
of prostaglandins in the human enteric nervous system
and their potential as drug targets.
Conclusion
There have been major advances in our understanding of
the enteric nervous system but there is still much that we
do not know. What is clear is that with the wealth of
talented investigators in the field, great strides in our
understanding will continue to be made and in the long
term will be reflected in clinical practice.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 207–208).
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of neuronal phenotypes.
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126 Small intestine
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