Nrgastro 2014 103

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Neuroplasticity and dysfunction after

gastrointestinal inflammation
Stuart M. Brierley and David R. Linden
Abstract | The gastrointestinal tract is innervated by several distinct populations of neurons, whose cell bodies
either reside within (intrinsic) or outside (extrinsic) the gastrointestinal wall. Normally, most individuals are
unaware of the continuous, complicated functions of these neurons. However, for patients with gastrointestinal
disorders, such as IBD and IBS, altered gastrointestinal motility, discomfort and pain are common, debilitating
symptoms. Although bouts of intestinal inflammation underlie the symptoms associated with IBD, increasing
preclinical and clinical evidence indicates that infection and inflammation are also key risk factors for the
development of other gastrointestinal disorders. Notably, a strong correlation exists between prior exposure
to gut infection and symptom occurrence in IBS. This Review discusses the evidence for neuroplasticity
(structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. Such
changes are evident during inflammation and, in many cases, long after healing of the damaged tissues,
when the nervous system fails to reset back to normal. Neuroplasticity within distinct populations of neurons
has a fundamental role in the aberrant motility, secretion and sensation associated with common clinical
gastrointestinal disorders. To find appropriate therapeutic treatments for these disorders, the extent and time
course of neuroplasticity must be fully appreciated.
Brierley, S.M. & Linden, D.R. Nat. Rev. Gastroenterol. Hepatol. advance online publication 8 July 2014; doi:10.1038/nrgastro.2014.103
Introduction
Visceral Pain Group,

Centre for Nutrition
andGastrointestinal
Diseases,Discipline
ofMedicine,
Universityof Adelaide,
South Australian Health
and Medical Research
Institute (SAHMRI),
Adelaide, SA 5000,
Australia (S.M.B.).
Department of
Physiology and
Biomedical Engineering
and Enteric
NeuroScience Program,
Mayo Clinic College of
Medicine, Rochester,
MN 55905, USA
(D.R.L.).
Correspondence to:
S.M.B.
stuart.brierley@
adelaide.edu.au
Neural control of gastrointestinal function is provided

by distinct populations of neurons, whose cell bodies lie
either within or outside the gut wall (Box1). Neuronal
control involves interactions between the following
reflexes: local enteric reflexes within the gut wall; extra
spinal reflexes that originate in the gut wall and pass
through prevertebral sympathetic ganglia without involv
ing the central nervous system (CNS); and reflexes that
pass to and from the gut via the CNS1 (Figure1). These
neurons and their nerve terminals reside within a complex
signalling environment, in which they are subjected to
mechanical distortion during distension or contraction
and a changing milieu of neuroactive signalling mol
ecules. This environment, and concomitantly neuronal
function, can be modulated at numerous levels by stress,2,3
the immune system,4 gut microbiota,5 enteric glia,6 as well
as macronutrients,7 and the circadian8 and feeding state9
of the host. In particular, inflammation of the gut, either
through abnormal immune responses or via gut infec
tion has been consistently demonstrated to cause neuro
plasticity (that is, structural, synaptic or intrinsic changes
that alter neuronal function). In turn, neuroplasticity
contributes to abnormal secretion, motility and sensa
tion, resulting in the development of discomfort, pain
Competing interests
S.M.B. receives research support from Ironwood
Pharmaceuticals Inc. None of the details relating to this
research support are discussed in this review. D.R.L. declares
no competing interests.
and diarrhoea or constipation. This Review focuses on

short-term (hours or days) neuroplasticity, the resultant
effects of gut inflammation on neuronal function in the
gutbrain axis, and the persistent (weeks and months)
neuroplasticity and dysfunction that remains after resolu
tion of inflammation. As these studies have largely been
conducted in animal models, it is instructive to present an
overview of the clinical symptoms of gastrointestinal dys
function to which neuroplasticity probably contributes.
For brevity, we describe the accumulated evidence avail
able for dysfunction in IBD and, in part, IBS. Information
on other inflammatory diseases of the gastrointestinal
tract can be found in Supplementary Box 1 online.
Clinical manifestations of neuroplasticity

IBD
IBD includes Crohns disease and ulcerative colitis, which
are characterized by chronic remitting and relapsing
inflammation of the intestine. Although the aetiology
of IBD is unknown, it is generally accepted that these
diseases develop through an inadequately suppressed
or exaggerated immune response to luminal antigens,
probably derived from the gut microbiota, in genetically
susceptible individuals.10 Abdominal pain, diarrhoea,
gastrointestinal bleeding and malnutrition are clinical
symptoms of IBD, and current medical and surgical
therapies for IBD seek to resolve mucosal inflammation
and reduce symptoms. Although biologic therapies for
IBD seem to demonstrate greater mucosal healing than
symptom recovery,11 steroid and 5aminosalicylic acid
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Key points
Gastrointestinal infection and inflammation are key risk factors for the
development of numerous clinical gastrointestinal disorders that present with
symptoms such as altered motility or secretion, abdominal discomfort and pain
Neuronal processing along the gutbrain axis is crucial for the function and
modulation of key gastrointestinal processes; findings suggest that this
processing can be altered by gut inflammation or infection
Inflammation or infection causes specific changes in enteric neuronal
excitability, which can persist after inflammation has resolved; in some
experimental models, inflammation also causes a rapid loss of myenteric
neurons and viscerofugal neurons
Inflammation causes a specific hypersensitivity of visceromotor sympathetic
neurons in prevertebral ganglia, which persists long after inflammation
hasresolved
Extrinsic gut sensory afferents express pronociceptive channels and receptors
that can be activated in response to inflammatory and immune mediators,
leading to acute neuronal hyperexcitability, visceral hypersensitivity and
neurogenic inflammation
Inflammation causes lowering of mechanical activation thresholds of highthreshold or low-threshold afferents, which leads to hyperexcitability in afferent
neuronal cell bodies, and increased activation of nociceptive pathways in the
central nervous system
therapies tend to provide greater symptom relief than

mucosal healing. 12 One interpretation of these find
ings is that the mechanisms contributing to mucosal
inflammation and symptoms are distinct. Interestingly,
there seems to be a subset of patients with IBD (20%),
whose symptoms do not subside following near com
plete endoscopic recovery.13,14 A wealth of studies have
demonstrated defined patterns of motor, sensory and
autonomic dysfunction as well as neuropathies indicative
of neuroplasticity in IBD, which are discussed later.
Motility changes in active IBD
Patients with active ulcerative colitis have been shown to
display slower whole-gut transit 15 and although inflam
mation is localised to the colon, reduced small-bowel
transit compared with healthy individuals.15 Numerous
studies indicate that colonic and rectal motor patterns
in patients with ulcerative colitis can be different from
healthy individuals as controls, with reduced rhythmic
phasic contractions and increased high-amplitude and
low-amplitude propagating contractions. 16,17 Activity
of rhythmic phasic contractions is inversely correlated
with increased stool frequency in patients with ulcera
tive colitis.17 Interestingly, simultaneous pressure and
myoelectrical activity recordings show reduced con
currency between spike potentials and increases in
pressure, especially in response to a meal (the gastro
colonic response).18 This observation is consistent with
intracellular recordings of circular smooth muscle cells
from patients with ulcerative colitis, in which contractile
activity is coupled more frequently to slow waves rather
than spike potentials. 19 Colonic scintigraphy shows
increased to-and-fro movements of tracer in both resting
and postprandial states in patients with ulcerative colitis
compared with healthy individuals,20 as well as proximal
colonic stasis and increased sigmoidal transit.15 The lack
of rhythmic phasic contractions is considered consistent
with the lack of haustra, or segmenting contractions, in
lead pipe radiographic images. Compared to ulcerative

colitis, motility studies in patients with active Crohns
disease are lacking. Dynamic MRI assessing smallbowel motility has demonstrated reduced ileal motility
in patients with Crohns disease.21 Other noninvasive
recording methods, such as hydrogen breath tests, have
identified decreased orocecal transit time in patients with
active Crohns disease.22 Furthermore, subsets of patients
with Crohns disease display delayed gastric emptying
of solid but not liquid meals.23,24 By contrast, rectoanal
manometry has been inconclusive, with reports of either
absent 25 or normal26 rectoanal inhibitory reflexes with
reduced, 27,28 unchanged 25 or increased 29 resting and
maximal squeeze anal pressures.
Motility changes in IBD in remission
Few studies have investigated motor function during the
postinflammatory state of IBD, and conflicting results
have been reported. Reports suggest normal30 or even
increased31 rhythmic phasic contractions compared with
healthy controls and either reduced30 or normal31 gastro
colonic responses during remission from ulcerative
colitis. Reports also indicate an increased incidence of
single and clustered propagating contractions compared
with controls, which importantly relates to the reporting
of symptoms during remission from Crohns disease. 32
In patients in remission from either Crohnsdisease or
ulcerative colitis, duodenal pressure waves initiated by
luminal acid are increased, whereas the propagation of
lipid-induced duodenal pressure waves is reduced.33 In
addition, a subset of patients in remission from Crohns
disease exhibit delayed gastric emptying.24 Whether
identified motor disturbances during active or remit
ting IBD are attributable to neuroplasticity or non-
neural mechanisms (see Supplementary Box 2 online) in
humans remains unclear. However, studies from animal
models (see later) suggest that neuroplasticity might have
some role in motility disturbances in IBD in remission.
Enteric neuropathy in active IBD
Several lines of evidence indicate that the structure
and neurochemical composition of the enteric nervous
system (ENS) is altered during active IBD.34,35 Numbers
of mucosal and muscular nerve fibres increase, along with
immunoreactivity of neurochemicals including tyrosine
hydroxylase, substanceP, calcitonin gene-related peptide
(CGRP), vasoactive intestinal polypeptide (VIP; also
known as VIP peptides), 5hydroxytryptamine (5-HT),
and nitric oxide synthase (NOS).36,37 These findings are
by no means unequivocal, as some studies have identified
reduced or no change in VIP immunoreactivity,38,39 no
change in immunoreactivity of multiple neuropeptides,40
and a reduction of tyrosine-hydroxylase-immunoreactive
nerve fibres.41 However, evidence exists of axon degenera
tion in Crohns disease,42,43 with cyclooxygenase (COX)2
expression greatly increased in myenteric ganglia during
active IBD.44
Changes in the number of enteric neurons during
active IBD are controversial with studies yielding conflict
ing reports of increased,45,46 no change,45,47 or decreased48
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Box 1 | Neuronal populations of the gastrointestinal tract
Enteric neurons
The enteric nervous system consists of networks, or
plexuses, of neurons. Their axons and neuronal cell bodies
coalesce with enteric glia as ganglia within the plexus
and interganglionic fibre tracts of varying nerve density.
The myenteric, or Auerbachs plexus, resides between the
longitudinal and circular muscle layers in the muscularis
externa. It is continuous, essentially running from the
mid-oesophagus to the anal sphincter. The submucosal,
or Meissners plexus, resides within the submucosa and
is absent or sparse in the oesophagus and stomach, but
present throughout the intestines.
Individual enteric neurons function either as intrinsic
afferents (cells that respond, with or without non-neural
transducer cells, to mechanical or chemical stimuli to
initiate reflexes), efferents or motor neurons (cells that
transmit information to effector cells such as arterioles,
glandular epithelium, or smooth muscle), or interneurons
(cells that relay, integrate and modify reflexes). Individual
enteric ganglia are composed of apparently random,
intermingled selections of different classes of neurons.
Intrinsic reflex activity that is responsible for co-ordinating
intestinal motility is accomplished via overlapping circuits
of afferent, interneuronal and efferent neurons located
throughout the length of the gut. On the basis of their
electrophysiological properties enteric neurons can be
subdivided functionally into either AH neurons (intrinsic
afferents) or synaptic (S) neurons (interneurons and
motorneurons).
Extrinsic sensory afferent neurons

Extrinsic sensory afferent neurons project to the central
nervous system and give rise to perceivable sensations.
Vagal afferents innervating the gut have cell bodies in
the nodose/jugular ganglia, whilst spinal afferents have
cell bodies in multiple dorsal root ganglia. The latter are
further subdivided into splanchnic and pelvic afferents
based on the nerves through which they project. Vagal
afferent neurons project centrally to the brainstem, whilst
spinal afferents project centrally to the spinal cord.
As such, these extrinsic sensory neurons provide the
afferent limb of spinal and brainstem reflexes, provide
input to central autonomic processing centres and
result in sensations of visceral origin, including pain.
Vagal afferents are generally associated with signalling
physiological events, such as fullness and satiety,
whereas spinal pathways are generally associated with
higher-threshold sensations such as pain, discomfort,
bloating and urgency. Importantly, however, these neurons
also serve efferent function and utilize axonal reflexes to
mediate neurogenic inflammation and modulate synaptic
transmission in enteric and prevertebral ganglia. The
peripheral projections of vagal and spinal nerve fibres
terminate at various levels within the gut wall, including
the mucosa, muscle layers, enteric ganglia, and blood
vessels in the submucosa, serosa and mesentery. Many of
these endings are specialized structures, rather than the
traditionally perceived free nerve endings.
numbers of myenteric neurons. Mechanisms contribut

ing to changes in nerve structure might include increased
apoptosis49 and increased levels of nerve growth factor.46
Future studies that account for patient stratification and
temporal considerations might help resolve these dis
crepancies. Despite its proximity to the lamina propria,
Viscerofugal neurons
Viscerofugal neurons have cell bodies within the myenteric
plexus, but have projections out of the gut wall, via
extrinsic nerve trucks, to prevertebral ganglia. These
viscerofugal neurons sense and receive information
regarding mechanical distension of the intestine and
transmit this information to postganglionic sympathetic
visceromotor neurons in the prevertebral ganglia.
Sympathetic neurons
Sympathetic neurons are an anatomically defined division of
the autonomic nervous system. Preganglionic sympathetic
neurons involved in regulating gastrointestinal function
are located in the intermediate zone (or lamina VII) of the
thoracolumbar spinal cord where they cluster with other
preganglionic neurons that serve different functions.
These neurons integrate synaptic input from sympathetic
premotor neurons located in several nuclei of the brain
stem and hypothalamus as well as spinal interneurons
and primary afferent neurons. The axons of these neurons
project through the ventral root and the gray rami to the
paravertebral ganglia where a small portion terminates in
the paravertebral ganglia. The majority do not synapse, but
rather project through the splanchnic nerves and terminate
in the prevertebral ganglia. Postganglionic sympathetic
fibres fasciculate with sensory neurons and course through
the mesentery in close proximity to the many branches
ofthe coeliac, superior mesenteric and inferior mesenteric
arteries. Axons of postganglionic vasomotor neurons that
extensively innervate the arterioles within the gut wall
and mesentery providing direct vasoconstrictor control of
gastrointestinal blood flow arise from both paravertebral
and prevertebral ganglia. Axons of visceromotor neurons
that innervate enteric ganglia, the deep muscular plexus
and to a lesser extent the mucosa arise from prevertebral
ganglia and alter intestinal motor and secretory function.
Parasympathetic neurons
Parasympathetic neurons are a separate division of
the autonomic nervous system with inputs to the gut
concentrated in the oesophagus, stomach and upper small
intestine and also the rectum and anal sphincter. There is
relatively little parasympathetic innervation of the mid-gut.
The dorsal motor nucleus of the vagus and the nucleus
ambiguous contain the cell bodies of preganglionic
parasympathetic neurons innervating the proximal
gastrointestinal tract. The parasympathetic nuclei in the
lower lumbar and sacral levels of the spinal cord contain
the cell bodies of the preganglionic parasympathetic
neurons innervating the hindgut. Neuronal tracing studies
in animals reveal that the myenteric plexus is the major
innervation target of preganglionic parasympathetic
neurons, with few exceptions, indicating that the
postganglionic parasympathetic neurons are the enteric
neurons themselves. Highly branched varicose endings
in the ganglia are in close proximity to most myenteric
neurons where released acetylcholine activates both
excitatory and inhibitory enteric neural pathways to
modulate gut function via intrinsic reflex circuitry.
where inflammation is apparent in both Crohns disease

and ulcerative colitis, little evidence exists for altered
numbers of ganglion cells in the submucosal plexus of
patients with IBD.37 However, plexitis (inflammatory
infiltrate of the submucosal or myenteric plexuses) is
common in Crohns disease33,37,40 ulcerative colitis36,40,43

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Cortical reflexes,
hypothalamic
reflexes and
perception
Extrinsic neurons
Second and third order neurons
of the anterolateral system
Parasympathetic motor neurons
Preganglionic/postganglionic
symapthetic neuron
Vagal afferent neuron
Spinal afferent neuron
Telencephalon
and diencephalon
Intrinsic neurons
Secretomotor/vasomotor neuron
Interneuron
Excitatory motor neuron
Inhibitory motor neuron
Intrinsic primary afferent neuron
Viscerofugal neuron
Midbrain
Supraspinal
and vago-vagal
reflexes
Medulla
Thoracic
spinal cord
Spinal
reflexes
Epithelial cells
Enteroendocrine cell
Secretory epithelial cell
Sacral
spinal cord
Prevertebral
ganglia
Extraspinal
reflexes
Longitudinal muscle
Myenteric plexus
Circular muscle
Intrinsic reflexes
and sensory
neuron axonal
reflexes
Submucosal plexus
Mucosa
Figure 1 | Neural innervation and multiple levels of reflex control of gastrointestinal function. Intrinsic (enteric) neurons
have cell bodies and processes within the gut wall and form neural networks to control motility, secretion and vasodilation.
Viscerofugal neurons are enteric neurons that project to postganglionic sympathetic visceromotor neurons in the
prevertebral ganglia that lie just ventrolateral to the aorta. Reflexes that are activated by viscerofugal neurons are called
extraspinal reflexes, as they do not involve the CNS. Postganglionic sympathetic neurons project to the gut wall to modulate
secretion, blood flow and motility. These neurons also receive input from preganglionic sympathetic neurons in the spinal
cord that form the efferent limb of CNS reflexes. The other efferent limb of CNS reflexes arises from parasympathetic motor
neurons in the sacral spinal cord and brainstem. Extrinsic afferent neurons have peripheral endings within the gut wall
andcommunicate with the CNS via vagal and spinal pathways. Vagal afferents have cell bodies in the nodose and jugular
ganglia and central projections into the nucleus of the solitary tract, whereas spinal afferents follow the splanchnic and
pelvic nerve trucks, have cell bodies in the thoracolumbar and lumbosacral dorsal root ganglia and have central projections
into the dorsal horn of the spinal cord. Extrinsic afferents form the afferent limb of central reflexes and pathways
contributing to conscious perception, but also have efferent function via axon reflexes that can be local or extraspinal.
Abbreviation: CNS, central nervous system. Mayo Clinic.
and other gastrointestinal disorders40 (see Supplementary

Box1 online). Notably, levels of major histocompatability
complex (MHC) antigens are increased in enteric glia and
neurons in both Crohns disease and ulcerative colitis50,51
and might contribute to immune infiltration. Importantly,
plexitis occurs in otherwise histologically normal tissue
outside the involved segments of bowel.52 In fact, plexitis
in marginal resected tissue is predictive of recurrence in
Crohns disease following surgery,53,54 which suggests that
plexitis and perhaps neuroplasticity-induced dysfunction

might precede mucosal involvement.
Sensation abnormalities in active IBD
Reduced stool volume and increased stool frequency
during ulcerative colitis suggest that patients have
reduced thresholds for the urge to defecate. 55 The
maximal tolerable balloon volume might also be reduced
in patients with active ulcerative colitis, 55,56 with pain
REVIEWS
reported at lower cross-sectional areas of the rectum
compared with healthy individuals.57 This finding might
be due to increased muscle tone, as pain responses rela
tive to muscle tension are similar between patients and
healthy controls.57 In Crohns disease, although a subset
of patients experience urgency to defecate,58 the thresh
old pressure for discomfort in patients with Crohns
disease is substantially higher than healthy controls.26
The reporting of abdominal pain is in the range of
4090% of patients with IBD,55,59,60 although pain in IBD
seems to be affected by the age at onset. In particular,
paediatric patients with IBD have a higher incidence of
pain61 than patients diagnosed >40years of age.62
Levels of the proinflammatory cytokine, TNF, are
elevated in colonic biopsy samples from patients with
active ulcerative colitis. Supernatants from these biopsy
samples and TNF itself can activate and sensitize colonic
dorsal root ganglion (DRG) neurons from mice by
enhancing the voltage-gated sodium (Na V) currents,
and suppressing the voltage-gated potassium (KV) cur
rents, in particular IA (A-type) and IK (delayed rectifier)
that regulate neuronal excitability.63 Notably, these are
the same currents that are altered in numerous animal
models of inflammatory and postinflammatory hyper
algesia (see later), suggesting a potential underlying
mechanism for pain during active ulcerative colitis.
Sensation abnormalities in IBD in remission
Several studies suggest that subsets of patients with IBD
in remission retain altered rectal hypersensitivity and
remain intolerant to rectal distension.56 Overall, 2060%
of patients experience persistent pain during remission
from IBD,60,64,65 whereas other patients with IBD report
that rectal sensitivity returns to normal during remis
sion.55,66 Interestingly, sensation of duodenal acid or lipid
is not different from healthy controls during remission
from Crohns disease or ulcerative colitis.33 One study of
patients with ulcerative colitis in remission demonstrated
inhibition of activity in the limbic and paralimbic brain
regions; conversely, these brain regions were activated by
colorectal distension in patients with IBS.67
Autonomic dysfunction in IBD
During active IBD there is evidence of imbalanced auto
nomic function with increased sympathetic influence
and decreased parasympathetic influence.52,68,69 Testing
numerous autonomic reflexes reveals hyper-reflexia in
patients with active IBD that correlates with the degree of
systemic inflammation.70 Interestingly, an 2-adrenergic
receptor agonist can restore normal autonomic cardio
vascular function and improve IBD disease activity index
scores,68 which is consistent with previous findings of
a beneficial effect of clonidine treatment for IBD.71
However, conflicting results are reported for IBD in
remission, with either parasympathetic predominance,72
or reduced parasympathetic function reported.73
IBS
IBS is a prevalent chronic functional gastrointestinal
disorder that affects 714% of the population. 74 This
disorder is characterized by abdominal pain or dis

comfort associated with altered bowel habit, and is
subclassified as constipation-predominant IBS (IBSC),
diarrhoea-predominant IBS (IBSD), alternating or
mixed IBS (A/M-IBS) and postinfectious IBS (PI-IBS).
Neuroplasticity is well appreciated in IBS,75 with symp
toms (most predominantly abdominal pain) being trig
gered or worsened by stress, possibly via altered central
noradrenergic signalling. 76 Persistent neuroplasticity
might arise after acute bouts of intestinal inflammation
that resolve, or might be the result of low-grade inflam
mation not identified during routine clinical screen
ing.77,78 Interestingly, in their original description of IBS,
Peters and Bargen75 wrote with passion for the need to
define IBS as distinct from inflammatory diseases. This
distinction was necessary because contemporary gastro
enterologists were defining functional syndromes with
terms such as membranous enteritis, membranous
colitis, mucous colitis, neurogenic mucous colitis or
spastic colitis.79 It is perhaps because of the subsequent
whole-hearted adoption of clear boundaries between
functional and organic digestive diseases that assertions
of the concept that IBS and IBD are on the same clinical
spectrum have met with controversy. However, a failure
to understand the overlap between IBS and IBD might
contribute to delays in proper diagnosis and therapy.80,81
~40% of patients with IBD in remission meet symptom
criteria for diagnosis of a functional bowel disorder.80,81
Furthermore, the incidence of IBS is two to three times
higher in patients with IBD in remission than the general
population.82 IBS is also a risk factor for IBD.83 Whether
these data reflect the development of new disease or a
delayed diagnosis remains to be resolved.80,81 Perhaps
areason for the overlap lies with the gut microbiota, as
mucosal barrier function is disturbed in patients with
IBD84 and increased epithelial permeability is evident
in the small intestine and colon of patients with IBS.85,86
These changes might enable bacteria to gain access to
the interstitial compartment, initiate innate immune
responses87 and access neurons. Indeed, several animal
studies have identified that cell products from Salmonella
enterica and Escherichia coli NLM28 can activate or
sensitize extrinsic sensory afferents.8891
Postinfectious IBS
The most compelling case for inflammation-induced
persistent neuroplasticity is the development of symp
tomatic IBS after infectious gastroenteritis, a clinical
entity known as PIIBS.9294 Numerous clinical studies
attribute IBS symptom development in 336% of indivi
duals93,94 to infection with Campylobacter, Salmonella,
Shigella, E.coli or Giardia lamblia.93,94 In the short-term
setting of tissue damage, inflammation in response to
infection is a protective process that facilitates wound
healing. However, these clinical findings, in addition to
the preclinical findings detailed below, suggest that in
these individuals with PI-IBS the peripheral and central
neuroplasticity induced by infection and inflammation
is maintained and fails to reset back to normal, long after
healing of the intestinal tissue.

REVIEWS
Low-grade inflammation and IBS
Several lines of evidence suggest that IBS is associated
with a persistent low-grade inflammation within the gut
wall95,96 and altered immunological function.97100 Plexitis
occurs in 70100% of patients with IBS or dysmotil
ity symptoms who consent to undergo full-thickness
biopsy, and might be a contributing factor in the overlap
of IBSand IBD.101,102 In mucosal biopsy samples from
patients with IBS, evidence indicates increased levels of
IL1,103 and increased numbers of mucosal mast cells96
and intraepithelial lymphocytes.104 Correspondingly,
supernatants from biopsy samples from patients with IBS,
but not healthy individuals, activate extrinsic sensory
nerve endings and neuronal cell bodies from mice via
the histamine H1 receptor and serine protease mecha
nisms.105 In addition, these mediators activate human
submucosal enteric neurons ex vivo.106 Thus, inflamma
tory mediators potentially contribute to the mechanisms
underlying abdominal pain and dysmotility in patients
with IBS. Changes are also evident in peripheral blood
mononuclear cells (PBMCs) from patients with IBS.97100
In particular, evidence indicates increased activation of
T cells,99,100 and correlation of pain with levels of several
proinflammatory cytokines, including TNF, IL1 and
IL6, in PBMC supernatants from patientswithIBSD.
Notably, PBMC supernatants from patients with
IBSDevoke mechanical hypersensitivity of colonic affer
ents from mice.9799 These findings also demonstrate two
distinct mechanisms by which cytokines increase noci
ceptive signalling from the colon. The first example is
IL1, which causes direct action potential discharge of
colonic afferents via a NaV1.7 dependent mechanism.97
The second is TNF, which causes mechanical hyper
sensitivity via a transient receptor potential ankyrin1
(TRPA1) dependent mechanism.97 Additional evidence
suggests that patients with IBS tend to harbour an IL10
gene polymorphism associated with reduced production
of this anti-inflammatory cytokine.107 Overall, these find
ings suggest that neuronal function is a balance between
both excitatory and inhibitory mechanisms and that
shifting this balance towards excitation results in aber
rant neuronal activity. If maintained, this imbalance
results in the development and maintenance of persistent
neuroplasticity and gastrointestinal symptoms.
Neuroplasticity in animal models

Animal models of gastrointestinal inflammation have
been used to answer the mechanistic questions posed
by the clinical studies described earlier. Several impor
tant points must be noted regarding preclinical animal
models of gastrointestinal inflammation. First, although
no current animal model recapitulates all aspects of
human digestive diseases, these models are essential
because they can be tightly controlled for species, age,
genetic background, diet, stress and experimental time
course. This level of control is something that cannot be
said for the use of human tissue in functional experi
ments. Second, not all experimental models are the same,
nor does the same inducing manipulation result in the
same immune response and neuroplasticity in different
animal species or strains, or even in different labora

tories. Overall, experimental animal models of gastro
intestinal inflammation can be broadly grouped into four
major categories: chemical-induced, infection-induced,
adoptive-transfer-induced and genetically induced
(Supplementary Table1 online). Third, gastrointestinal
inflammation is not a single response, but rather a broad
spectrum of innate and cell-mediated immune responses.
As such, these models, similar to the clinical disorders
they intend to mimic, differ in immune responses and
resultant neuroplasticity based on the inducing manipu
lation. These factors include the chemical, infectious
agent, cell transfer, genetic manipulation, dose, route
and time course of the manipulation. Contributing
factors during the inducing manipulation also include
the species and strain of the animals, and the environ
mental factors that contribute to the state of the animals,
especially their stress levels. Overall, data from numerous
laboratories using varying inflammatory models suggest
that short-term and long-term neuroplasticity occurs at
every level of the braingut axis.
Inflammation-induced functional changes

Active inflammation
Inflammation-induced dysmotility is highly dependent
on the model of inflammation used.108 Hypercontractility
and enhanced motility are hallmarks of type 2 Thelper
(TH2) models, including Trichinella spiralis or Nippo
strongylus brasiliensis infection. 109112 By contrast,
type1 T helper (TH1) models, such as trinitrobenzene
sulphonic acid (TNBS) ileitis and colitis, are character
ized by hypocontractility and reduced motility.113115 In
TNBS-induced colitis, propulsive motility is actually
temporarily or completely halted, but only at specific
sites of ulceration (Figure2).116 Neural and mast cell
interactions with the epithelium produce ion-transport
abnormalities during infection with N.brasiliensis.111,117
In particular, they produce a shift away from cholinergic
to noncholinergic regulation, with increased amounts
of the proinflammatory neuropeptide, substanceP,118
defective mucosal cAMP production and inhibition of
ionic secretion.119 Furthermore, nitric oxide derived from
inducible nitric oxide synthase (iNOS) mediates, in part,
inflammation-induced suppression of neurally evoked
electrolyte transport.120 Notably, TNBS-induced colitis
results in inhibition of calcium-dependent secretion in
the noninflamed proximal colon via a reduction of the
contribution of the ENS.121
Resolved inflammation
Many of the alterations observed during inflammation
persist into the postinflammatory state (Figure2). In
mice, persistent gut dysfunction is evident in chronic
parasitic infection with Trichuris muris, which is
independent of the continued presence of the parasite
and is maintained by an inflammatory process that
includes eosinophils.122 Similarly, gastric and intestinal
dysmotility is evident in mice 70days postinfection with
T.spiralis, which can be normalized by dexamethasone
administration.123 TNBS-induced colonic dysmotility
REVIEWS
Submucosal ganglia
Inflammation and postinflammation
Hyperexcitable AH neurons
Facilitated synaptic transmission
Inflammation and
postinflammation
Altered gut motility
Altered secretion
Myenteric ganglia
Indiscriminate loss of enteric neurons
Loss of viscerofugal neurons
Hyperexcitable AH neurons
Hyperexcitable ascending S neurons
Facilitated synaptic transmission
Figure 2 | Neuroplasticity in enteric neurons during and after gut inflammation.

Inthe enteric nervous system, inflammation causes a rapid loss of enteric
neuronsand viscerofugal neurons. Of the remaining enteric neurons, specific
subpopulations located in the myenteric and submucosal ganglia become
hyperexcitable (AH neurons) and synaptic transmission between them is facilitated.
These changes in neuronal function result in decreased secretion and disrupted
motility. Many of the neuronal changes evident during inflammation are still present
after resolution of inflammation, with hyperexcitable enteric neurons and facilitated
synaptic transmission still evident in the postinflammatory state. Mayo Clinic.
also persists in the postinflammatory state, but unlike

the dysmotility evident during inflammation, cannot
be reversed by COX2 inhibitors.124 Furthermore, there
is evidence of prolonged neurally mediated ion secre
tion after resolution of colitis,125 which might contribute
to the dysfunction. In general, these findings of post
inflammatory dysmotility are consistent with the altered
function reported in patients with IBS and in patients in
remission from IBD.
Neuroplasticity in enteric neurons

Plexitis and neuron loss
Inflammation clearly has profound effects on enteric
neural circuits. However, as with the contrasting reports
of altered numbers of enteric neurons in patients with
active IBD, there are also differing reports in animal
models of inflammation. In the mouse ileum, evidence
indicates considerable myenteric neuron damage, but
not loss, during Schistosoma mansoni infection126 and
similarly no loss of neurons, but a reduction in levels
of NOS after TNBS-induced ileitis.127 Correspondingly,
no evidence exists of neuronal proliferation during
ileitis, although mitosis is evident in myenteric glia.128
By contrast, TNBS-induced colitis is associated with
progressive and selective alterations in myenteric plexus
structureand function,129 which seems to consistently
cause up to a 20% loss in myenteric neurons, with apop
tosis and transglutaminase upregulation also apparent.130
This neuronal loss is evident as early as 12h after the
inflammatory insult,131 and is partly mediated by neutro

phil granulocyte infiltration132 and by activation of a neu
ronal signalling complex composed of purinergic P2X7
receptors and pannexin1 channels.48 Loss of myenteric
neurons after a single inflammatory event is still evident
2months later, long after inflammation has resolved,131
which is also consistent with the observed lack of prolif
eration. Although this loss of neurons seems to be indis
criminate across different enteric neuronal populations,
there is an 80% loss in viscerofugalneurons (Figure2).133
Notably, this loss of viscerofugal neuronsonly occurs in
the area of inflammation and does not occur in colitis
induced by acetic acid treatment in guinea-pigs, which
again suggests that neuronal loss is associated with
neutrophil infiltration and specific immune processes.133
The loss of viscerofugal neurons in the colon corresponds
with a reduced frequency of ongoing synaptic potentials
in visceromotor neurons within the prevertebral ganglia.
These changes are still present 2months postinflam
mation, again highlighting the profound long-term
neuroplasticity that can be evoked by a single inflam
matory insult.133 Evidence also suggests that enteric
neuron density can contribute to the overall severity
of intestinal inflammation,134 perhaps via a neurogenic
inflammation-mediated mechanism. Such findings are
consistent with clinical observations that enteric neuron
hyperplasia might be a predisposing factor to subsequent
mucosalinflammation.135
Enteric neuron excitability and synaptic plasticity
Evidence of hyperexcitability of myenteric AH neurons
causing dysmotility after TNBS-induced inflammation136
and T.spiralis 137 infection is extensive (Figure2). The
mechanisms by which this process occurs is different
as the TNBS-induced effects are COX2 dependent,138
whereas the T.spiralis-induced hyperexcitability can
be suppressed with acute exposure to blockers of hista
mine, adenylate cyclase, COX or leukotriene pathways.137
Colitis also causes enhanced synaptic facilitation in
the inflamed myenteric plexus in guinea-pigs, which
involves a presynaptic increase in activity of protein
kinase A.139 AH neuron hyperexcitability and synaptic
facilitation is also evident in the colonic submucosal
plexus, the latter due to increased noncholinergic trans
mission.140 Evidence suggests that prejunctional 2aadrenoceptors contribute to enhanced inhibitory control
of cholinergic and noradrenergic transmission, both at
the inflamed colon and at distant noninflamed sites.141
Correspondingly, evidence also exists for reduced acetyl
choline release from the myenteric plexus of rats with
T.spiralis 142 and TNBS-induced141 inflammation.
Inflammation-induced dysmotility at specific sites of
ulceration is due to a transient reduction of inhibitory
purinergic neuromuscular transmission, which thereby
reduces smooth muscle relaxation and disrupts coordinated motility and propulsion.116 Myenteric neuron
loss might contribute to a reduction in neuromuscular
transmission as the inhibition of neuronal pannexin-1
during TNBS-induced colitis, which reduces cell loss,
protects against postinflammation deficits in inhibitory

REVIEWS
neuromuscular transmission in mice.48 In TNBS-induced
colitis in guinea-pigs, inhibitors of hyperpolarizationactivated cyclic nucleotide-gated channels, which con
tribute to AH neuron excitability, normalize motility in
the ulcerated regions143 and contribute to the increased
motility at either side of ulcers116 (Figure2). These data
strongly support a causal relationship between neuronal
excitability and dysmotility. As such, these alterations at
the site of inflammation or those on either side of the
ulceration, might explain differing reports of motility
changes in humans with IBD.
Inflammation-induced enteric neuroplasticity is not
only localised to the colonileitis also alters synaptic
transmission and AH neuron excitability.144 Furthermore,
it is also apparent that inflammation in one region of the
gut can profoundly influence other noninflamed regions.
For instance, inflammation of the guinea-pig ileum
induces hypersensitivity in submucosal AH neurons and
enhances synaptic transmission in the distal colon.145 The
changes to colonic neurons during ileitis are very similar
to changes in colonic neurons during colitis. However,
colitis-induced changes in the submucosal plexus of
the ileum are very different; hyperexcitability is largely
absent, slow synaptic transmission is profoundly altered
and noncholinergic secretion is reduced.146 Colitis causes
an increased excitability and depolarization of myenteric
AH neurons in the ileum of guinea pigs, which seems
mechanistically different from ileitis-induced excita
bility.147 Overall, these findings suggest that changes
in enteric neural circuits are contributing factors in
inflammation-induced dysfunction at sites distant from
a localized inflammatory insult. These findings might
explain why patients with ulcerative colitis, for instance,
display reduced small-bowel transit.15
Hyperexcitability of AH neurons, facilitated fast syn
aptic transmission in both the submucosal and myen
teric ganglia and intestinal dysmotility are all still evident
in the postinflammatory state.124,125,147 These findings in
animal models might explain the continued dysmotil
ity in patients with IBD in remission, or perhaps the
dysmotility of patients with IBS. Collectively, these
findings demonstrate the long-term effects of a single
inflammatory insult on enteric neurons.
Neuroplasticity in autonomic efferent neurons

Reports of autonomic dysfunction in animal models of
gastrointestinal inflammation are numerous, which are
consistent with the autonomic dysfunction described
in humans. For example in rats, mice and guinea-pigs
during TNBS-induced, dextran sodium sulphate (DSS)induced or T.spiralis-induced colitis, evidence indicates
altered sympathetic function within the gastrointestinal
tract, with reduced evoked norepinephrine release occur
ring in both inflamed and noninflamed gut regions.148,149
This reduced norepinephrine release occurs via steroidsensitive and IL1-mediated processes that do not require
Tcells. Reduced evoked release can occur via increased
levels of autoinhibitory presynaptic 2a-adrenoreceptors141
or via reduced voltage-gated calcium currents. 149
Therefore, these changes might contribute to functional
alterations in both the inflamed and noninflamed regions

of the gastrointestinal tract during inflammation.
Evidence also indicates that colitis impairs sympa
thetic vasoconstrictor regulation of mesenteric arter
ies150 and submucosal arterioles, via changes in blood
flow, and reduces purinergic transmission.151 Extrinsic
afferent nerves have also been shown to participate in a
cardiovascular depressor reflex in N.brasiliensis-infected
rats, 152 whereby capsaicin evoked arteriolar dilation
involves the release of histamine from mast cells, which
then dilates the vessels by a nitric-oxidedependent
mechanism. 153 Sympathetic vasoconstriction of sub
mucosal arterioles is impaired during TNBS-induced
or DSS-induced colitis in mice because of increased
ectonuclease-mediated reduction of purinergic neuro
transmission.125,154 Taken together, these findings suggest
that a disruption in the balance between vasoconstrictor
and vasodilator influences might lead to altered blood
flow and altered intestinal motility.
In prevertebral ganglia (PVG), hyperexcitability of
visceromotor neurons is evident from 12h after initi
ation of TNBS-induced colitis. This hyperexcitability
seems to be mediated via enhanced activity of NaV chan
nels,155 and can be maintained for at least 2months after
the inflammatory insult. By contrast, PVG vasomotor
neurons exhibit normal excitability during inflamma
tion (Figure3).155 These data indicate that enhanced
sympathetic drive from hyperexcitable visceromotor
neurons might protect the colon by reducing secretion
and motility, but might also contribute to intestinal dys
function during colitis.155 In fact, reduced small-bowel
transit is temporally correlated with hyperexcitability of
visceromotor neurons.147 Furthermore, similar hyper
excitability also occurs in visceromotor neurons, but
not in vasomotor neurons, in the celiac ganglion follow
ing acute TNBS-induced ileitis (Figure3).156 Reduced
evoked release of norepinephrine from these neurons,
described earlier, might compensate for the observed
hyperexcitability. These primary and compensatory
effects might explain the varying reports of motility
changes in patients withIBD.
To our knowledge, no study has investigated pre
ganglionic sympathetic neurons in the spinal cordduring
intestinal inflammation. However, several studies have
demonstrated changes in parasympathetic brainstem
nuclei after inflammation. 153155 cFos expression, a
widely used marker for neuronal activation, is increased
in the nucleus of the solitary tract following N.brasili
ensis infection, which might reflect increased affer
ent activity (see below), and probably influences vagal
outflow.157 In addition, levels of cFos are increased in
the brainstem of mice and rats after DSS-induced158 or
iodoacetamide-induced159 gastritis. The vagus nerve
seems to have a crucial role in regulating immune res
ponses by dampening immune cell activation via an 7
nicotinic receptor mechanism.160162 This newly appreci
ated interaction between the CNS and the immune
system in modulating gastrointestinal inflammation
through both neuronal and humoral pathways is expertly
reviewedelsewhere.160162
REVIEWS
Aorta
Prevertebral ganglia
Hyperexcitable visceromotor
neurons during colitis and ileitis
Reduced viscerofugal input
Greater and lesser

splanchnic nerves
Coeliac
ganglia
Superior
mesenteric
ganglion
Superior
mesenteric
artery
Lumbar
splanchnic
nerves
Ileiocecal
nerve
Intermesenteric
nerve
Inferior
mesenteric
ganglion
Colonic
nerves
Pelvic
nerves
Hypogastric
nerves
Ileum
Ileum
Colon
Colon and ileum

Reduced evoked norepinephrine
release during chronic colitis
Reduced purinergic vasoconstriction
Figure 3 | Neuroplasticity in sympathetic neurons during and after gut inflammation.

In the prevertebral ganglia, although synaptic input from viscerofugal neurons is
reduced, sympathetic visceromotor neurons are actually hyperexcitable. Enhanced
sympathetic outflow results in decreased secretion and reduced motility. Changes
in autoinhibitory adrenergic receptors and voltage-gated calcium channels in
sympathetic terminals reduce evoked norepinephrine release and might restore
more normal sympathetic drive because neurons remain hyperexcitable following
resolution of inflammation. Sympathetic vasomotor neurons are not hyperexcitable,
but purinergic vasoconstriction from these neurons is reduced. Mayo Clinic.
Neuroplasticity in extrinsic afferent pathways

Acute neuroplasticity
Extrinsic afferents innervating the gastrointestinal tract
provide sensory input to central processing centres,
resulting in sensations of visceral origin, including pain.
Experimental studies can be focussed on nerve termi
nals in the periphery (receptive fields) or the cell bodies
of afferents in vagal or spinal ganglia, or determining
downstream effects of afferent activation by studying
central pathways or pain-related behaviours. Overall,
it is clear that experimentally induced inflammation
or infection causes afferent hypersensitivity, neuronal
hyperexcitability and, correspondingly, hyperalgesia
and allodynia in animal models. These studies also indi
cate that the mechanisms underlying inflammatory and
chronic long-term postinflammatory neuroplasticity are
varied, but originate from the periphery.95,96
Receptive fields
Acid-induced and pepsin-induced oesophagitis in ferrets
causes a decrease in basal mechanosensitivity, although
this decrease is offset by a sensitizing response to P2X
purinoceptor agonists.163 In eosinophilic oesophagi
tis, which is characterized by increased infilt ration
and degranulation of eosinophils in the oesophagus,
eosinophil-derived cationic proteins do not activate
guinea-pig oesophageal vagal afferents, but instead cause
sensitization to oesophageal distension.164 By contrast, in
a guinea-pig model of mast-cell-induced oesophagitis,
sensitization of TRPA1, via a protease-activated recep
tor 2 (PAR2)-dependent mechanism, has an important
role in vagal afferent mechanical hypersensitivity. 165
Similarly, experimentally induced gastritis in rats causes
sensitization of mechanosensitive vagal afferents in the
stomach. 166 Evidence indicates that TNBS-induced
inflammation in mice causes mechanical hypersensitiv
ity of both low-threshold and high-threshold afferents
in the colon,167169 with highthreshold afferents also
displaying reduced activation thresholds to mechani
cal stimuli.167 The time course of this hypersensitivity
can vary between splanchnic and pelvic pathways, 167
but when present in mice is mediated by nociceptive
ion channels including the acid sensing ion channel 3
(ASIC3),170 TRPA1,171,172 transient receptor potential val
linoid (TRPV)-4173,174 and TRPV1.168,175,176 Thesechan
nels can be sensitized by mediators released during
inflammation including bradykinin, 171,177 5HT, 178
histamine,179 PAR2174 and the PAR2-dependent medi
ator cathepsinS, 180 to cause neuronal hyperexcita
bility and hyperalgesia (Figure4). Notably, TRPA1,
TRPV4and TRPV1 can also contribute to the inflam
matory response themselves, by inducing neuropeptide
release from peripheral afferent terminals and sub
sequent neurogenic inflammation. 181,182 As TRPV4 is
also expressed on intestinal epithelial cells, its activa
tion induces chemokine release and induces colitis.183
Hypersensitivity is also likely to be induced via sensitiza
tion of mechanically insensitive afferents, also known as
silent afferents.184,185
Afferent cell bodies
Most studies utilizing chemical (for example, acetic
acid, iodoacetamide, or TNBS), nematode (T.spiralis
and N.brasiliensis) or bacterial (Citrobacter rodentium)
models of inflammation show that afferent neurons
innervating the stomach,186,187 small intestine188,189 and
colon190192 display pronounced hyperexcitability during
gastrointestinal inflammation (Figure5). Increases in
NaV currents, in particular NaV1.8,190,192 and suppression
of KV currents, in particular IA and IK currentsm,187,191 are
implicated in this hyperexcitability.
Central pathways and pain-related behaviours
Crucially, neuroplasticity in vagal peripheral afferent
endings and vagal neuronal function during inflam
mation translates to hypersensitive responses to gastric
distension invivo,158,159,193 and increased neuronal activa
tion in the brainstem following N.brasiliensis infection,

REVIEWS
Tissue damage
Bacterial cell
LPS
Bradykinin
H+
ATP
Mast cell
Cathepsin S
Histamine
NaV1.8
NaV1.7
NaV1.9
Trypsin
Thrombin
Immune cell
Enterochromaffin cell
5-HT
Serine
proteases
Prostaglandins
5-HT3
P2X PAR2
ASIC H1-3
IL-10
IL-1
TNF
IL-16
-endorphin
TNF-R1
IL-10R
IL-1R
IL-6R PAR4
-opioid
TRPM8
TRPA1
TRPV1
TRPV4
CB1
-opioid
TLR
OTR
B1
Pronociceptive/excitatory channel or receptor

Antinociceptive/inhibitory channel or receptor
Figure 4 | Inflammation-induced neuroplasticity: contribution of neuroactive

signalling molecules and the channels/receptors they act on. Numerous
mediators can directly activate gut afferents by binding to the numerous cell
surface receptors and channels expressed on their peripheral endings. The
majority of the channels and receptors identified here result in afferent activation,
sensitization and neuronal hypersensitivity and hyperexcitability. Furthermore,
once activated, the nociceptors themselves can release substanceP and CGRP
from their peripheral terminals, inducing neurogenic inflammation. TRPA1, TRPV1
and TRPV4 are implicated in this process. By contrast, activation of another set of
channels and/or receptors results in reduced neuronal excitability and resultant
antinociceptive effects. Pronociceptive mechanisms seem to be upregulated
during inflammatory and postinflammatory states. Some antinociceptive
mechanisms are downregulated, whereas some are upregulated in inflammatory
and postinflammatory states (-opioid and OTR). Abbreviations: 5-HT, serotonin;
ASIC, acid sensing ion channel; CB1, cannabinoid receptor 1233; CGRP, calcitoningene related peptide; H1, histamine 1 receptor; LPS, lipopolysaccharide; OTR,
oxytocin receptor; PAR4, protease activated receptor 4234; TLR, Toll-like receptor;
TRPA1, transient receptor potential cation channel, subfamily A, member 1;
TRPM8, transient receptor potential melastatin8235; TRPV, transient receptor
potentialvallinoid.
DSS-induced 158,159 or iodoacetamide-induced gastri

tis.157,158 Similarly, neuroplasticity in colonic peripheral
afferent endings and DRG neuronal function during
inflammation translates to hypersensitive responses to
colonic distension168,175 and increased neuronal activa
tion within the thoracolumbar and lumbosacral spinal
cord invivo194,195 (Figure5). Overall, this inflammationinduced neuroplasticity might underlie the sensory
abnormalities experienced by patients with IBD and IBS
and those patients with other clinical gastrointestinal
disorders during inflammatory episodes.
Persistent neuroplasticity
Persistent neuroplasticity of sensory pathways is evi
dent across a range of different experimental models.
However, much like the clinical gastrointestinal dis
orders they intend to mimic, some inflammatory models
produce contrasting effects with different afferent sub
types, different neuronal pathways and time courses
involved in this process.167 For example, although mouse
jejunal afferents do not display changes in mechano
sensitivity in postinfectious N.brasiliensis, they do show
changes in chemosensitivity to somatostatin-receptor2
stimulation.196 Furthermore, these mouse jejunal affer
ents also display neuronal hyperexcitability, which is
mediated by NaV1.8, but not NaV1.9.188 Although puriner
gic mechanisms have no role in healthy small-intestinal
mechanosensitivity, they do contribute to mechanical
hypersensitivity after T.spiralis infection.197 The develop
ment of long-term mechanical hypersensitivity at 1 and
2months postinfection198 is dependent upon a process
involving a P2X7 receptor-dependent increase in immune
cell expression and release of IL1. Notably, P2X7 recep
tor knockout animals display attenuated innate inflam
matory responses and no postinfectious mechanical
hypersensitivity at any time point,199 again demonstrat
ing the causal link between long-term neuroplasticity
and inflammation.
Long-term neuroplasticity is also evident in colonic
pathways with suppression of KV IA currents contribut
ing to postinfectious C.rodentium-induced neuronal
hyperexcitability in mice.191 In a rat model, deoxycholic
acid (an unconjugated secondary bile acid) induces
a mild, transient colitis that causes exaggerated longterm visceromotor responses to colorectal distension,
referred pain to mechanical stimulation, and increased
dorsal horn neuron activity. 200 A postinflammatory
mouse model of T.spiralis demonstrates colonic hyper
sensitivity and gut dysmotility that can be normalized
by administration of an anti-inflammatory treatment.123
Although there are some inconsistencies in the report
ing of persistent TNBS-induced neuroplasticity, these
discrepancies probably relate to the precise time-point
studied and the severity of mucosal inflammation, which
is a predictor of alterations of visceral sensory function in
rodents201 and in patients with IBS.202 However, evidence
also exists for mild, asymptomatic colitis inducing longlasting visceral hyperalgesia in the presence of additional
stimuli in animal models. 201 Overall, TNBS-induced
postinflammatory hyperalgesia has been identified from
between 3weeks to 4months after resolution of inflam
mation.203,204 The extent of mechanical hypersensitivity
in high-threshold afferents is increased in postinflamma
tory states, whereas in some studies pelvic high-threshold
afferents only become hypers ensitive postinflamma
tion, again suggesting that distinct immune processes
contribute to the development of neuroplasticity.167 Evi
dence also supports the emergence of increased propor
tions of silent afferents in postinflammatory states.185
Postinflammatory afferent hypersensitivity is also corre
lated with an increased density and sprouting of colonic
afferent central terminals in the thoracolumbar spinal
REVIEWS
Extrinsic spinal afferent endings
Inflammation
Sensitization of afferents
Mechanical hypersensitivity of afferents
Reduced mechanical activation thresholds
Altered expression/pharmacology
Postinflammation
Further hypersensitivity of afferents
Maintained reduction of mechanical activation thresholds
Hypersensitivity of additional afferent classes
Altered receptor/channel expression/pharmacology
Serosal
Muscular
Whole animal visceromotor response

Hyperalgesia and allodynia
Extrinsic spinal afferent
central terminals
Postinflammation
Sprouting of colonic
afferent central
terminals into different
dorsal horn regions
Dorsal horn neurons

Inflammation and
postinflammation
Increased numbers
activated by
noxious distension
Mesenteric
MIA
Muscular/
mucosal
Mesenteric
attachment
DRG
Mucosal
Spinal cord
Distal colon
Extrinsic spinal afferent cell bodies

Inflammation
Hyperexcitability of colonic afferent neurons
Altered NaV and KV currents
Altered receptor and channel expression
Postinflammation
Maintained hyperexcitability of colonic afferent neurons
Maintained alteration of NaV and KV currents
Altered receptor and channel expression
Figure 5 | Neuroplasticity in extrinsic sensory afferent pathways during and after resolution of gut inflammation. During
inflammation sensory afferent endings become hypersensitive, are activated at reduced stimulus intensities, and display
enhanced mechanical responsiveness, whereas their cell bodies in the nodose ganglia or DRG display hyperexcitability. This
hyperexcitability results in increased neuronal activation in the nucleus of the solitary tract or the dorsal horn of the spinal
cord, respectively. In whole-animal studies, this process translates to enhanced pain responses to either gastric or colorectal
distension. Many of these changes are still present or are even enhanced following resolution of inflammation. Nociceptive
sensory afferent endings now display increased mechanical hypersensitivity, and their cell bodies in the nodose and DRG
remain hyperexcitable. An increased density of colonic afferent central terminals is now also evident, as is sprouting of these
terminals into different regions of the dorsal horn of the spinal cord. This plasticity results in increased numbers of dorsal
horn neurons in the spinal cord being activated in response to noxious colorectal distension. Evidence indicates enhanced
pain responses to gastric and colorectal distension, the extent of which can be dependent upon the experimental model
used and influenced by the severity of the initial insult (note, for the purposes of clarity only the pathways innervating the
colon are illustrated). Abbreviations: DRG, dorsal root ganglia; MIA, mechanically insensitive afferent.
cord and an increased number of activated dorsal horn

neurons within the spinal cord in response to noxious
colorectal distension (Figure5).205 Studies have reported
potential targets to reverse this hypersensitivity, with
the identification of substantial increases in the expres
sion and function of inhibitory kappa-opioid 206 and
oxytocin207 receptors in colonic DRG neurons in the
postinflammatory state.
DSS-induced colitis in mice also has contrasting
effects on inducing afferent mechanical hypersensitivity
or short-term or long-term hyperalgesia.208 These differ
ences might be dependent on the severity of inflamma
tion and the specific time-course studied. For example,
mild and acute, but not chronic DSS-induced colitis
is associated with visceral hypersensitivity.209 In acute
colitis, an increased responsiveness to colorectal disten
sion is observed, which is accompanied by granulocyte
infiltrate and increased expression of substanceP. In
chronic DSS-induced colitis, infiltration by lymphocytes,
accompanied by opioid receptor and endorphin
upregulation, provides an antinociceptive mechanism

that restores normal visceral perception. 209 Colonic
supernatants from chronic DSS-treated mice with
chronic colitis have a 14-fold increase in endorphin
levels, which suppresses the excitability of nociceptive
colonic DRG neurons.210 These findings might provide
insight as to why some patients with IBD do not report
pain, depending on the type and degree of inflamma
tion. However, DSS-treated animals do display increased
visceral sensitivity to capsaicin and 5HT,211,212 thereby
providing another example whereby overall neuronal
function at any given time-point is a resultant func
tion of the balance in pronocieptive and antinociceptive
influences (Figure4). Another example of differential
effects is acute zymosan treatment, which recruits a dif
ferent immune response, resulting in brief monocyte
infiltration, but no increase in myeloperoxidase activ
ity. This mouse model seems to preferentially affect
low-t hreshold distension sensitive afferents 185 and
induce visceral hyperalgesia invivo, which is partially

REVIEWS
dependent on TRPV1,175 ASIC3175 and P2X receptors.213
Unlike TNBS treatment, zymosan does not seem to alter
high-threshold colonic afferent function.185
Overall, inflammation-induced neuroplasticity prob
ably underlies the increased sensory perception and
increased incidence of pain reported in patients with
the clinical digestive diseases detailed above, includ
ing oesophagitis, gastritis and IBD. Long-term neuro
plasticity might also explain why symptoms are apparent
in functional gastrointestinal disorders, such as func
tional dyspepsia and IBS, in which no overt pathology
is evident.
Stress plus inflammation

Numerous models of stress have been shown to increase
visceral pain sensitivity.3 However, stress in conjunc
tion with colitis induced by either C.rodentium,214 or
TNBS215 results in additive increases in peripheral noci
ceptive signalling of colonic afferents, their cell bodies
and correspondingly visceral hyperalgesia. These pro
cesses occur via protease, 2 adrenergic, glucocorticoid
receptor and PAR2 mechanisms.214 Other models such as
infection with T.spiralis combined with acute restraint
stress demonstrate the essential role of mast cells in post
infectious hyperalgesia,216 with substantial increases in
the expression of VGLUT3, a vesicular transporter for
presynaptic packaging of the neurotransmitter gluta
mate, in the lumbosacral spinal dorsal horn. 217 Taken
together, these interactions might potentially explain
why stress can trigger or worsen symptoms in patients
with IBS and IBD. Interestingly, this additive hyper
algesia does not occur when combining stress and the
DSS model of inflammation,218 which again suggests that
specific neuroimmune interactions and a skewed balance
toward pronociceptive mechanisms are involved in the
development of neuroplasticity and chronic hyperalgesia.
Neonatal insult and long-term neuroplasticity
One of the most consistent displays of persistent visceral
neuroplasticity occurs after a neonatal inflammatory
insult. Neonatal colonic irritation results in chronic vis
ceral hypersensitivity, allodynia and hyperalgesia in adult
animals, which is associated with central neuronal sensi
tization in the absence of identifiable peripheral abnor
malities. Evidence exists for TRPV1 219 and TRPA1220
initiating colonic hypersensitivity and early increases in
growth factor expression resulting in permanent changes
in TRPV1,219 P 2X 221 and TRPA1220 function, thereby
maintaining the hypersensitivity induced by acetic acid
or mustard oil colonic irritation in neonatal animals.
In some studies, the same dose of irritant is unable to
induce visceral hypersensitivity in adult animals, sug
gesting that the immature nervous system is more sus
ceptible to inflammatory insult. This finding might
potentially explain why pain associated with IBD has a
higher incidence in paediatric-onset than in adultonset
disease in humans.61
Similar mechanisms of neonatal neuroplasticity are
evident in the upper gut, which might be applicable to
functional dyspepsia. Neonatal gastric irritation can
induce chronic gastric hypersensitivity and gastric motor

dysfunction in adults, in the absence of detectable gastric
pathology.222 Gastric hypersensitivity in adult animals can
be attenuated by the GABAB agonist baclofen, although
this process seems to occur via central rather than periph
eral mechanisms.223 Interestingly, gastric hypersensitivity
in adult animals can also be induced by neonatal colonic
TNBS administration. This single intervention results in
aberrant increases of plasma corticosterone in neonates,
increased plasma levels of norepinephrine, increased levels
of nerve growth factor in the gastric fundus, increased
brain-derived neurotrophic factor in DRG and the spinal
cord, and downregulation of the potassium channel Kv1.1
in DRG.224 Overall, these findings again highlight how a
single inflammatory insult can induce a cascade of events
that results in increased neurotrophic factor expres
sion, epigenetic changes, altered neuronal function and
ultimately pronounced long-term neuroplasticity.
CNS neuroplasticity
Several reports indicate that chemical and infectioninduced gut inflammation is accompanied by changes
in behaviour that include anorexia225,226 and anxietylike behavior.227 T.muris-induced-colitis in mice can
lead to decreased levels of hippocampal brain-derived
neurotrophic factor and anxiety-like behaviour, which
can be normalized by administration of the probiotic
Bifidobacterium longum. 228 Similarly, C.rodentium
infection causes anxiety-like behaviour in mice and
stress-induced memory dysfunction.227 Notably, admin
istration of probiotics both before and during the infec
tion prevents memory dysfunction, indicating a clear
peripheral aetiology.229 Changes in food intake, gastric
emptying and visceral hypersensitivity are evident during
Helicobacterpylori infection in mice, which improve after
bacterial eradication. Interestingly, these mice display a
feeding pattern reminiscent of early satiety, which per
sists after H.pylori eradication and is accompanied by
increased TNF levels in the brain.230 Similarly, reduced
food intake is apparent during TNBS-induced colitis
in rats,225 with central IL1 receptors or prostaglandins
contributing to suppression of feeding during acute
colitis.226,231 Impaired gastric emptying via sensitized
pelvic afferent neurons during colitis232 might also con
tribute to reduced food intake. Finally, evidence indicates
that colitis causes converging sensitisation of visceral and
somatic pathways,204 with colitis being associated with
bladder overactivity and enhanced skin responses to
mechanical and thermal stimulation. Overall, these find
ings again support a role for altered gutbrain pathways
in the maintenance of postinfectious or postinflammatory
gut dysfunction, which might underlie symptoms within
and those extending beyond the gastrointestinal tract.
Conclusions
Work towards mechanistic understanding of gastro
intestinal inflammation-induced neuroplasticity has
burgeoned over the past decade. Despite the absence of
perfect preclinical models to replicate clinical gastro
intestinal disorders, animal models have identified
REVIEWS
molecular mechanisms that might potentially under
lie neuroplasticity in the clinical setting. These models
have specific immune responses, which lead to distinct
interactions between immune cells and neurons. These
neuroimmune interactions cause neuroplasticity either in
the form of neuronal loss, altered synaptic transmission
or altered neuronal ion channel and receptor expression
and ultimately aberrant neuronal function that might be
evident in the postinflammatory state. Persistent neuro
plasticity might explain the symptoms of functional
bowel disorders, in which overt pathology is absent
from the gastrointestinal tract. It is also clear from animal
studies that neuroplasticity is a dynamic process. As such,
tremendous potential remains for increased understand
ing of the mechanisms of inflammatory neuroplasticity
in human disease. Developing stringent stratification
is required for patients with digestive diseases, either
organic or functional, and future studies designed to
test neuroplasticity in humans should account for the
dynamics of the disease. Identifying correlative markers
of disease progression or resolution to aid further patient
stratification will provide much needed insight to inflam
matory neuroplasticity. Overall, this information might
reveal that several different therapeutic strategies exist
for the treatment and prevention of gastrointestinal
dysfunction. Targeting neuronal populations displaying
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neuroplasticity is the ultimate goal to treat patients

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Review criteria
For this Review we conducted a number of PubMed
database searches involving combinations of terms that
included neuroplasticity, inflammatory bowel disease,
ulcerative colitis, Crohns disease, inflammation,
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literature found by these database searches that did not
appear in the original searches, such as those prior to
1966, were also retrieved for information. Together, the
authors have a combined 33years of experience in thefield
of neuroplasticity with much of that work associated with
animal models of gastrointestinal inflammation. This
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Acknowledgements
The authors wish to thank J. Applequist at the Mayo
Clinic College of Medicine and J. Maddern at the
University of Adelaide, Australia, for their secretarial
assistance. S.M.B. is supported by an NHMRC R.D.
Wright Biomedical Fellowship and by NHMRC
Australia Project grants (1008100, 1049682,
1049928 and 1063803). D.R.L. is supported by
NIHgrant DK76665.
Author contributions
S.M.B. and D.R.L. contributed equally to the
discussion of content, writing and reviewing/editing
the manuscript before submission.
Supplementary information is linked to the online
version of the paper at www.nature.com/nrgastro.

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REVIEWS

Neuroplasticity and dysfunction after

Visceral Pain Group,

Neural control of gastrointestinal function is provided

and diarrhoea or constipation. This Review focuses on

Clinical manifestations of neuroplasticity

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY

ADVANCE ONLINE PUBLICATION | 1

therapies tend to provide greater symptom relief than

lead pipe radiographic images. Compared to ulcerative

2 | ADVANCE ONLINE PUBLICATION

Extrinsic sensory afferent neurons

numbers of myenteric neurons. Mechanisms contribut

where inflammation is apparent in both Crohns disease

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY

ADVANCE ONLINE PUBLICATION | 3

and other gastrointestinal disorders40 (see Supplementary

plexitis and perhaps neuroplasticity-induced dysfunction

4 | ADVANCE ONLINE PUBLICATION

disorder is characterized by abdominal pain or dis

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY

ADVANCE ONLINE PUBLICATION | 5

Neuroplasticity in animal models

animal species or strains, or even in different labora

Inflammation-induced functional changes

6 | ADVANCE ONLINE PUBLICATION

Figure 2 | Neuroplasticity in enteric neurons during and after gut inflammation.

also persists in the postinflammatory state, but unlike

Neuroplasticity in enteric neurons

inflammatory insult,131 and is partly mediated by neutro

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY

ADVANCE ONLINE PUBLICATION | 7

Neuroplasticity in autonomic efferent neurons

alterations in both the inflamed and noninflamed regions

8 | ADVANCE ONLINE PUBLICATION

Greater and lesser

Colon and ileum

Figure 3 | Neuroplasticity in sympathetic neurons during and after gut inflammation.

Neuroplasticity in extrinsic afferent pathways

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY

ADVANCE ONLINE PUBLICATION | 9

Pronociceptive/excitatory channel or receptor

Figure 4 | Inflammation-induced neuroplasticity: contribution of neuroactive

DSS-induced 158,159 or iodoacetamide-induced gastri

10 | ADVANCE ONLINE PUBLICATION

Whole animal visceromotor response

Dorsal horn neurons

Extrinsic spinal afferent cell bodies

cord and an increased number of activated dorsal horn

upregulation, provides an antinociceptive mechanism

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Stress plus inflammation

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neuroplasticity is the ultimate goal to treat patients

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