GASTROENTEROLOGY 1996;111:1683–1699
SPECIAL REPORTS AND REVIEWS
The Immunomodulation of Enteric Neuromuscular Function:
Implications for Motility and Inflammatory Disorders
STEPHEN M. COLLINS
Intestinal Diseases Research Unit and Division of Gastroenterology, Department of Medicine, McMaster University Health Sciences Centre,
Hamilton, Ontario, Canada
Gastrointestinal motility and sensory perception are al-
tered in a variety of mucosal inflammatory conditions
of the gut, ranging from peptic esophagitis to ulcerative
colitis. Studies in animal models now clearly indicate
a causal relationship between the presence of mucosal
inflammation and altered sensory-motor function. In
many instances, these changes occur in the absence
of any discernible encroachment of the deeper neuro-
muscular layers by the inflammatory infiltrate, which
remains largely within the lamina propria. Accordingly,
attention has focused on local sources of mediators,
and recent studies indicate that smooth muscle cells
and enteroglia are sources of and targets for cytokines
such as interleukin 1b and interleukin 6. In several
instances, neuromuscular dysfunction persists after
mucosal inflammation has subsided; this state may be
maintained by locally produced mediators. Studies also
show the ability of enteric muscle to modulate lympho-
cyte function via major histocompatibiity complex II–
restricted antigen presentation. Clinical observation
and experimental data also suggest that nerves modu-
late intestinal inflammation via local release of proin-
flammatory neuropeptides (substance P) and via the
activation of extensive circuits that may involve the
brain. Taken together, these findings provide plausible
explanations for a variety of clinical scenarios ranging
from inflammatory bowel disease to pseudo-obstruc-
tion syndromes and subgroups of functional bowel dis-
orders.
T his review addresses the hypotheses that the im-
mune system modulates gastrointestinal motility
and that cells that constitute part of the motor apparatus
of the gut, such as smooth muscle cells and nerves, have
the ability to influence inflammatory or immune pro-
cesses.
Introduction and Conceptual
Framework
Function and Control of Normal Motility
Motility of the gut serves several purposes, includ-
ing the orderly passage of food into the gut via the
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oropharynx and esophagus, its storage and trituration in
the stomach before transfer to the small intestine, passage
through the intestine at a rate that optimizes digestion
and absorption, and slower passage through the large
intestine to permit the formation and ultimate expulsion
of solid stool. This broad repertoire of motor events is
controlled by highly complex and integrated systems that
include neural, myogenic, and local hormonal regulatory
mechanisms. In addition, gut motility is subject to the
effects of circulating hormones, including those of the
female reproductive system and the thyroid gland.
Consequences and Causes of Altered
Motor Function
Disturbances of motor function produce a variety
of symptoms, including chest pain and dysphagia in the
esophagus, bloating, nausea and vomiting in the stomach
and proximal small intestine, and diarrhea or constipa-
tion in the remainder of the gut. These symptoms can
arise in the context of inflammation or immune activation
in various gut regions and embrace such common entities
as esophagitis, gastritis, and idiopathic inflammatory
bowel disease (IBD). These observations suggest that mo-
tility of the gut is also subject to the influence of the
immune system. In this context, the motor system may
play an important role in defending the gut against nox-
ious stimuli present in the lumen, as shown in Figure
1. This notion is reflected, for example, by the observa-
tion of Vantrappen et al., who showed that bacterial
overgrowth in the small intestine is accompanied by dis-
ruption of the normal cyclic pattern of interdigestive
motility in the small intestine.1 This observation
prompted consideration of the possibility that motor
function is necessary for controlling the luminal bacterial
population. This work was extended in rats in which
Abbreviations used in this paper: IL, interleukin; L-NAME, NG-nitro-
L-arginine methyl ester; TNB, trinitrobenzene.
q 1996 by the American Gastroenterological Association
0016-5085/96/$3.00
gasa WBS-Gastro
1684 STEPHEN M. COLLINS
Figure 1. Schematic representation of the role of gastrointestinal
nerve and muscle in the defense of the gut against noxious stimuli.
Mucosal injury and inflammation results in immune activation. These
events lead to changes in activity in enteric nerves and muscle, re-
sulting in the eviction of the agent from the gut lumen.
opiate-induced suppression of migrating myoelectrical
activity caused bacterial overgrowth, which disappeared
once the normal motor pattern was restored.2 Similarly,
Sukhdeo and Croll showed that opiate-induced inhibition
of motility in mice infected with nematode parasites
prolonged the enteric phase of the infection.3 Thus, dis-
ruption of normal motor function leads to proliferation
of enteric flora or the prolongation of enteric infections
and supports the concept that the motor system contri-
butes to the defense of the gastrointestinal tract.
The Motor System as an Extension of the
Immune System
This concept was initially extended in studies us-
ing animals immunologically sensitized to antigen by
showing that intraluminal exposure of the animal to the
sensitizing antigen causes diarrhea as well as marked
changes in intestinal myoelectrical activity4 and in aboral
propulsive forces5 in a manner aimed at evicting the
antigen from the gut.4 Thus, the motor system may,
under certain conditions, act as an extension of the muco-
sal immune system in host defense; the immune system
serves to recognize foreign and potentially harmful or-
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GASTROENTEROLOGY Vol. 111, No. 6
ganisms or substances in the gut lumen to contain and
limit their access to the intestinal milieu and to recruit
physiological systems such as the motor system to assist
in the eviction of these agents from the gut.
This review will, in part, address mechanisms underly-
ing the activation of the motility apparatus of the gut
by the mucosal immune system in the contexts of in-
flammation and hypersensitivity reactions. In this con-
ceptual model, the motor system is recruited and in-
volved as an ‘‘innocent bystander.’’
There now is some evidence that the neuromuscular
tissues of the gut may also play a more active participa-
tory role during inflammation and immune activation;
enteric nerves may modulate immune function via the
activation of a more extensive neural circuitry than has
been traditionally envisaged. In addition, smooth muscle
cells may undergo a phenotypic shift whereby, through
autoregulated cytokine production, they are capable of
maintaining inflammation-induced trophic and contrac-
tile changes that may persist long after the mucosal re-
sponse to injury has subsided.
Taken together, these proposed roles of the neuromo-
tor system in primary inflammatory or immunologic in-
juries to the gut provide putative mechanisms underlying
the extensive and, in some instances, persistent nature
of gut dysfunction observed in association with inflam-
mation or immune activation in the gastrointestinal
tract. Pertinent clinical scenarios include the influences of
stress or smoking on IBD and the persistence of irritable
bowel–like symptoms in patients after remission of IBD6
or after an enteric infection.7
Observations on Altered
Neuromotor Function In Vivo After
Inflammation or Immune Activation
Altered Motility in the Inflamed Gut
Originally, it had been suspected that altered mo-
tor activity producing muscular spasm and possibly is-
chemia might be an etiologic factor in the development
of experimental colitis in dogs,8 but subsequent work
indicated that the converse is more likely, namely, that
inflammation alters motility. Kern et al.9 described a
temporal relationship between altered rectosigmoid mo-
tility and the presence of inflammation in patients with
ulcerative colitis. It was these original studies, later ex-
tended by Snape et al.,10 that provided the impetus for
studying the mechanisms underlying altered motility in
the inflamed bowel and that later precipitated in vitro
studies on the relationship between the immune and
motor systems in the gut. Further observations in hu-
mans and in animals underscored the existence of this
relationship.
WBS-Gastro
December 1996
In the esophagus, induction of inflammation produced
a reduction in lower esophageal sphincter pressure in cats
with acid-induced esophagitis.11 A similar causal linkage
between inflammation and altered motility was sug-
gested by the development of abnormal contractile activ-
ity in the colon of cats12 and subsequently dogs13 with
acetic acid–induced colitis. It is interesting to note that
in the feline models of esophagitis or colitis, altered mo-
tor activity persisted after recovery of the mucosa.11,12
Similar observations have been made in humans with
persistently altered esophageal motility after resolution
of peptic esophagitis14 and in patients with ulcerative
colitis, where motor and transit disturbances persist in
the face of quiescent colitis.15 This may provide an expla-
nation as to why patients with quiescent colitis experi-
ence irritable bowel syndrome–like symptoms with a
higher-than-expected prevalence.6 These types of obser-
vations raise questions regarding the mechanisms under-
lying the uncoupling of the initiating inflammatory
event in the mucosa from the persistent changes that
occur in the underlying neuromuscular tissues. This may
have bearing on the proposed ‘‘active role’’ of neuromus-
cular tissues in inflammatory processes and will be dis-
cussed later in the review.
The Role of Afferent Nerves
There is increasing awareness of the role of altered
sensory perception as a basis for symptom generation in
gastrointestinal disease, including both functional and
inflammatory conditions.16 Increased rectal sensitivity to
balloon distention is well documented in IBD,17,18 and
low-grade inflammation of the colon (using acetic acid)
is accompanied by increased visceromotor responses, in-
dicative of pain, in the rat.19 Thus, part of net change
in motor activity that accompanies inflammation may
arise as a result of altered afferent nerve input into intrin-
sic and extrinsic neural circuits. Altered sensory percep-
tion arising as a result of intestinal inflammation may
also be influenced by imbalance of the autonomic nervous
system that has been documented in some patients with
IBD.20,21
Altered Neuromotor Function in Other
Conditions of Immune Activation
While initial studies focused on motor changes
that occur in the context of intestinal inflammation, later
observations broadened the clinical context within which
interactions between the immune and motor systems of
the gut occur. Motor abnormalities and abnormal respon-
siveness to hormonal and mechanical stimuli have been
documented in early cases of scleroderma.22 Radiological
studies suggested that motor abnormalities occur after
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THE IMMUNOMODULATION OF GUT MOTILITY 1685
oral challenge in patients with milk protein allergy,23
and breath hydrogen testing showed delayed orocecal
transit in patients with untreated celiac disease.24 These
findings prompted consideration that antigen-specific
immunologic responses may involve the motor system of
the gut. More recently, an acute colonic pseudo-obstruc-
tion has been documented after therapy with the cytokine
interleukin (IL) 225,26 and reinforces the notion that prod-
ucts of immune cells can dramatically alter intestinal
motility. Histological findings in some cases of pseudo-
obstruction reveal massive lymphoid infiltration of the
myenteric plexus and muscularis externa.27,28 The well-
described motor abnormalities, morphological changes,29
and high prevalence of antineuronal antibodies30 in acha-
lasia suggest that motility disturbances may arise from
autoimmune mechanisms.31 Thus, interactions between
the immune and motor systems of the gut may occur in
a broad spectrum of clinical disorders.
Putative Cellular Targets for
Immune Cells Modulating Gut
Motility
Gastrointestinal motility is normally determined by
myogenic, efferent, and afferent neural and hormonal con-
trol mechanisms. Each of these mechanisms is subject to
modulation by the immune system, whose products have
been shown to influence the excitability of smooth muscle,
peripheral, enteric, and central nerves. In addition, strategi-
cally important cells such as the pacemaker interstitial cells
of Cajal are also subject to modulation by immune cell
products or inflammatory mediators (Der-Filaphet, Hui-
zinga, and Collins, unpublished observation, May 1996).
There is evidence that inflammation at one site in the gut
may produce altered motor function at a remote nonin-
flamed site, and motor abnormalities have been shown in
the stomach and small bowel of patients with ulcerative
colitis.15,32 These findings suggest that inflammation may
induce changes in enteric nerves at remote noninflamed
sites as shown by Dvorak et al.33 or activate neural circuits
outside the gut.20,21 In addition, it is also known that
intestinal inflammation is accompanied by functional and
structural changes in the central nervous system in both
animals34 and humans,35 possibly via abnormal afferent
input from the gut. Thus, inflammation or immune activa-
tion may alter gut motility via changes at extrinsic and
central neural control sites in addition to changes in cell
types intrinsic to the gut wall.5,36
Altered Muscle Function
Observations From Animal Models of
Gastrointestinal Inflammation
Earlier studies in a cat model of esophagitis were
intriguing in that they combined in vivo and in vitro
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1686 STEPHEN M. COLLINS
approaches. The initial in vivo studies showed a decrease
in the resting tone of the lower esophageal sphincter after
perfusion of the distal esophagus with 0.1N HCl for 30
minutes daily for 4 days. Histological analysis revealed
that the acute inflammatory infiltrate did not invade the
muscle layers that appeared entirely normal, leading the
investigators to predict that muscle function would also
be normal in the presence of esophagitis.11,37 However,
subsequent studies in the same model showed that there
was a reduction in the basal tone of lower esophageal
sphincter circular muscle in vitro38 and that this was
accompanied by an inability of sphincteric muscle cells
to use intracellular calcium.39
A similar approach was taken to study the effects of
intestinal inflammation on muscle contraction using rats
infected with nematode parasites. Farmer showed a tran-
sient acceleration of intestinal transit of 51Cr on day 8
after a primary infection with Nippostrongylus brasiliensis.40
Studies performed in vitro shortly thereafter showed an
increase in the contractile responses of intestinal longitu-
dinal muscle to agonists41 and that this could be attenu-
ated by suppressing the inflammatory response to the
parasite using a corticosteroid,42 implicating the in-
flammatory process rather than the parasite as the cause
of altered muscle function. Subsequent studies showed
that, in contrast to the increased force generation by
longitudinal muscle in this model, circular muscle exhib-
ited a reduction in its contractile responses.43 This obser-
vation may reflect inherent differences in the responses
of circular and longitudinal muscles to inflammatory me-
diators, such as prostaglandins.44 In addition to differ-
ences between circular and longitudinal muscles, there
are also differences in the responses of muscle from differ-
ent gut regions to inflammation. Within the same model,
longitudinal muscle in the jejunum exhibits increased
contractility whereas it exhibits decreased contractility
in the terminal ileum45 and colon46 to the same inflam-
matory stimulus. Similarly, the actions of inflammatory
mediators, such as prostanoids, on muscle vary between
gut regions.47,48 A similar profile has emerged from very
limited data available in human IBD, where there is
increased contractility in muscle resected from the small
intestine of patients with Crohn’s disease49; however, a
reduction in contractility was observed in muscle from
patients with colitis.50 Whether this reflects the trend
observed in animals or merely a chance finding remains
to be determined. In animal studies, there is consistency
of tissue response to inflammation provided that the time
frame of the inflammation is comparable and the same
regions are studied. For example, Grossi et al. showed
that responses of longitudinal muscle to acute distal coli-
tis were similar when the colitis was induced by four
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GASTROENTEROLOGY Vol. 111, No. 6
different stimuli.46 Similarly, Sjogren et al. found a simi-
lar profile of change in slow wave activity in the rabbit
ileum inflamed by either trinitrobenzene (TNB) or ri-
cin.51 Thus, inflammation-induced changes in muscle
contraction are region specific, are different between cir-
cular and longitudinal muscles, and appear independent
of the type of injury (i.e., chemical, infectious, immuno-
logic, and so on) that induces the inflammatory response.
However, it should be emphasized that these generalities
apply to models of acute inflammation (all õ1 week)
and cannot be extrapolated with confidence to more long-
term models that are less ubiquitous and, as yet, mostly
unstudied with respect to accompanying neuromuscular
changes.
Changes at the Level of the Smooth
Muscle Cell
There have been some investigations into the al-
terations that occur at the level of the smooth muscle
cell during inflammation but few, if any, generalizations
can be made. This reflects the use of different animal
models and species as well as differences in approach.
The most extensively studied models are those of TNB-
induced colitis or ileitis and small bowel inflammation
attributable to nematode infection. In TNB-induced ile-
itis or colitis, a reduction in force generation is observed
in virtually all studies and there are accompanying alter-
ations in receptors on muscle cells from the inflamed
segment. In TNB-induced ileitis in the guinea pig, there
is a down-regulation of receptors for platelet-activating
factor and in receptors for b2-adrenergic agonists, whereas
a1- and a2-adrenergic receptors are up-regulated.52,53 In-
terestingly, the changes in adrenergic receptors could
be attenuated using mast cell stabilizers or NG-nitro-L-
arginine methyl ester (L-NAME), implicating mast cells
and nitric oxide in the down-regulatory process. Cytokine
receptors, such as the IL-1 type I receptor, have been
shown directly on muscle cells from healthy rabbit colon,
but the extent to which they are altered during inflam-
mation remains to be determined.54 This is a potentially
important receptor on muscle because its activation dur-
ing inflammation may result in the release of IL-1b55
and IL-656 as well as prostaglandins.54 More information
is required regarding the regulation of IL-1 receptors on
muscle cells during inflammation.
In the nematode model, the increase in contractility
of longitudinal muscle from the inflamed jejunum is not
restricted to particular pharmacological classes of agonist;
therefore, it is not surprising to observe that there were
no substantial changes in the affinity or number of mus-
carinic receptors on muscle during inflammation.57,58
Receptor-independent mechanisms have also been in-
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December 1996
vestigated, and studies show a marked reduction in the
sodium-potassium pump in muscle cells, as illustrated
by a ú85% decrease in nitro-phenol-phosphatase activity
and in the ouabain-sensitive uptake of 86rubidium.58 Fur-
ther study has shown that this down-regulation was evi-
dent at the gene level59 with a marked reduction in
expression of messenger RNA for the a1 subunit, which
is considered to be the most important isoform contribut-
ing to membrane polarity in intestinal smooth muscle.60
Preliminary data suggest that IL-1b may contribute to
this down-regulation of Na/,K/ –adenosine triphospha-
tase.61
Others have shown that there is an increase in the expres-
sion of messenger RNA for the contractile filament a-
actin in hypercontractile muscle cells from the intestine of
nematode-infected rats62 as well as abnormalities in the rate
of cross-bridging of contractile filaments in hypocontractile
muscle from rabbits with immune complex colitis.63 Thus,
inflammation alters contractility at several loci in the muscle
cell; these are likely to reflect the actions of several mediators
of inflammation converging on the cell.
Trophic Changes in Muscle in Inflamed Gut
Inflammation alters the trophic properties of
smooth muscle; this had been observed in several animal
models of inflammation64,65 and is implied in human
IBD,66 particularly in the context of stricture forma-
tion.67 The latter is a result not only of muscle cell prolif-
eration but also the deposition of collagen by muscle as
a result of stimulation by cytokines such as platelet-
derived growth factor. Interestingly, IL-1b, which can
be produced by muscle cells,55 activates collagenase and
inhibits collagen synthesis by human intestinal smooth
muscle cells.67 This and results of other studies68 raise
the prospect of developing medical approaches to the
prevention of stricture formation in IBD. This subject
has recently been reviewed in depth by Graham67 and
will not be covered here.
On the Origin and Nature of Inflammatory
Mediators Responsible for Altered Muscle
Function
Inflammation-induced changes in smooth muscle
contraction occur even when an inflammatory infiltrate
is mild and is restricted to the mucosa46 and when the
muscularis externa is macroscopically normal.69 This
raises questions regarding the origin of putative media-
tors responsible for altered muscle function in the pres-
ence of mucosal inflammation. Kao and Zipser69 showed
that the muscularis externa was the site of increased
prostaglandin E2 production in a rabbit model of colitis.
In addition, Khan and Collins70 showed the expression
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THE IMMUNOMODULATION OF GUT MOTILITY 1687
of several cytokines, including IL-1b, tumor necrosis fac-
tor a, IL-6, and transforming growth factor b in the
region of the longitudinal muscle–myenteric plexus in
the nematode-infected rat intestine. Thus, the mediators
that may be important in the induction and maintenance
of altered neuromuscular function during inflammation
may originate from resident cells in that tissue, including
smooth muscle cells.
Many mediators have been shown to alter smooth mus-
cle function. As has been described already, prostaglan-
dins E2 and F2 contract rabbit and human colonic longi-
tudinal muscle but relax circular muscle from these
species.48,71 Leukotriene D4 relaxed all muscles studied,
whereas B4 had no effect.71 In TNB-induced colitis in
rats, the observed increase in colonic myoelectrical activ-
ity was mediated by platelet-activating factor, IL-1, and
leukotrienes (except D4 or prostaglandins),72 although,
paradoxically, colonic transit changes observed in this
model were not altered by platelet-activating factor
blockade but were attenuated by a leukotriene D4 antago-
nist.73 These results show the complex pharmacology of
inflammation and the difficulties in extrapolating in vitro
data to the in vivo system not only in healthy tissue but
also between healthy and disease states. It follows that
the rationalization of treatments based on an understand-
ing of how a substance works in healthy subjects does
not necessarily predict its effect in the presence of a
disease process such as inflammation.
There is much current interest in the role of NO
during inflammation because it has effects on blood flow
and vascular permeability that could facilitate the in-
flammatory process. In addition, NO has well-described
effects on motility and is believed to be the major inhibi-
tory neurotransmitter in the gut. Studies in TNB-in-
duced colitis in the rat suggest that NO plays a selective
role in the inflammatory process because L-NAME im-
proved some but not all aspects of the colitis.65 Moreover,
the role of NO seems to change depending on the model
under study because the effects of L-NAME were quite
different in the inflamed intestine of the nematode-in-
fected rat compared with its action in TNB-induced coli-
tis.65,74 In humans, there may also be some selectivity in
the distribution and hence the role of NO in ulcerative
colitis and Crohn’s disease. In ulcerative colitis, NO syn-
thase activity was increased 8-fold in the mucosa but not
the muscularis of patients with ulcerative colitis and was
normal in the mucosa and reduced in the muscle layer
of patients with Crohn’s disease.75 This is in agreement
with a study that examined the role of NO in toxic
megacolon. In that study, NO synthase activity was nor-
mal in muscle strips from uncomplicated patients with
colitis or colon cancer but increased in megacolon cases.
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1688 STEPHEN M. COLLINS GASTROENTEROLOGY Vol. 111, No. 6

Whether these differences in NOS activity in uncompli-

cated patients with Crohn’s disease or colitis is reflective
of differences in the contractility of these tissues observed
in other studies in vitro49,50 remains to be determined.
However, NO synthase was substantially increased in
muscle strips from patients with toxic megacolon,76 and
the investigators interpreted their findings to implicate
NO as a mediator of toxic dilatation by virtue of its
ability to relax smooth muscle. This finding is consistent
with a previously proposed hypothesis regarding the role
of inhibitory reflexes in the development of toxic megaco-
lon because NO is considered to be an important inhibi-
tory neurotransmitter in the gut.77
In addition to the products of arachidonate metabo-
lism, cytokines also affect smooth muscle contraction.
Studies in the nematode-infected rat and mouse have
suggested that lymphocytes are responsible for inflam-
mation-induced changes in muscle contractility (see be-
low) and activation of T lymphocytes in vivo using anti-
CD3 antibody.78 However, the cytokine mediators of
these changes remain to be identified. Preliminary data
indicate that exposure of muscle to TH2 cytokines such
as IL-4 rather than TH1 cytokines increase the contractile
response to subsequent stimuli.79 Similar effects were
observed after transfer of the IL-4 gene to the gut using
an adenovirus as vector80 (see below). The effects of other
categories of cytokines on intestinal smooth muscle con-
traction have yet to be determined.
The Immunologic Basis for Altered Smooth
Muscle Function
Observations that changes in transit3 and muscle
contraction45 could be abrogated by corticosteroid treat- Figure 2. Transmission electron microscopy of longitudinal muscle
ment in animal models of intestinal inflammation sug- (LM) from the jejunum of a rat infected 1 day previously with T. spiralis.
gested that they occur as a result of the inflammatory The close approximation (arrowhead ) and cell surface contact (arrow)
between a lymphocyte (Ly) and a muscle cell are shown. There are
process. no signs of cellular injury in muscle cells adjacent to lymphocyte
(original magnification 12,9501; bar Å 1 mm).
Role of T Lymphocytes
Recent work suggests that intestinal muscle pro-
vides a hospitable environment for lymphocytes by pro- tion.85 In each of these conditions, there are alterations
moting the survival of T cells via the inhibition of in muscle contraction86 and growth.64
apoptosis.81 This may contribute to the observation that In the nematode model, studies using athymic rats
lymphocytes are prominent among the few inflammatory indicate that the increased contractility87 and hyperplasia
or immune cells found in the muscularis externa during, but not hypertrophy of intestinal muscle88 is T cell de-
for example, intestinal inflammation resulting from nem- pendent because changes were absent from infected
atode infections in rats82 or after intestinal transplanta- athymic rats but restored in infected congenitally
tion and during early graft rejection in rats.83 In the athymic rats after successful reconstitution of T cell func-
nematode model, ultrastructural analysis indicates close tion.87 Similarly, we found that activation of endogenous
communication between lymphocytes and muscle cells T cells through the administration of anti-CD3 in vivo
as shown in Figure 2. Lymphocytes are also evident in resulted in an increase in intestinal muscle contractility
the neuromuscular layers of the inflamed intestine in in vitro.78 While the exact mechanism underlying T cell–
Crohn’s disease84 or in certain types of pseudo-obstruc- induced changes in muscle remains to be determined,

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December 1996
recent work in the mouse indicates that the cytokine IL-
4 has the ability to increase the contractility of intestinal
muscle after prolonged exposure in vitro89 or in vivo by
IL-4 gene transfer to the gut using an adenovirus vector.80
The extent to which endogenous IL-4 mediates these
changes during nematode infection remains to be deter-
mined, but the expression of this cytokine is increased
during infection and seems to be important in the process
of worm expulsion from the gut.90 If altered muscle con-
tractility contributes to the process of worm expulsion,
which is TH2 mediated,91 then it is possible that TH2
cytokines such as IL-4 and IL-5 alter the contractile prop-
erties of enteric smooth muscle.
Mast Cells and Muscle Contractility
Although activation of mast cells results in muscle
contraction in vitro, mainly through the release of 5-
hydroxytryptamine in rats,92,93 there is no evidence that
mast cell products alter the intrinsic properties of smooth
muscle. Moreover, studies in vivo suggest that antigen-
induced changes in motor function is mediated, in large
part, via nerves. This will be covered later in the review.
Macrophages and Muscle Contractility
Macrophages are normally present in the muscu-
laris mucosa94 and are among the earliest cells to prolifer-
ate in that tissue following mucosal inflammation (Be-
rezin, Huizinga, and Collins, unpublished observation,
December 1995). Macrophages are believed to be im-
portant sources of cytokines such as IL-1b that alter mus-
cle contractility indirectly by suppressing the release of
important neurotransmitters such as acetylcholine95 and
norepinephrine.96 In addition, these cells seem to influ-
ence muscle cells directly, as has been reported in the
lung, where macrophage activation enhanced bronchial
muscle contractility.97 Macrophages may also directly af-
fect intestinal muscle; in a recent report involving rabbit
ileal circular muscle, endogenous macrophages were
stimulated with the bacterial peptide f-met-leu-phe and
resulted in a decrease in the amplitude of myogenic slow
waves.98 The site of action of the peptide was localized
to macrophages by fluorescence microscopy, and the ac-
tion was resistant to tetrodotoxin and was thus considered
to reflect a direct interaction between macrophages and
smooth muscle.98
Neutrophils and Monocytes
When human peripheral blood neutrophils were
activated with A23187 and the supernatant exposed to
rabbit colonic circular muscle before stimulation with
bethanechol, there was a significant reduction in the con-
tractile response.99 Although leukotriene B4 and superox-
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THE IMMUNOMODULATION OF GUT MOTILITY 1689
ide anion were detectable in the supernatant, the ob-
served suppression could not be attributed to the actions
of these substances.99 Using a similar approach, these
investigators were unable to detect a significant change
in muscle contractility after exposure to peripheral blood
monocytes.99
Eosinophils
Eosinophils are found in the gut wall in such
diverse conditions as IBD100 and achalasia.29 Because eo-
sinophils bear immunoglobulin E receptors, it is possible
that some of the contractile responses observed after acti-
vation of these receptors using anti–immunoglobulin E
antibody92,93 may reflect, at least in part, eosinophil-
mediated responses. Studies involving tracheal smooth
muscle have shown that the supernatant of activated eo-
sinophils from the peritoneal cavity potentiated contrac-
tile responses to histamine. The action did not require
the presence of tracheal epithelium and was considered
to reflect an effect on smooth muscle mediated by leuko-
trienes C4 , D4 , and E4 .101
Altered Neural Function
Observations in Humans
Disturbances in intestinal physiology provide in-
direct evidence of altered neural function in the inflamed
gut. The apparent intolerance of patients with IBD to
balloon distention of the rectum17,18 provides further sup-
port for this concept. More direct evidence comes from
demonstrated abnormalities of structure and neurotrans-
mitter content in the enteric plexuses of patients with
entities such as IBD, achalasia, or pseudo-obstruc-
tion.28,29 In these studies, changes in the number of gan-
glia have been reported together with evidence of axonal
degeneration and infiltration with a variety of cells, in-
cluding lymphocytes, mast cells, eosinophils, and macro-
phages.27 – 29,33,66,84,102 Another important observation is
that structural changes to enteric nerves in IBD is not
restricted to the site of active inflammation but may also
be found at noninflamed sites,66 and this may have bear-
ing on the findings that physiological disturbances are
not restricted to the site of inflammation but may also
occur at noninflamed remote sites.15,32 There is also evi-
dence that nerves outside the gut are altered in the pres-
ence of inflammation attributable to Crohn’s disease103
and preliminary data suggesting that structural abnor-
malities exist in the central nervous system in some pa-
tients with IBD compared with age- and sex-matched
controls.35 Autonomic imbalance also exists in some pa-
tients with IBD, with sympathetic dysfunction occurring
in Crohn’s disease21 and vagal dysfunction in ulcerative
colitis.20 Together, these observations suggest that intes-
WBS-Gastro
1690 STEPHEN M. COLLINS
tinal inflammation in humans is accompanied by neuro-
logical changes that are extensive both within and outside
the gut and may involve the central nervous system.
While a number of studies have identified changes in
the neurotransmitter content of the inflamed gut,32,104,105
there have been few common findings. Among these is a
decrease in vasoactive intestinal peptide,106 – 108 although
initial reports suggested an increase in this peptide in
IBD.104,105 It has been suggested that the destruction of
vasoactive intestinal peptide–containing nerves subse-
quent to inflammation results in a compensatory increase
in messenger RNA for vasoactive intestinal peptide,
thereby excluding a primary defect at the gene expression
or posttranscriptional levels.107 A reduction in the tissue
concentration of this peptide correlated with an impair-
ment of inhibitory neural function in circular muscle
from patients with Crohn’s colitis.109 An increased sub-
stance P concentration is reported in ulcerative coli-
tis,110,111 which may have bearing on the apparent in-
crease in sensory perception reported in active colitis.17,18
The demonstration by Geboes et al.112 of major histo-
compatibility complex II expression on enteroglial cells,
together with the presence of UCHL-1–positive T lym-
phocytes in the enteric nervous system in IBD, has sug-
gested that changes in the enteric nervous system in IBD
are immunologically mediated. In pseudo-obstruction as-
sociated with small cell carcinoma of the lung, antineu-
ronal antibodies have been reported113 and there is pre-
liminary evidence that these antibodies perturb enteric
neural reflexes in an in vitro preparation from guinea pig
ileum.114 These observations indicate that inflammation
or immune activation may lead to widespread distur-
bances of neural function in humans. Some insights into
the mechanisms underlying inflammation-induced
changes in neural function have been obtained from ani-
mal studies.
Observations in Animal Studies
In a model of ileitis induced in rabbits by ricin,
Goldhill et al. showed that inflammation increased non-
cholinergic excitation mediated by substance P and that
hyperpolarization of circular muscle was NO mediated
in the ricin-induced inflamed gut.115 In a rabbit model
of TNB-induced colitis, Goldhill et al. also showed that
inflammation was associated with a defect in the modula-
tion of secretomotor neurons by acetylcholine and prosta-
glandin E2 .116 Studies involving quantification of radiola-
beled neurotransmitter release from myenteric plexus
preparations have shown substantial changes in the
evoked release of both 3H-noradrenaline117,118 or 3H-ace-
tylcholine119 during inflammation of the nematode-in-
fected small intestine or during TNB-induced colitis.
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GASTROENTEROLOGY Vol. 111, No. 6
Interestingly, in the model of TNB-induced distal colitis,
a marked suppression of 3H-noradrenaline release was
observed not only in the inflamed distal colon but also in
the noninflamed transverse colon and terminal ileum,118
providing a possible functional correlate of the ultrastruc-
tural abnormalities noted in enteric nerves at nonin-
flamed sites in patients with Crohn’s disease33 as well
as altered intestinal motility in patients with ulcerative
colitis.32
On Mechanisms Underlying Altered Neural
Function in Animal Models of Intestinal
Inflammation
In most models, the inflammatory infiltrate origi-
nates in the mucosa and lamina propria and does not
penetrate the myenteric plexus. Our preliminary observa-
tions indicate that, in the nematode-infected rat, there
is activation of macrophage-like cells or glia within the
plexus within 24 hours after infection (Berezin and Col-
lins, unpublished observation). In addition, we have
shown that there is increased expression of messenger
RNA and protein for IL-1b in the myenteric plexus and
longitudinal muscle within 24 hours after this infection
and that this is followed by the expression of other cyto-
kines such as IL-6 and tumor necrosis factor a,70 which
are known to alter myenteric neural function (see below).
These observations raised the possibility that these
proinflammatory cytokines mediate the altered myenteric
neural function exhibited in this model. Initial studies
showed the abilities of several cytokines to mimic these
changes when exposed to longitudinal muscle–myenteric
plexus preparations from healthy rats; IL-1b caused a
pronounced suppression of the release of both acetylcho-
line120 and noradrenaline121 by a process that was depen-
dent on protein synthesis. Similar observations were
made with respect to the ability of tumor necrosis factor
a to suppress noradrenaline release.122 There are also
synergistic interactions between cytokines such as IL-1
and IL-6 evident both pharmacologically123 and electro-
physiologically.124 Our data suggested that the actions
of these cytokines were mediated by the release of endog-
enous IL-1b, which in turn suppressed neurotransmitter
release. However, more recent experiments have sug-
gested that IL-1b acts via the cytokine leukemia inhibi-
tory factor because the action of exogenous IL-1b was
inhibited by anti–leukemia inhibitory factor antibod-
ies.125
In the nematode model of intestinal inflammation, the
changes in neurotransmitter release could be abrogated
by treatment of rats with a receptor antagonist against
IL-1, implicating IL-1 as a mediator of these changes,126
in addition to the observed increase in immunoreactive
WBS-Gastro
December 1996
substance P.127 Thus, the cytokine-mediated alterations
in enteric nerve function likely reflect a cascade of events
involving the induction and release of several cytokines
within the plexus.
The question emerges as to the origin of these cyto-
kines in the myenteric plexus. In the brain, astroglia
are sources of several cytokines that play a role not only
in the response to injury128 but also in the maturation
process of the developing brain. 129 Enteroglial cells
share some of the characteristics of astroglia130,131 and
undergo hyperplasia in conditions such as pseudo-ob-
struction that are associated with enteric neuropa-
thy.132 In preliminary studies, we have developed a
culture of purified enteroglial cells that retain their
surface markers S-100 and glial fibrillary acidic protein
and respond to exposure to cytokines such as IL-1b
to induce IL-6 secretion.133 Moreover, the action of
cytokines on enteric glia is itself altered by neurotrans-
mitters such as noradrenaline.133 Taken together, these
observations suggest a pivotal role for enteroglia not
only in inflammatory conditions but also in bidirec-
tional neuroimmune interactions in the gut.
Mast cells are also potentially important mediators
of neuroimmune interactions. Mast cells lie in very
close proximity to nerves in the human and rat intes-
tine in both health and in disease (see Stead134 for
review). Mast cells release mediators such as histamine
in response to certain neuropeptides135 and are there-
fore strategically placed to mediate neuroimmune in-
teractions. A compelling example of this is the demon-
stration of Pavlovian conditioning of mast cell
degranulation in the gut,136 which may have bearing
on altered motor function occurring in cases of pseudo-
allergic reactions to food.137
Mast cell – mediated changes in enteric neural activ-
ity may play a role in immediate hypersensitivity –
based reactions to food. Scott et al. showed that expo-
sure of the gut to ovalbumin produced diarrhea and
extensive changes in intestinal myoelectrical activity
in rats previously sensitized to ovalbumin. 4 This rapid
and extensive response cannot be attributed to a local
interaction between antigen and enteric smooth mus-
cle and suggests that enteric intrinsic and extrinsic
nerves have been activated. This is supported by the
studies of others in which mast cell degranulation in-
duced changes in colonic myoelectrical activity that
seemed to involve capsaicin-sensitive afferent nerves 138
and increases fos protein expression in hypothalamic
nuclei.139 In addition, Frieling et al. have shown that
antigen exposure on tissue from nematode-sensitized
animals results in increased neuronal excitability and
suppression of nicotinic transmission at fast choliner-
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THE IMMUNOMODULATION OF GUT MOTILITY 1691
gic synapses mediated in part by local histamine re-
lease.140 Thus, mast cell degranulation may alter intes-
tinal physiology by activating extensive neural
circuitry.
There is abundant evidence from nongastrointesti-
nal systems that inflammation alters the activity of
afferent nerves, mainly through the recruitment of pre-
viously silent c fibers,141 and this has been implicated
as a peripheral component in the development of vis-
ceral hyperalgesia syndromes.16,142 Recent work76,142
has shown that low-grade inflammation or chemical
‘‘irritation’’ of the colon with acetic acid produces en-
hanced sensory perception, as reflected by an increase
in vasopressor and abdominal visceromotor responses
to colonic distention.19 This is accompanied by an in-
crease in the expression of fos proteins in the case of
colitis143 and an increase in substance P immunoreac-
tivity in the case of jejunal inflammation in the dorsal
root ganglion and spinal cord.144 Using a similar para-
digm to assess the sensory response to noxious stimuli
in the gut, others have found that visceral distention
increases abdominal wall responses in the presence of
TNB-induced colitis and that this is mediated by bra-
dykinin.145 Other studies have shown that inflamma-
tory mediators such as cytokines like human recombi-
nant IL-1b, IL-1b, and tumor necrosis factor a146; mast
cell products147,148 in addition to 5-HT 3 agonists139;
and the sensory neuropeptides substance P and calcito-
nin gene-related peptide, both of which are increased
during inflammation,127,144,148 are likely to contribute
to the increase in sensory perception found in IBD
and related conditions and offer innovative therapeutic
targets for symptomatic treatment in these disorders.
Altered Endocrine Function
Relatively little is known about perturbations of
the gut endocrine system during inflammation. Early
studies from the parasitology literature suggested that
intestinal inflammation is accompanied by increases in
the circulating levels of gastrointestinal hormones such
as gastrin,149 secretin, and glucagon and a decrease in
the concentration of cholecystokinin.150 There have been
few studies on the effects of inflammation on gut hor-
mone levels in IBD, and one recent study detected only
minor changes in the circadian fluctuation in plasma
gastrin and somatostatin levels in patients with ulcerative
colitis.151 However, the recent interest in the relationship
between Helicobacter pylori gastritis and reciprocal changes
in plasma gastrin and somatostatin152 and the ability of
cytokines such as human recombinant IL-1b to influence
gastrin release from G cells153 should stimulate future
work on the effect of local and remote inflammation on
WBS-Gastro
1692 STEPHEN M. COLLINS GASTROENTEROLOGY Vol. 111, No. 6

Figure 3. Schematic representation of the bidirectional interactions between inflammatory or immune cells and enteric smooth muscle.
Inflammation or immune activation in the mucosa results in changes in smooth muscle contraction and growth. Muscle also undergoes
phenotypic transformation under these conditions, resulting in its ability to express surface molecules, elaborate cytokines, and activate T
lymphocytes via antigen presentation. A state of persistent dysfunction of muscle may emerge from this scenario and persist after resolution
of the mucosal responses to injury.

the release of hormones, such as motilin, that have effects
on gut motility and other aspects of enteric physiology.
The Case for an Active
Participatory Role for Enteric
Nerves and Muscle in Immunologic
or Inflammatory Processes in the
Gut
This part of the review addresses the hypothesis
that cells that constitute part of the motor apparatus of
the gut, such as smooth muscle cells, have the ability to
influence inflammatory or immune processes; this con-
cept is shown in Figure 3.
Immune Modulation by Smooth Muscle
Cells
Recent studies suggest that the interaction be-
tween T cells and smooth muscle may be bidirectional.
After exposure to interferon gamma, intestinal smooth
muscle cells express surface molecules major histocom-
patibility complex II and intercellular adhesion molecule
1,154 which are prerequisite for antigen presentation to
T cells. In addition, smooth muscle cells produce cyto-
kines such as IL-656 and human recombinant IL-1b.55
In these studies, smooth muscle cells were grown to
confluence and expressed g-actin, suggesting preservation
of a smooth muscle phenotype. After exposure to human
recombinant IL-1b, the cells expressed messenger RNA
and protein for IL-6 through a receptor-mediated event,
as shown in Figure 4, indicating that smooth muscle
cells are a target for and a source of cytokines. These
muscle-derived cytokines may act as costimulatory sig-
nals during antigen presentation. In studies using oval-
bumin-sensitized mice, Hogaboam et al. have shown that
smooth muscle cells present antigen in a major histocom-
patibility complex II–restricted manner to T lympho-
cytes isolated from mesenteric lymph nodes, causing T-
cell activation and proliferation.155 Thus, intestinal
muscle has the capacity to function as a nonprofessional
antigen-presenting cell. This may be relevant to observa-
tions made during intestinal inflammation after nema-
tode infection, where there is major histocompatibility
complex II expression in the muscularis externa, although
this has not been definitively localized to muscle cells.82

/ 5e14$$0043 11-20-96 08:35:07 gasa WBS-Gastro

December 1996
Figure 4. Enteric smooth muscle as a target for and a source of
cytokine. Smooth muscle cells from rat intestine were incubated with
human recombinant IL-1b in the presence or absence of human re-
combinant IL-1 receptor antagonist. IL-6 was measured in the super-
natant by bioassay. IL-1b caused a receptor-mediated increase in IL-
6 production by smooth muscle cells. h, Control; j, IL-1b; , IL-1b-
RA; , boiled IL-1. Adapted and reprinted with permission.56
Because intestinal epithelial permeability is invariably in-
creased during inflammation156 and because there is also
evidence of increased permeability and endothelial activa-
tion in blood vessels supplying the muscle layers during
intestinal inflammation,157 it is likely that muscle cells are
exposed to luminal and parasite-derived antigens. Taken
together, these observations raise the possibility that mus-
cle may engage in immunoregulation during intestinal
inflammation by engaging T cells via antigen presenta-
tion. One may speculate that this is a protective process
insofar as the magnitude of T cell activation induced
by muscle is weak in comparison with that induced by
professional antigen-presenting cells.155 As a result, anti-
gen entering the muscularis externa through a leaky vas-
/ 5e14$$0043 11-20-96 08:35:07 gasa
THE IMMUNOMODULATION OF GUT MOTILITY 1693
culature would be mopped up by muscle without risking
a broad amplification of the immune response in a tissue
whose protective role is essentially to facilitate the evic-
tion of noxious stimuli from the lumen. In this regard,
it is also important to recognize that the immunomodula-
tory role intestinal smooth muscle is subject to modula-
tion by the nervous system. This is illustrated by the
ability of neurotransmitters such as substance P to en-
hance the activation of T lymphocytes by smooth muscle
cells158 and by the abilities of certain neurotransmitters
to modulate cytokine production by smooth muscle cells.
Vasoactive intestinal peptide, calcitonin gene-related pep-
tide, and noradrenaline, but not carbachol or somato-
statin, augmented the IL-1b–induced increase in IL-6
production by smooth muscle cells at a posttranscriptional
level.159 Thus, cytokines acting on smooth muscle cells
in a neuropeptide-rich environment may induce the ex-
pression of surface molecules such as major histocompati-
bility complex II and intercellular adhesion molecule I,
allowing the muscle cells to participate in immune regu-
lation to different degrees and subject to neural input.
These properties of muscle cells also allow them to become
targets for inflammatory or immune cell attack, resulting
in a myopathy such as that seen in certain cases of pseudo-
obstruction.27,28,132
The ability of muscle cells to elaborate cytokines,
which are known to alter neuromuscular function, may
be a basis for the persistence of neuromotor dysfunction
that is seen in patients with IBD in remission and in
patients with irritable bowel syndrome that is precipi-
tated by a previous enteric infection.6,7 This persistence
of motor dysfunction after resolution of mucosal in-
flammation has been observed in both humans and in
animal models. A mouse model of this phenomenon has
recently been established,160,161 and preliminary data sug-
gest that genetic as well as immunologic factors are im-
portant in the expression of persistent dysfunction, be-
cause it occurs only in one strain tested (NIH-Swiss) and
requires the presence of T lymphocytes at the time of
the acute inflammatory event.162,163
An Active Role for Nerves in Intestinal
Inflammation
A wide range of clinical observations suggest that
the nervous system plays an active role in modulating
intestinal inflammation. In the past, surgical denervation
of the pelvis164 or vagotomy165,166 have been used success-
fully to ameliorate refractory IBD. Reports of the appar-
ent therapeutic benefit of drugs such as clonidine,167 nico-
tine,168 and lidocaine169 raise the possibility that the
inflammatory process is subject to the neural influences in
IBD, although direct anti-inflammatory actions of drugs
WBS-Gastro
1694 STEPHEN M. COLLINS
such as lidocaine likely contribute to their effect in IBD.
Speculation of a neuromodulatory component to the
pathophysiology of IBD is also supported by growing
awareness of the ability of neurotransmitters to influence
the behavior of immune170 or inflammatory cells171 as
well as the juxtapositioning of nerves and immuno-
cytes.134 Certainly, results obtained in animal models of
intestinal inflammation support this concept. There is
general agreement that capsaicin-sensitive primary affer-
ents play an anti-inflammatory role because depletion of
these nerves by prior exposure to capsaicin enhances the
inflammatory response in the colon148,172 and in the small
intestine.127 These data seemingly conflict with evidence
that treatment with an anti–substance P antibody or a
substance P antagonist attenuates intestinal inflamma-
tory responses in mice.173 However, these observations
may be reconciled by the hypothesis that primary affer-
ents contribute to mucosal protection via neural reflexes
but that the local antidromal release of substance P from
these nerves or the release of substance P from cells such
as eosinophils174 is proinflammatory.
Inflammation stimulates ongoing remodeling of en-
teric nerves,175 and it is possible that, under these condi-
tions, there may be a shift in nerve phenotype resulting
in an increase in either the number of substance P–
containing nerves or an increase in the substance P con-
tent of nerves in the gut, as has been shown in intestinal
inflammation attributable to nematode infection.127 Fur-
thermore, intestinal inflammation substantially decreases
the tissue level of neutral endopeptidase,176 resulting in
a marked increase in the bioavailability of any substance
P released locally in the inflamed gut; this would serve
to amplify its proinflammatory effects. As a balance to
contain the neurogenic component to inflammation,
there is evidence that neurokinin-1 receptors become in-
ternalized after inflammation in the airways.177 Taken
together, these observations support the concept that
nerves play an active role in modulating the inflammatory
processes in the gut and expose a number of potential
therapeutic targets for the treatment of intestinal in-
flammation.
Clinical Implications and Future
Directions
The literature to date clearly establishes the fact
that mucosal inflammation alters function in the deeper
neuromuscular tissue and is accompanied by alterations
in motility. A number of observations warrant emphasis.
First, changes in neuromotor function occur even with
mild and superficial inflammation restricted to the mu-
cosa or lamina propria; penetrating inflammation is not
a prerequisite. Thus, motor or sensory changes should be
/ 5e14$$0043 11-20-96 08:35:07 gasa
GASTROENTEROLOGY Vol. 111, No. 6
considered as a basis for symptom generation in condi-
tions accompanied by mild and superficial grades of in-
flammation. Conversely, inflammation should be consid-
ered as a therapeutic target in those conditions expressed
clinically as disorders of sensory-motor function in which
there is low-grade inflammation (superficial nonerosive
gastritis or esophagitis or some cases of irritable bowel
syndrome178 [see Gwee et al.179 for review]). However,
given the fact that mucosal inflammation may become
temporally dislocated from underlying inflammation-in-
duced neuromuscular changes, symptomatic improve-
ment may lag behind improvement of mucosal inflam-
matory changes, as has been noted in some cases of peptic
esophagitis and H. pylori ulcer-negative gastritis.
Second, inflammation in one region of the gut is ac-
companied by changes in neuromuscular function at adja-
cent or remote noninflamed sites. Thus, colonic transit
changes as well as altered intestinal transit and delays
in gastric emptying may occur even with quite limited
inflammatory disease, e.g., distal colitis.
Third, the clear demonstrations of interactions be-
tween immune cells, such as lymphocytes, and smooth
muscle and enteric nerves provides a putative mechanism
for the severe motility disturbances found in cases of
pseudo-obstruction in which there is infiltration of the
myenteric plexus or muscularis externa by lymphocytes
and other immunocytes. Furthermore, these observations
provide a basis for considering immunomodulatory or
immunosuppressive therapy to prevent disease progres-
sion.
Fourth, the increasing recognition of the fact that mus-
cle is capable of synthetic and secretory function (cyto-
kines, growth factors, and collagen) should promote
stronger consideration of the development of medical
approaches to the prevention of more obvious problems
such as strictures in Crohn’s disease or diverticular dis-
ease.
Fifth, an appreciation of the immunomodulatory po-
tential of smooth muscle, either in the form of T cell
activation through antigen presentation or via cytokine
production, raise at least the theoretical possibility that
muscle may be a target for gene or immunotherapy,
particularly because enteric myocytes are among the most
stable cell populations in the gut.
In conclusion, the emerging field of immunophysiol-
ogy has yielded a substantial body of evidence indicating
that the motor-sensory apparatus of the gut is subject to
modulation by the immune system. This, in turn, has
offered a number of scientifically plausible scenarios that
shed light on hitherto unexplained clinical issues and
yield innovative therapeutic strategies.
WBS-Gastro
December 1996
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Received May 6, 1996. Accepted August 20, 1996.
Address requests for reprints to: Stephen M. Collins, M.B., B.S.,
F.R.C.P., F.R.C.P.C., Room 4W8, GI Division, HSC, McMaster Univer-
sity, Hamilton, Ontario, Canada L8N 3Z5. Fax: (905) 521-4958.
Supported by the Medical Research Council of Canada and the
Crohn’s and Colitis Foundation of Canada.
The author thanks Gil Castro for his inspiration and encouragement
in this field and numerous colleagues, postdoctoral fellows, and stu-
dents at McMaster University, who have contributed to much of the
work reviewed in this paper.
WBS-Gastro