Gastroenterology 2016;150:1280–1291

Fundamentals of Neurogastroenterology: Basic Science

Stephen J. Vanner,1 Beverley Greenwood-Van Meerveld,2 Gary M. Mawe,3
BASIC SCIENCE

Terez Shea-Donohue,4 Elena F. Verdu,5 Jackie Wood,6 and David Grundy7

1
Gastrointestinal Diseases Research Unit, Kingston General Hospital, Kingston, Ontario, Canada; 2Oklahoma Center for
Neuroscience, Department of Physiology, VA Medical Center, University of Oklahoma, Health Sciences Center, Oklahoma City,
Oklahoma; 3Department of Neurological Sciences, Pharmacology and Medicine Division, Gastroenterology and Hepatology,
University of Vermont, Burlington, Vermont; 4Department of Medicine and Physiology, University of Maryland School of
Medicine, Baltimore, Maryland; 5Farncombe Family Digestive Health Research Institute, McMaster University, Health Sciences
Center, Hamilton, Ontario, Canada; 6Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio;
7
Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom

This review examines the fundamentals of neuro- to these ostensibly conflicting functions is the ability to
gastroenterology that may underlie the pathophysiology of monitor events in the gut wall and within the gut lumen to
functional GI disorders (FGIDs). It was prepared by an orchestrate reflexes that bring about appropriate patterns of
invited committee of international experts and represents motility, secretion, and blood flow to digest and absorb or to
an abbreviated version of their consensus document that dilute and expel. GI sensory mechanisms play a pivotal role
will be published in its entirety in the forthcoming book in triggering these reflexes by conveying sensory informa-
and online version entitled Rome IV. It emphasizes recent tion to the enteric reflex circuits that provide local control
advances in our understanding of the enteric nervous and through afferent pathways to the CNS.
system, sensory physiology underlying pain, and stress
signaling pathways. There is also a focus on neuro- Pathways From Gut to Brain
immmune signaling and intestinal barrier function, given Sensory information is conveyed from the GI tract to the
the recent evidence implicating the microbiome, diet, and brainstem and spinal cord via vagal and spinal (splanchnic
mucosal immune activation in FGIDs. Together, these ad-
and pelvic) afferents, respectively. Most dorsal root ganglion
vances provide a host of exciting new targets to identify
neurons innervate somatic structures. It is estimated that
and treat FGIDs, and new areas for future research into
the proportion of dorsal root ganglion neurons innervating
their pathophysiology.
the GI tract range between 3% and -7%. The dominance of
somatic afferent input to the spinal cord and the conver-
Keywords: Sensory Physiology; Enteric Nervous System; Neu- gence of visceral and somatic afferents on ascending spinal
roimmune Signaling; Mucosal Barrier Function. pathways accounts for the phenomenon of referred pain. In
addition, afferent fibers from the colon and rectum may
converge with fibers from other pelvic organs, contributing
to cross-organ sensitization between gut, bladder, and
I n the 8 years since the publication of Rome III there
has been rapid expansion in our understanding of the
fundamentals of neurogastroenterology. What has fueled
reproductive organs that often complicates the clinical
diagnosis of pelvic pain.1 The low density of innervation,
convergence with somatic inputs, and viscerovisceral
this advance is the desire to integrate basic science research
convergence in the spinal cord can explain why gut pain
with clinical gastroenterology to better diagnose and treat
generally is localized poorly.
functional gastrointestinal disorders (FGIDs). This research
continues to shed light on the complex hierarchy of neural, Subtypes of Visceral Afferents
molecular, and cellular interactions that control gut func- GI afferent fibers terminate within the gut wall mainly as
tion. However, what recent research also has shown is the bare nerve endings and are classified according to their
complex interaction between the host gut wall and the
luminal microbial environment that is responsible for
balancing immune tolerance with protection against path-
Abbreviations used in this paper: CNS, central nervous system; CRF,
ogenic and antigenic material. Neuroimmune function and corticotrophin-releasing factor; DC, dendritic cell; EC, enterochromaffin;
the mechanisms that regulate mucosal barrier function, ELA, early life adversity; ENS, enteric nervous system; FGID, functional
gastrointestinal disorder; HPA, hypothalamic-pituitary-adrenal; 5-HT,
immune surveillance, innate and adaptive immunity, sen- 5-hydroxytryptamine; IBS, irritable bowel syndrome; ICC, interstitial cells
sory signaling, and central nervous system (CNS) adaptation of Cajal; IEC, intestinal epithelial cells; IEL, intraepithelial lymphocytes; IL,
consequently are the major themes for this review. interleukin; ILC, innate lymphoid cells; PAG, periaqueductal gray; PFC,
prefrontal cortex; PRR, pattern recognition receptor; SERT, serotonin-
selective reuptake transporter; TLR, Toll-like receptor; TRP, transient
receptor potential; VIP, vasoactive intestinal polypeptide.
The Basis of Brain–Gut Interactions Most current article
The GI tract has important barrier and immune functions
© 2016 by the AGA Institute
that interface with the luminal microbiota and protect 0016-5085/$36.00
against potential pathogenic and antigenic material. Integral http://dx.doi.org/10.1053/j.gastro.2016.02.018
May 2016 Neurogastroenterology Basic Science 1281

terminal distribution as mesenteric, serosal, muscular, ionotropic or metabotropic receptors to stimulate sensory
ganglionic (intraganglionic laminar endings), or mucosal endings. This indirect mechanism relies on close association
endings.2 The location of these endings plays an important between afferent endings in the gut wall and various other
role in determining the functional properties of the afferent. cell types that are a source of these chemical ligands. These
Mucosal afferents respond to distortion of the mucosal include mast cells, epithelial cells, enteroendocrine cells,
epithelium and to luminal chemicals. Stretch or distension is macrophages, interstitial cells of Cajal (ICC), and enteric

BASIC SCIENCE
effective for stimulating endings in the muscle layers, neurons. Considerable attention has been paid to the role of
ganglia, and serosa. These endings express an array of 5-hydroxytryptamine (5-HT) and adenosine triphosphate in
membrane receptors and ion channels that determine sensory signaling, especially in the context of post-
neuronal excitability, mechanosensitivity, and modulation inflammatory hypersensitivity.5
by a host of chemical mediators within the GI milieu.
Different populations of afferents respond over a range of
Luminal Sensing
distension volumes from innocuous (physiological) to
Some vagal and pelvic afferent endings come into close
noxious levels that cause pain. Powerful contractions,
proximity to the mucosal epithelium, but never penetrate
especially against an obstruction, cause traction on the
through to the lumen. However, their proximity to the mu-
mesentery and is especially painful.
cosa exposes them to chemicals absorbed across the
There is a continuous barrage of information projecting
mucosal epithelium or released from enteroendocrine cells
from the gut to the CNS. Many afferent endings respond to
whose apical membrane is exposed to luminal content. This
levels of distension that occur as part of normal digestion
is similar to the relationship seen between taste buds in the
and these usually go unperceived. Instead, this information
mouth and gustatory afferents and as such provides a
is used in reflexes that control motility, secretion, blood
mechanism by which mucosal afferents can taste luminal
flow, and other aspects of GI function. In contrast, there are
contents. This is important for controlling digestive function
other afferents that respond only at high levels of stimulus
via reflex effects on motility and secretion. However,
intensity and function as nociceptors that mediate pain.
nutrient detection also influences metabolic activity and
Some afferents (so-called silent or “sleeping” nociceptors)
energy intake. The molecular basis for each modality of
are mechanically insensitive under normal circumstances
gustatory taste has been identified. Strikingly, many of these
but can be awakened in response to inflammation or
same G-protein–coupled receptors and ion channels are
injury. In patients this process of sensitization can give rise
expressed within the GI tract. The cells expressing taste-
to altered pain perception. In some cases, stimuli that
receptor molecules in the GI mucosa have a characteristic
normally are innocuous can cause pain (allodynia),
morphology, which is typified by the enterochromaffin (EC)
whereas responses that are painful can become exagger-
cell.6 However, EC cells are just one of a diverse family of
ated (hyperalgesia).
enteroendocrine cells that are scattered diffusely in the GI
mucosa and whose mediators can act in a paracrine fashion
on afferent fibers or diffuse into the blood stream for more
Mechanotransduction
distant endocrine actions. Each type of enteroendocrine cell
Mechanotransduction refers to the process by which
has a characteristic distribution along the GI tract. Among
stimulus energy is interpreted by sensory nerve endings,
the mediators released, cholecystokinin and glucagon-like
leading to the generation of action potentials. There are
peptide-1 play important roles in reflex control of GI func-
specific molecular mechanisms that underlie mechano-
tion and in regulating food intake.
transduction. Moreover, the excitability of the afferent
ending is determined by various voltage-gated and calcium-
dependent ion channels3 that set gain in the system, and Peripheral Sensitization
that can change according to external influences leading to Sensory neurons express a large array of receptors that
hypersensitivity. are activated by mediators released from various cellular
Sensory endings contain a variety of mechanosensitive sources within the gut wall. Neurotrophins, for example,
ion channels that can convert the stimulus energy into ac- play a role in axon guidance and remodeling of the sensory
tion potentials. They respond to membrane deformation, innervation after inflammation and injury. Their receptors
causing channels to open or close, carrying ionic currents are expressed on different populations of GI sensory neu-
into or out of the nerve terminal to cause depolarization. rons. Both nerve growth factor and glial-derived neuro-
Three main ion channel families have been identified as trophic factor are important in the adaptive response to
mechanosensitive: (1) the DEG/ENaC family that includes nerve injury and inflammation. Both also are possible me-
the acid-sensing ion channels 1, 2, and 3; (2) the transient- diators underlying chronic pain. Increasing neurotrophin
receptor potential (TRP) channel family; and (3) the 2-pore signaling causes increased TRP channel expression (eg,
potassium channel family that includes TREK-1 and TRAAK. TRPV1 and TRPA1), an increase in sodium channel
Different combinations of these channels exist in different expression (NaV1.87), and a decrease in potassium channels.
populations of vagal, pelvic, and splanchnic afferents, sug- Any, or all of these, could contribute to the development of
gesting a complex heterogeneity in sensory signaling.4 hypersensitivity.8
Another mechanism of mechanotransduction occurs Many other mediators are released during inflammation,
when a secondary sense cell releases mediators that act on injury, and ischemia, from platelets, leukocytes, lymphocytes,
 1282 Vanner et al Gastroenterology Vol. 150, No. 6

Figure 1. Mechanisms
underlying sensitization.
Luminal factors and medi-
ators released in response
to ischemia, injury, and
BASIC SCIENCE

inflammation act on the

sensory endings to drive
sensitization. These pe-
ripheral mechanisms are
reinforced by central
mechanisms in the spinal
cord and CNS. ATP,
adenosine triphosphate;
LIF, leukemia inhibitory
factor; NGF, nerve growth
factor; PGE, prostaglandin
E; TNF, tumor necrosis
factor. Modified from
Grundy and Brookes2 with
permission from Morgan
and Claypool.

macrophages, mast cells, glia, fibroblasts, blood vessels, In the brain and spinal cord there are central neuro-
muscle, and neurons. Some mediators act directly on sensory plastic changes, termed central sensitization, that contribute
nerve terminals and others act indirectly, causing release of to chronic pain. Within the dorsal horn of the spinal cord,
yet other agents from nearby cells. This “inflammatory soup” there are 2 mechanisms that increase pain signals reaching
(Figure 1) contains amines, purines, prostanoids, proteases, the brain: (1) increased synaptic transmission via glutamate,
cytokines, and so forth, which act on sensory nerve terminals calcitonin gene-related peptide, and substance P onto
to increase sensitivity to both mechanical and chemical ascending excitatory pathways, and/or (2) decreased
stimuli (referred to as “plasticity”). Recent data have sug- descending inhibitory modulation. In the brain, sensitization
gested that bacterial products also may drive afferent can occur in the second-order spinal neurons, such as the
signaling.9 Hypersensitivity is a feature of chronic pain states thalamus, periaqueductal gray (PAG), parabrachial nucleus,
and is considered to be a hallmark of FGIDs including irri- and locus coeruleus. Increased signaling from those nuclei
table bowel syndrome (IBS). Moreover, because these then can promote neuroplasticity, similar to long-term
afferents also trigger reflexes that coordinate gut function, potentiation mechanisms, that strengthen and/or add syn-
sensitization also can cause hyper-reflexia or dysreflexia, aptic connectivity. The enhanced signaling then promotes
leading to altered transit, resulting in diarrhea and abnormal processing of pain within the extended pain ma-
constipation. trix (prefrontal cortex [PFC], anterior cingulate cortex,
Peripheral sensitization normally develops rapidly and is amygdala, insula), which can amplify the discomfort and
relatively short-lived. However, in the presence of main- negative emotions associated with chronic visceral pain,11
tained injury or inflammation, the sensitization can be pro- and/or a decrease in the descending pain inhibitory sys-
longed by changes in gene expression. These genes may alter tem through the PAG and rostroventral medulla.12 In
the expression of channels, receptors, or mediators in the particular, the amygdala is a key nucleus that integrates
sensory neuron.8 They also may modify the amount and noxious visceral signals with anxiety/fear behaviors and
pattern of neurotransmitters released by central nerve ter- hyperactivation could influence not only multiple nuclei in
minals in the brain and spinal cord. This alters the way that the central pain matrix, but also descending brainstem
sensory signals are processed within the CNS and contrib- nuclei that modulate GI function.13 Multiple clinical imaging
utes to “central sensitization,”10 and may prolong hyper- studies also have shown differences in function, connectiv-
sensitivity beyond the acute period of injury or inflammation. ity, and structure between IBS and healthy controls. Thus,
central sensitization can promote chronic abdominal pain in
IBS through remodeling of connections within both the
Central Sensitization brain and spinal cord.
These mechanisms can undergo plasticity in response to
injury and inflammation, leading to hypersensitivity and
chronic pain states. These neurons transmit visceral signals ENS Neurobiology
to ascending spinal pathways via glutamate and neuropep- A universal perception of the enteric nervous system
tides. These transmitter mechanisms are up-regulated in (ENS) as a brain-in-the-gut implies that, similar to the brain
response to inflammation and injury and contribute to and spinal cord, the ENS is assembled in a hierarchy of
hypersensitivity. neural organization.14,15 Output from the ENS determines
May 2016 Neurogastroenterology Basic Science 1283

moment-to-moment behavior of the gastrointestinal The functional characteristics of the circular muscle as a
musculature, secretory glands, and blood vasculature. Inte- self-excitable electrical syncytium implies that ICC networks
gration of output to the muscles and secretory glands is should continuously evoke contractions that spread in 3
reflected by coordinated patterns of motility and secretion, dimensions throughout the entire syncytium, which is in
recognizable during clearly defined digestive states. Five effect the entire length of the intestine. Nonetheless, in the
different behavioral states are recognizable in the small normal bowel, long stretches of intestine are found in a state

BASIC SCIENCE
intestine: (1) physiological absence of motility; (2) post- of physiological ileus. Attention to the functional electrical
prandial state with segmenting (mixing) motility integrated syncytial properties of the musculature suggests that
with set-point feedback control of luminal pH and osmo- inhibitory musculomotor neurons and control of their ac-
larity; (3) migrating motor complex in the interdigestive tivity by the integrative microcircuits in the ENS have
state also integrated with set-point feedback control of evolved as a mechanism that determines when ongoing slow
luminal pH and osmolarity; (4) a defensive state with waves initiate a contraction, as well as the distance and
copious neurogenic hypersecretion and orthograde or direction of propagation after the contraction starts.
retrograde power propulsion associated with urgency, Overall, a normal ENS is essential for a healthy bowel
diarrhea, and cramping abdominal pain; and (5) emetic and absence of irritating symptoms, such as those associ-
program, which includes reversal of peristaltic propulsion in ated with Rome-based diagnostic criteria for FGIDs. Any
the upper jejunum and duodenum to rapidly propel luminal neuropathic change in the ENS most likely will result in a
contents toward the open pylorus and relaxed antrum and symptomatic bowel. Functional propulsive motility and its
corpus. Coordinated neurogenic patterns of behavior in the integration with specialized secretory functions cannot
large intestine are recognized as haustral formation, physi- work in the absence of the ENS, as underscored in the
ological absence of motility, defecatory power propulsion aganglionic terminal segment of Hirschsprung’s disease and
and defense that also is associated with urgency, diarrhea, autoimmune ENS denervation of the lower esophageal
and cramping lower abdominal pain. sphincter in achalasia.
Similar to the CNS, the ENS functions with chemical
synaptic connections between sensory neurons, in-
terneurons, and motor neurons. Interneurons are inter- ENS Neuroplasticity in
connected synaptically into neural networks, which process Pathophysiological Conditions
information on the state of the gut, contain a library of Gut functions are altered under various pathophysio-
programs for different patterns of behavior, and control the logical conditions, and it has become increasingly clear that
activity of motor neurons. Motor neurons innervate the alterations in the intrinsic reflex circuits of the gut are
musculature, secretory glands, and blood vessels. Muscu- involved. Over the past decade, much progress has been
lomotor neurons initiate or inhibit the contractile activity of made toward determining what elements of the circuits are
the musculature when they fire.15 Modulation of their firing altered, the mechanisms of these alterations, which changes
frequency, by input from interneuronal microcircuitry, de- persist after recovery from inflammation, and the effects of
termines minute-to-minute contractile strength. Secreto- neuroplasticity on propulsive motility.
motor neurons stimulate secretory glands to secrete
chloride, bicarbonate, and mucus,16,17 and determine the
osmolarity and liquidity in the lumen. Neurogenic control of Mucosal Serotonin Signaling
bicarbonate secretion maintains a physiological pH set-point One mechanism of activating enteric neural reflex cir-
in the lumen and accounts for some of the mucosal pro- cuits is the release of 5-HT from EC cells in the intestinal
tection against acid delivery from the stomach. A subset of mucosa.19 Serotonin released from EC cells activates
secretomotor neurons simultaneously innervates both intrinsic enteric reflexes and also sends signals related to
secretory glands and periglandular arterioles, and thereby digestive reflexes, satiety, and pain to the CNS via vagal and
enhance blood flow with secretion. spinal afferents. Serotonin signaling is terminated by reup-
Interaction of the ENS with ICC18 is a major determinant take into epithelial cells, all of which express the serotonin
of each of the motility programs stored in its library. Elec- selective reuptake transporter (SERT) on their basal surface.
trically conducting junctions (gap junctions) connect smooth A consistent feature of mucosal 5-HT signaling in the
muscle fibers one to another to form a functional electrical inflamed bowels of human beings and experimental animals
syncytium. Action potentials propagate from muscle fiber to is a decrease in SERT expression.19 This has been shown in
muscle fiber in 3 dimensions and trigger a contraction as ulcerative colitis and diverticulitis in human beings, and also
they enter each neighboring muscle fiber. ICC are non- in diarrhea-predominant and constipation-predominant IBS.
neuronal pacemaker cells that also connect one to another The effects of decreased SERT expression are likely to be
to form electrical syncytial networks that extend around the comparable with those related to serotonin-selective–
circumference and throughout the longitudinal axis of the receptor inhibitor use, with increased mucosal 5-HT avail-
small and large intestine. The ICC networks generate elec- ability resulting in alterations in gut reflexes.
trical pacemaker potentials (also called electrical slow waves) Decreased SERT expression in the inflamed bowel is likely
that spread via gap junctions into the intestinal circular to involve the actions of the proinflammatory cytokines, tu-
muscle, where they depolarize the muscle to action potential mor necrosis factor a, and interferon g.20 The contributing
threshold and thereby trigger contractions. factors for decreased SERT in IBS have not been identified,
 1284 Vanner et al Gastroenterology Vol. 150, No. 6

but it may involve a genetic predisposition, given that certain of contradictory ascending and descending signals at a given
polymorphisms of the SERT gene are associated with site, and a decrease in the ability of the ENS to generate the
decreased SERT expression. It also is possible that altered pressure gradient that result in propulsive motility, result-
SERT expression in IBS develops as a compensatory response ing in a form of pseudo-obstruction. Experimentally,
to altered gut function; however, SERT expression is not increasing AH neuron excitability in normal colons disrupts
altered in opiate-induced constipation.21 motility whereas suppressing hyperexcitability of AH neu-
BASIC SCIENCE

rons in inflamed preparations improves motility.23

Furthermore, when the inhibitory junction potential is
Impact of Enteric Neuroplasticity protected and AH neuron activity is attenuated in trini-
on Gut Functions trobenzene sulfonic acid–inflamed colons, propulsive
Inflammation is associated with changes along the ENS motility is restored to its control velocity.24 These findings
reflex circuitry that include increased 5-HT availability, hy- underscore the delicate balance of enteric neural signaling,
perexcitability of AH (sensory) neurons, interneuronal syn- especially as it relates to motor functions.
aptic facilitation, and suppressed purinergic neuromuscular
transmission22 (Figure 2). It is highly likely that these alter-
ations lead to changes in neurogenic secretory and motor Neuroimmune Cross-Talk
functions in the bowel, but the nature of the changes probably No perfect animal model exists for investigating the
differs between secretory and motor responses. Neurogenic neurophysiological basis of altered motility in FGIDs, but
secretion can be activated by 5-HT release from EC cells, and one approach that has been used is to determine what
involves a 2-neuron reflex circuit consisting of an AH neuron inflammation-induced neuroplastic changes persist beyond
and an S neuron. With increased 5-HT availability, AH neuron the recovery of inflammation. This approach is obviously
hyperexcitability, and a strengthening of synaptic signals to relevant to postinfectious IBS, but in the past decade a
the secretomotor (S) neurons, it is likely that secretion is number of studies have shown that IBS is accompanied by a
enhanced. One potential pitfall in this scheme is that 5-HT detectable increase in immune cells and inflammatory me-
receptors on the processes of AH neurons could become diators in the mucosal layer. Furthermore, many inflam-
desensitized by increased exposure to 5-HT. matory bowel disease patients show IBS-like symptoms
The effects of neuroplastic changes on motility are more after resolution of their macroscopic inflammation. There-
convoluted than secretion because the reflex circuitry is fore, inflammation-induced changes in neuronal function
more complicated, involving an excitatory signal passing could be a contributing factor in IBS and refractory in-
upstream from a given site and an inhibitory signal passing flammatory bowel disease, but these changes in neuronal
downstream. For an unequivocal set of signals to be trans- excitability and synaptic strength would not be detectable
mitted, there cannot be much noise in the system. This with current diagnostic techniques. Several inflammation-
quiescent background state is disrupted in the inflamed induced changes in the ENS, including AH neuron hyper-
colon by increased 5-HT availability in the lamina propria excitability, do persist beyond recovery of inflammation,25,26
and by increased spontaneous activity of AH neurons supporting the possibility that long-term changes in enteric
throughout the inflamed regions. This results in an overlap circuitry could contribute to FGIDs.

Figure 2. Diagram show-

ing inflammation-induced
changes in the propulsive
motor circuitry of the
colon. Modified from
Mawe22 with permission
from Journal of Clinical
Investigation.
May 2016 Neurogastroenterology Basic Science 1285

Neuroimmune Function receptors on resident immune cells to initiate immune re-

For many years, the contribution of immune cells to the sponses. IECs also amplify immune responses by producing
pathogenesis of FGIDs largely was ignored. Recent evidence chemokines, such as IL8, that recruit immune cells. Immune
derived from patient and animal studies, however, has mediators binding to IEC receptors affect function through a
shown the untapped therapeutic potential of the mecha- variety of signaling pathways or through activation of
nisms involved in the cross-talk among immune cells, transcription factors that control expression of specific

BASIC SCIENCE
epithelial cells, smooth muscle, enteric nerves, and their role genes. The close association of epithelial cells, nerves, and
in the generation of symptoms in FGIDs. immune cells greatly facilitates their interactions.
The intestine is a unique compartment containing Intraepithelial lymphocytes. Intraepithelial lympho-
enteric neurons and a large number of regionally distrib- cytes (IELs) are a heterogeneous population of T-cell
uted resident immune cells. The expression of receptors for subtypes—distinct from peripheral T cells—that are inter-
neurotransmitters on immune cells, and receptors for im- spersed among IECs. IELs express surface markers that play
mune mediators on neurons/nerves, provides a foundation a role in their migration and retention in the mucosal
for neuroimmune interactions (Figure 3). Immune cells compartment and generate molecules, allowing them to
synthesize and release mediators that alter neuronal activity tether epithelial cells. In human beings, the majority of IELs
though neural expression of receptors for pathogen- and are found in the proximal small intestine where they are
damage-associated molecules and for cytokines generated important in mucosal tolerance and in maintenance of
by resident and infiltrating cells. Immune cells also release barrier function through the production of cytokines that
classic neurotransmitters, fostering the concept of the affect permeability.27
Innate lymphoid cells. Innate lymphoid cells (ILCs)
“neuroimmune synapse.” Neuroimmune cross-talk is
are a recent discovery, arise from a poorly defined precur-
involved in proinflammatory and anti-inflammatory neural
sor pool, and generate cytokines identified with polarized
reflexes and is important for the full development of the gut
adaptive immune responses (T-helper [Th]1, Th2, or Th17).
immune system and maintenance of mucosal homeostasis.
Unlike T cells, ILCs lack antigen receptors and are not
Amplification of the bidirectional communication among
involved in immune memory,28 but are important for the
epithelial cells, innate and adaptive immune cells, and ENS
initiation of host immune responses. ILC fate is modulated
provides a bridge to the adaptive immune response to
by the cross-talk among epithelial cells, luminal factors, and
physiologic or pathogenic stimuli.
other immune cells, implicating them in both protective and
inappropriate immune responses.29
Cells Involved in Neuroimmune Interactions Dendritic cells. Intestinal dendritic cells (DCs) shape
Intestinal epithelial cells. Intestinal epithelial cells adaptive immune responses to harmful or infectious intra-
(IECs) express pattern recognition receptors (PRRs), luminal stimuli through acquisition of luminal antigens and
including membrane-spanning Toll-like receptors, intracel- migration to mesenteric lymph nodes to present these an-
lular nucleotide oligomerization domain-like receptors, and tigens to naive T cells. Sensory neuropeptides participate in
retinoic acid-inducible gene 1–like receptors, all of which the recruitment of DCs during neurogenic inflammation, and
respond to pathogen-derived signals to promote tissue- activation of vasoactive intestinal polypeptide (VIP) re-
specific innate immunity. Epithelial-derived cytokines (eg, ceptors inhibits the migration of mature DCs to sites of
interleukin [IL]25, thymic stromal lymphopoietin) activate inflammation, inducing a more tolerogenic phenotype. DCs

Figure 3. Nerves express

receptors for immune cell
mediators. Immune medi-
ators bind to receptors on
nerves and can result in
either excitation or inhibi-
tion of gut function. PAR,
protease activated recep-
tor; TNF, tumor necrosis
factor; TRP, transient re-
ceptor potential; TTX-s,
tetrodotoxin sensitive Naþ
channels.
 1286 Vanner et al Gastroenterology Vol. 150, No. 6

express nicotinic and dopaminergic receptors that shift innervate gut-associated lymphoid structures and modulate
function toward production-specific profiles of cytokines the responses of immune cells expressing adrenergic re-
and this neuromodulation may play a role in inflammatory ceptors. Proinflammatory actions of sympathetic nerves are
GI pathologies. mediated by a2-adrenergic receptors whereas anti-
T cells. As central constituents of the adaptive immune inflammatory effects are mediated by the b3-adrenergic
response, T cells are natural targets of the nervous system. receptor. Catecholamines bind with higher affinity to a
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Specific cell markers subdivide populations of effector T than to b receptors, so the distance from the source of the
cells into different phenotypes including cytotoxic (CD8þ), immune cells that express both receptors can influence the
T helper (CD4þ), memory (CD4þ or CD8þ, CD45RO), and response.
regulatory (CD25þ). Some effector cells are retained and Neurogenic inflammation is a response triggered by
differentiate into resident tissue memory cells, which are serine proteases, elaborated by enteric pathogens, mast
responsible for rapid responses to subsequent antigenic cells, and neutrophils. Cleavage of protease-activated re-
stimuli. T cells express receptors for neurotransmitters ceptor 2 on extrinsic primary afferents sensitizes TRP
including 5-HT, dopamine, norepinephrine, glutamate, and channels and releases proinflammatory sensory neuropep-
acetylcholine (muscarinic and nicotinic). Their ability to tides such as substance P and calcitonin gene-related pep-
release acetylcholine and produce choline acetyltransferase tide. There is also a neuronal and nerve fiber hyperplasia in
allows them to function as a non-neuronal cholinergic inflammation that also may contribute to the severity of the
system.30 response.33
Mucosal mast cells. Mucosal mast cells reside in
healthy gut and are important in the transition from innate
to adaptive immunity. They release both preformed and Interaction of the Epithelial Barrier and
newly synthesized mediators including proteases, hista-
mine, prostaglandins, 5-HT, cytokines, and chemokines that the ENS With Gut Luminal Content
depend on the phenotype, which is influenced by the The intestinal epithelial barrier plays a critical role in the
microenvironment. The nature and timing of mediator maintenance of homeostasis within the gut and there is
release is determined by the type of receptors activated and growing evidence that alterations in this barrier may be an
the strength and duration of the stimuli. There is a well- important factor in the pathogenesis of FGIDs. The epithe-
documented anatomic and functional interaction between lium, along with underlying immune structures in the lam-
mucosal mast cells and nerves. ina propria, plays a pivotal role in controlling the host
Macrophages. Macrophages are the largest population immune response to luminal antigens. These luminal factors
of mononuclear phagocytes in the gut. Mucosal macro- also may signal directly or indirectly, through the host im-
phages respond to luminal contents and to specific IEC- mune response, to other effector systems including the ENS.
derived mediators. Macrophages associated with smooth These complex interactions, if dysregulated, can lead to gut
muscle are implicated in inflammation- and infection- dysfunction and symptom onset.
induced changes in gut motility.31 Macrophage activation
by Th1 cytokines leads to the development of the proin-
Intestinal Barrier Structure
flammatory classically activated phenotype, whereas Th2
The intestinal barrier (Figure 4) consists of a single layer
cytokines promote the development of the anti-
of epithelial cells that physically separates the host from the
inflammatory alternatively activated phenotype. Macro-
intestinal lumen.34 IECs are bound together by the epithelial
phages express nicotinic and muscarinic receptors for
apical junctional complex, comprised of tight junctions,
acetylcholine and are in close contact with cholinergic
adherens junctions, and other membrane complexes con-
neurons. Activation of these receptors enhances or inhibits
taining the membrane proteins nectin and junctional adhe-
macrophage phagocytosis and modulates production of cy-
sion molecule. Overlying the apical side of epithelial cells is
tokines. Macrophages also express a- and b-adrenergic re-
a mucus layer primarily produced by goblet cells, antimi-
ceptors as well as receptors for 5-HT, substance P, VIP,
crobial peptides, and immunoglobulins.35
adenosine, and a number of proteases that activate
protease-activated receptor 1 and protease-activated
receptor 2. Intestinal Barrier Function
Water and ion transport. The gut is capable of
handling approximately 9 L of fluid per day, absorbed
Immune Modulation of Integrated mainly by the small intestine. This fluid movement involves
Neural Responses both absorptive and secretory processes, which can occur
Activation of vagal nerves has beneficial effects that through the paracellular or the transcellular route. The
include inhibition of proinflammatory cytokines and atten- paracellular pathway involves water movements coupled to
uation of tissue injury. Recent evidence has shown an nutrient absorption (solvent drag), whereas the trans-
anatomic and functional interaction between macrophages cellular route involves the passage of water through apical
in the muscularis externa of the intestine with vagal efferent and basolateral membranes of epithelial cells by passive
fibers synapsing on cholinergic, nitric oxide, and VIP- diffusion, cotransport with ions and nutrients, or through
containing neurons in the ENS.32 Sympathetic nerves aquaporins.
May 2016 Neurogastroenterology Basic Science 1287

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Figure 4. Intestinal barrier
structure and function.
Adapted with permis-
sion from Natividad
et al.46 MAMP, microbe-
associated molecular
pattern; PRR, pattern
recognition receptors.

Antigen sampling. Immune sampling of luminal con- lectin receptors, and cytosolic DNA sensors. These receptors
tent is constant and key to mount an appropriate immune recognize evolutionary conserved pathogen-associated
response. Peyer’s patches are overlaid with specialized molecular patterns expressed by various microorganisms,
epithelial cells called microfold cells, through which anti- and shared by symbiotic microorganisms. Both epithelial and
gens are transported and exposed to antigen-presenting immune cells express PRRs. Upon activation, PRRs trigger
cells in the lamina propria. Direct sampling may occur sequential activation of intracellular signaling pathways and
through extension of dendrites by specialized dendritic lead to induction of a range of cytokines and chemokines that
cells. This process mainly occurs in the ileum, whereas in promote immune and physiological responses. PRR signaling
the upper small intestine sampling may be more dependent also facilitates the differentiation of T cells and B cells to
on changes in paracellular permeability. establish antigen-specific adaptive immunity.
Immune defense. Gastric and intestinal secretions, Critical intestinal barrier adaptations occur in response
and peristalsis, aid in digestion and immune defense by to microbial signals after gut colonization.37 In germ-free
flushing microbes and toxins. The outer layer of mucus in animals, expression of antimicrobial peptides is negligible,
the colon traps and contains large numbers of bacteria low levels of IgA are secreted, the composition of the mucus
whereas the inner layer is maintained relatively sterile, in is altered, TLR expression is reduced, and zonula occludens
part by antimicrobial proteins (defensins, cathelicidins, 1 proteins are diminished. After bacterial colonization, there
proteases, and C-type lectins) produced by various enter- is expansion of the lamina propria, along with increased cell
ocytes, Paneth cells, and innate immune cells. Some anti- proliferation and increased expression of innate microbial
microbial proteins are expressed constitutively and others recognition receptors.
are dependent on intestinal microbial colonization. Epithe-
lial cells also transport IgA produced by B cells into the gut
lumen. IgA deficiency is associated with increased pene- Interaction of the Intestinal Barrier
tration of bacteria into host tissues.36 Epithelial cells also With Luminal Content
are armed with antigen detection and immune signaling Gut microbiota. A key strategy of the mammalian in-
mechanisms, and in some cases can even act as antigen- testine in maintaining homeostasis is to regulate the inter-
presenting cells for neighboring IELs. action between luminal microbiota and the intestinal
epithelial cell, as well as immune surveillance cells in the
barrier. However, disruption of the epithelial barrier, for
Molecular Mechanisms of Interactions Between example, during acute gastroenteritis, could allow signaling
the Intestinal Barrier and Luminal Antigens by the microbiota directly to the immune system in the
A key process in innate recognition of microbial antigens lamina propria and possibly directly to enteric and nerve
is mediated by pattern recognition receptors (PRRs), which terminals of dorsal root ganglia neurons. Multiple TLRs also
include Toll-like receptors (TLRs), nucleotide binding oligo- are found on enteric and autonomic neurons and TLR acti-
merization domain-like receptors, RNA helicases, C-type vation can affect their excitability.
 1288 Vanner et al Gastroenterology Vol. 150, No. 6
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Figure 5. Chronic psychological stress plays a significant role in the pathophysiology of IBS. CRF, corticotropin releasing
factor. Reproduced from Barbara et al45 with permission from the Journal of Neurogastroenterology Motility.

Food components. There is increasing recognition that are not absorbed in the small intestine. These are
that luminal food components induce symptoms in many metabolized by colonic bacteria to short-chain fatty acids
patients with FGIDs.38 Enhanced signaling resulting from and intestinal gases. Studies suggest fermentable substances
altered intestinal barrier and/or exaggerated neuroimmune can cause colonic epithelial cells to express receptors for
responses could underlie these actions. One important these short-chain fatty acids, potentially altering the prop-
component is sensitivity to wheat-containing diets in some erties of enteric neurons, leading to changes in motility and
IBS patients. This sensitivity could be related to gluten secretion. Fermentable food components also produce a
because the gluten-derived peptide P31-43 increased IL15- number of gases, including H2, CH4, and CO2, which could
positive cells from biopsy specimens from celiac patients produce symptoms as a result of the gas-induced distension
and induced stress markers on epithelial cells. Other studies of the colon and secondary activation of neural reflexes. H2S
have shown that gliadin, the storage protein in gluten, in- gas, produced by sulfur-reducing bacteria in the intestinal
creases permeability, and studies in animal models of gluten lumen, also has been implicated in the regulation of gut
sensitivity have shown that gliadin or gluten can increase function, including secretion, motility, and nociceptive
permeability, which then leads to increased uptake of signaling. Finally, attention recently has centered on bile
microbiota antigens that further amplify the immune and acids, particularly in diarrhea-predominant IBS patients, in
functional responses to gluten. Other components in wheat whom such acids may induce alterations in intestinal
are capable of inducing innate immune responses that could physiology, by signaling to the epithelium, immune cells,
lead to gut dysfunction. Amylase trypsin inhibitors that blood vessels, smooth muscle, ENS, and autonomic nerves.
protect the grain from pests can activate the TLR-4 pathway.
Interestingly, amylase trypsin inhibitor reactivity has been
implicated in allergy and Baker’s asthma. Whether amylase Stress
trypsin inhibitors alter the epithelial barrier and play a role Although the etiology of FGIDs is unknown, there is
in a proportion of wheat-related IBS symptoms remains compelling evidence that psychological and physical
unknown, but may explain some allergic reactions to wheat stressors play an important role (Figure 5). It is a generally
components that potentially could lead to mast cell accepted hypothesis that dysfunction of the bidirectional
degranulation and symptoms. Another important compo- communication between the brain and the gut, in part
nent is the carbohydrates and smaller amounts of protein through activation of the principal neuroendocrine stress
May 2016 Neurogastroenterology Basic Science 1289

system, namely the hypothalamic–pituitary–adrenal (HPA) changes in females, however, the mechanisms are poorly
axis, plays a role in the symptomatology of IBS. The HPA axis understood. Effectively abolishing the activational role of
is activated by stress, causing the release of corticotropin ovarian hormones via ovariectomy reverses the effects of
releasing factor (CRF) from the paraventricular nucleus of early life adversity (ELA) on adult visceral pain hypersen-
the hypothalamus into the hypophyseal portal circulation to sitivity in female rats, whereas reintroduction of ovarian
bind in the anterior pituitary. Adrenocorticotropic hormone hormones via a subcutaneous estradiol pellet was sufficient

BASIC SCIENCE
then is released from the pituitary into the systemic circu- to induce visceral hyperalgesia.40 These data provide sup-
lation to cause the synthesis and release of the glucocorticoid port that ovarian hormones play a prominent role in
cortisol (corticosterone in rats) from the adrenal cortex. maintaining the persistent effects of ELA on increased pain
Clinical studies have implicated HPA axis dysregulation sensitivity in human beings and rodent models. Studies of
based on multiple reports of increased cortisol levels and neonatal maternal separation to induce ELA also have
exaggerated HPA responses to stressors in IBS patients. shown features of the IBS phenotype including motility
Multiple lines of evidence have shown activation of abnormalities, colonic hypersensitivity, and enhanced gut
central mechanism(s) resulting in colorectal hypersensitiv- permeability.40
ity, involving descending facilitation from the brain to Remodeling of the epigenome by the environment or
induce remodeling of colorectal responsiveness via sensiti- chronic stress may result in long-term changes in gene
zation of spinal dorsal horn neurons. Brainstem regions expression.41 A recent study showed the importance of his-
responsible for the modulation of descending inhibitory tone acetylation in stress-induced visceral pain by showing
pain signals are modulated by both pain and stress. The PAG that direct administration into the brain of a histone deace-
receives excitatory signaling from the PFC and inhibitory tylase inhibitor reversed visceral hypersensitivity induced by
signaling from the amygdala. The rostroventral medulla stress or activation of the amygdala with corticosterone.42,43
receives not only direct nociceptive information from the In another study, exposure to ELA was associated with CRF
spinoreticular pathway but also integrated pain and stress promoter hypomethylation and an increase in CRF tran-
signals from the amygdala and PAG. In addition, the locus scriptional responses to stress in adulthood suggesting that
coeruleus and amygdala form a circuit that can potentiate neonatal stress causes long-lasting epigenetic changes in the
both endocrine and autonomic stress responses. Central CRF expression within the HPA axis.44
structures regulating affective and sensory processes In summary, stress plays an important role in functional
including the amygdala, insula, cingulate, and PFC show bowel disorders with recent evidence from experimental
enhanced activation in IBS patients. In animal models and in models showing that chronic adult stress or early life stress
IBS patients, imaging studies have shown that limbic regions can recapitulate IBS phenotypes, and provide new insights
regulating sensory processing and emotion, including the into the underlying mechanisms of IBS.
amygdala, show greater responsiveness to visceral stimu-
lation. The amygdala is an important limbic structure
involved in the potentiation of the HPA axis, with diffuse Conclusions and Future Directions
connections to pain-modulatory networks, and has been This review highlights many advances in our under-
implicated in visceral sensitivity and aberrant HPA activity standing of the cellular and molecular mechanisms under-
observed in IBS patients.13 The amygdala is sensitive to lying GI physiological and pathophysiological systems that
corticosteroids but, in contrast to the hippocampus and PFC, may play a role in FGIDs. Examples of important themes and
the amygdala facilitates behavioral, neuroendocrine, and research questions for future research are as follows:
autonomic responses to stress. Thus, this altered balance in 1. Sensory mechanisms underlying sensitization of
stress modulation induced by amygdala hyperactivity may nociceptors and visceral hypersensitivity: which me-
represent an essential aspect of alterations in GI motor diators act to sustain signaling in specific patients and
function, colonic permeability, and colorectal sensitivity are there critical pathways? When and how are cen-
apparent in IBS. In support, increasing amygdala cortico- tral (CNS) and peripheral mechanisms (ENS/auto-
sterone in rats by stereotaxically implanting corticosterone nomic nervous system) dominant?
micropellets onto the central nucleus of the amygdala cau-
ses a persistent increase in the sensitivity to visceral stimuli 2. Barrier function regulating intestinal permeability,
as well as inducing anxiety-like behavior.39 These findings tight junction proteins, and microbiome signaling:
suggest that in IBS patients exposed to chronic stress, which pathways are involved in FGIDs and when?
increased amygdala activation dysregulates the HPA axis. Which mechanisms regulate them?
Clinical observations have suggested that abdominal
3. Neuroimmune function regulating immune mediators
pain and altered bowel habits are more common in females,
and bidirectional neural signaling: which immune
and that menstrual cycle–linked differences are observed in
cells are activated and which mediator(s) are most
symptom reporting. Differences in CNS processing of
important? What role do the vagal anti-inflammatory/
visceral information is a potential explanation because
sympathetic proinflammatory and central pathways
studies using positron emission tomography imaging have
play?
suggested that gender differences in regional brain re-
sponses to rectal pressure exist in IBS patients. Differences 4. ENS preprogrammed synaptic networks and neuro-
in pain sensitivity may be the result of cyclic hormonal plasticity: can peripheral (eg, microbiome) or central
 1290 Vanner et al Gastroenterology Vol. 150, No. 6

(eg, stress) pathways switch ENS networks to change 17. Fei G, Fang X, Wang GD, et al. Neurogenic mucosal bi-
symptoms (eg, alternating diarrhea and con- carbonate secretion in guinea pig duodenum. Br J
stipation)? When and how does ENS neuroplasticity Pharmacol 2013;168:880–890.
underlie FGIDs? 18. Sanders KM, Ward SM, Koh SD. Interstitial cells: regu-
lators of smooth muscle function. Physiol Rev 2014;
5. Psychological stress and the HPA axis/autonomic 94:859–907.
nervous system response: how does it lead to visceral
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19. Mawe GM, Hoffman JM. Serotonin signalling in the

hypersensitivity and alter gut function in FGIDs? gut–functions, dysfunctions and therapeutic targets. Nat
Rev 2013;10:473–486.
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in anxiety-like behavior and pain sensitivity. Behav Brain Diseases Research Unit, 76 Stuart Street, Kingston General Hospital,
Kingston, Ontario, Canada. e-mail: [email protected]; fax: (613) 544-3114.
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All authors contributed to the organization and writing of the review.
phic effects of unpredictable early life adversity on visceral
pain behavior in a rodent model. J Pain 2013;14:270–280. Conflicts of interest
41. Weaver IC, Cervoni N, Champagne FA, et al. Epigenetic The authors disclose no conflicts.
programming by maternal behavior. Nat Neurosci 2004; Funding
7:847–854. Supported by Canadian Institute of Health Research grant 110986 (S.V.);
National Institutes of Health grant DK62267 (G.M.); National Institutes of
42. Tran L, Chaloner A, Sawalha AH, et al. Importance of Health grant R01-DK083418 (T.S.-D.); and the European Community FP7
epigenetic mechanisms in visceral pain induced by Program (D.G.).