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Brain-gut interactions in IBS

Authors:

Abstract

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with an estimated prevalence of 10-20%. Current understanding of the pathophysiology of IBS is incomplete due to the lack of a clearly identified pathological abnormality and due to the lack of reliable biomarkers. Possible mechanisms believed to contribute to IBS development and IBS like symptoms include physical stressors, such as infection or inflammation, psychological, and environmental factors, like anxiety, depression, and significant negative life events. Some of these mechanisms may involve the brain-gut axis (BGA). In this article we review the current knowledge on the possible involvement of the BGA in IBS and discuss new directions for potential future therapies of IBS.
REVIEW ARTICLE
published: 05 July 2012
doi: 10.3389/fphar.2012.00127
Brain-gut interactions in IBS
Jakub Fichna
1
and Martin A. Storr
2
*
1
Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
2
Division of Gastroenterology, Department of Medicine, Ludwig Maximilians University of Munich, Munich, Germany
Edited by:
Angelo A. Izzo, University of Naples
Federico II, Italy
Reviewed by:
Cristina Giaroni, University of
Insubria, Italy
Peter Christopher Konturek, Teaching
Hospital of the University of Jena,
Germany
*Correspondence:
Martin A. Storr, Division of
Gastroenterology, Department of
Medicine, Ludwig Maximilians
University of Munich,
Marchioninistrasse 15, 81377 Munich,
Germany.
e-mail: gidoc@gmx.com
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with an estimated
prevalence of 10–20%. Current understanding of the pathophysiology of IBS is incomplete
due to the lack of a clearly identified pathological abnormality and due to the lack of reli-
able biomarkers. Possible mechanisms believed to contribute to IBS development and IBS
like symptoms include physical stressors, such as infection or inflammation, psychological,
and environmental factors, like anxiety, depression, and significant negative life events.
Some of these mechanisms may involve the brain-gut axis (BGA). In this article we review
the current knowledge on the possible involvement of the BGA in IBS and discuss new
directions for potential future therapies of IBS.
Keywords: irritable bowel syndrome, brain-gut axis, pathophysiology, autonomic nervous system, hypothalamo-
pituitary-adrenal axis
INTRODUCTION
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI)
disorder with an estimated prevalence of 10–20% (Philpott et al.,
2011). According to Thompson et al. (2000) it accounts for about
3% of all general practice and up to 40% of all GI referrals. IBS
causes considerable morbidity amongst its sufferers, who manifest
with abdominal pain and altered stool consistency and frequency
(Drossman and Dumitrascu, 2006; Lee et al., 2007; Adeyemo et al.,
2010). Although not life-threatening, it is a heavy economic bur-
den due to increased work absenteeism and impaired quality of
life of its sufferers, as well as increased use of health care services
(Sandler et al., 2002).
Current understanding of the pathogenesis of IBS is unsatisfac-
tory due to the lack of demonstrable pathological abnormalities
and reliable biomarkers. Traditionally, IBS has been considered
a purely functional disorder. A hypothesis based on specimens
obtained at endoscopy and in serological cytokine studies views
IBS as a localized low grade inflammatory disorder with mast cells
(MC) playing a particularly important role (Mayer and Collins,
2002; Philpott et al., 2011). An alternative hypothesis states that
food allergy may be responsible (Atkinson et al., 2004). Most
recently, the relationship between the neural and immunological
networks within the gut and the bi-directional communication
Abbreviations: ACC, anterior cingulate cortex; ACTH, adrenocorticotropic hor-
mone; ANS, autonomic nervous system; BDNF, brain-derived neurotrophic factor;
BZD, benzodiazepine; CNS, central nervous system; CRD, colorectal distension;
CRF, corticotrophin-releasing factor; DLPFC, dorsolateral prefrontal cortex; DRG,
dorsal root ganglia; DRN, dorsal raphe nucleus; ENS, enteric nervous system; GI,
gastrointestinal; HPA axis, hypothalamo-pituitary-adrenal axis; IBS, irritable bowel
syndrome; MC, mast cells; MRI, magnetic resonance imaging; NE, norepinephrine;
PAG, periaqueductal gray; PVN, paraventricular nucleus; SERT, serotonin trans-
porter protein; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective
serotonin re-uptake inhibitor; TCA, tricyclic antidepressant; UCN, urocortin.
between the gut and the central nervous system (CNS), often
related to as the brain-gut axis (BGA) attract most attention
(Collins and Bercik, 2009).
In this review we focus on the disturbances in the BGA as a
plausible cause of IBS. We overview the pathophysiological mech-
anisms contributing to symptom perception and generation and
the endogenous systems involved. Particular attention is given to
stress, emotion and psychological factors in the IBS pathogenesis.
We also discuss new directions for potential future therapies of IBS
based on discussed mechanisms.
THE BRAIN-GUT AXIS
The BGA constitutes the enteric nervous system (ENS) and the gut
wall in the periphery, the CNS, and the hypothalamo-pituitary-
adrenal (HPA) axis (Collins and Bercik, 2009). The bi-directional
communication between the gut and the CNS is based on the
neural, endocrine and neuroimmune pathways. Neuronal path-
ways include afferent fibers originating in the dorsal root of the
ganglia of the thoracic spinal cord (T1–T10) projecting to inte-
grative cortical areas, such as the cerebral, anterior and posterior
cingulate, insular, and amygdala cortices and efferent fibers to
smooth muscle and glands, originating in nuclei within the brain-
stem, as well as S2–S4 spinal levels (parasympathetic) and in the
lateral horn of the thoraco-lumbar spinal cord (T1–L3; sympa-
thetic; Mulak and Bonaz, 2004; Gaman and Kuo, 2008; O’Mahony
et al., 2011). The main pain signaling pathways in the BGA are
the spinothalamic tracts and dorsal columns with descending
supraspinal afferents originating from the rostral ventral medulla
(Gaman and Kuo, 2008).
In physiological conditions, signals from the GI tract influence
the brain, which in turn can exert changes in motility, secretion,
and immune function (Mayer et al., 2006). The axis is therefore an
important communication system for healthy regulation of food
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Fichna and Storr Brain-gut interactions in IBS
intake, digestion, gut sensations, and control of the bowel move-
ments. Structural and functional disruptions in the BGA cause
changes in perceptual and reflexive responses of the nervous sys-
tem and may lead to GI disorders, including IBS, which often
comorbid with chronic psychiatric diseases (Clarke et al., 2009;
Gros et al., 2009).
STRUCTURAL AND FUNCTIONAL ABNORMALITIES IN THE CENTRAL
NERVOUS SYSTEM
Visceral hypersensitivity is a key mechanism underlying abdom-
inal pain, one of the main symptoms of IBS (Azpiroz et al.,
2007; Barbara et al., 2011). Visceral hypersensitivity is thought
to be determined by central and peripheral mechanisms, as it
may result from altered transmission within the gut wall, the
spinal cord, or the brain. However, the specific contribution of
the BGA components to hypersensitive responses in IBS remains
unclear.
Direct imaging techniques were recently employed to detect
the abnormalities in the structure and functioning of the brain
and their possible implications in the pathology of IBS. There
is only one structural magnetic resonance imaging (MRI) study
(Davis et al., 2008), in which the thinning in the anterior mid-
cingulate and insular cortex, structures important for perception
of internal body states were observed in the IBS patients. These
results were later confirmed by functional MRI (Blankstein et al.,
2010). Although the underlying cause of cortical thinning was
not elucidated, factors like decreased cell size, apoptosis of neural
cells, death of glia and astrocytes, fewer dendritic spines, reduced
synaptic density, and excitotoxicity related to enhanced glutamate
signaling were suggested as possible contributors. Seminowicz
et al. (2010) reported morphometric brain differences between
female IBS patients and controls in terms of regional increases
and decreases in gray matter density. These alterations occurred
primarily in brain areas involved in attention and emotion modu-
lation, as well as cortico-limbic pontine pain modulatory systems
and in networks processing interoceptive information. Further
studies of Blankstein et al. (2010) evidenced increased gray matter
density in the hypothalamus of the IBS patients. Currently it is
not possible to discern whether these changes are a predisposing
factor for IBS or a secondary change after sustained visceral signals
(Fukudo and Kanazawa, 2011).
In their excellent paper on imaging techniques used in the stud-
ies of brain-gut interactions, Rapps et al. (2008) reviewed the
possible central mechanisms implicated in IBS and found pub-
lished reports somewhat contradictory. The region that attracted
most attention was the anterior cingulate cortex (ACC), one of
the six most commonly reported cortical areas that display pain-
evoked activity during acute stimulation in humans (Chen et al.,
2011). ACC showed altered activity during rectal stimulation in
IBS patients in comparison to healthy controls (Rapps et al., 2008
and citations therein). Interestingly, although greater pain by rec-
tal balloon distension was reported by the IBS patients with a
history of sexual or physical abuse, changes in their ACC activity
were less pronounced than in other IBS patients and the controls
(Ringel, 2002). In line with these observation was the study of
Mertz et al. (2000), who demonstrated differential activation of
the brain between IBS patients and controls. The ACC, the insula,
the prefrontal cortex, and the thalamus were more activated in the
IBS patients as compared with healthy controls and the pattern
was related to the experience of individuals.
Hall et al. (2010) revealed differences in the central responses
in health and in IBS to a single ramp-tonic distension of the colon
across a distributed network of regions, involving sensory, striatal,
limbic, and frontal areas. The IBS participants showed heightened
activation of the ACC, suggesting increased affective responses to
painful visceral stimuli. However, it was also observed that the acti-
vation of the thalamic, striatal, and dorsolateral prefrontal cortex
(DLPFC) regions was relatively greater in control subjects, as com-
pared to IBS patients, which may reflect increased ascending input
to the brain, in particular to the cortex and a heightened arousal
reaction to distension. Greater recruitment of the DLPFC by con-
trols than IBS patients is consistent with the notion of abnormal
descending modulation in IBS.
To further explore the central mechanisms of visceral hyper-
sensitivity in IBS, Lawal et al. (2006) examined total cortical
recruitment in response to subliminal (sub-conscious) stepped
changes in distension pressure and observed that visceral hyper-
sensitivity in IBS patients is due to increased afferent signaling
to the brain, rather than altered processing at the level of the
brain. However, the results of the study were later questioned,
among others by Lackner et al. (2006), who showed that cog-
nitive behavioral therapy in IBS patients is associated with a
reduction of baseline activity in the ACC and accompanied by
improvements of GI symptoms. Dorn et al. (2007) showed a
contributory part of neurosensitivity in the form of enhanced
activity with central neural networks independent of cognitive
function.
The most novel findings of Chen et al. (2011) showing that the
patients with IBS have white matter abnormalities in the insula,
ACC, and other brain areas associated with pain, interoception,
and homeostasis indicate that functional gray matter abnormali-
ties in IBS patients are accompanied by white matter aberrations.
The white matter deficiencies of the descending modulation of
pain and dysfunction of the medial pain system may be responsible
for the emotional aspect of pain in IBS.
In conclusion, as evidenced by the results of the meta-
analysis performed by Tillisch et al. (2011), a greater engage-
ment of regions associated with emotional arousal and endoge-
nous pain modulation, but similar activation of regions involved
in processing of visceral afferent information was observed in
patients with IBS compared to controls. These results support
a role for structural and functional abnormalities in the CNS
in IBS.
COGNITIVE–BEHAVIORAL MODEL OF IBS
IBS is often considered a bio-psychosocial disorder (Engel, 1977;
Camilleri and Choi, 1997; Drossman, 1998), which suggests that
psychological (e.g., emotions, cognitions, and behavior), social
(e.g., modeling, support), and physiological (e.g., cramps, bloat-
ing) factors may induce and exacerbate its symptoms (Toner et al.,
1998; Mach, 2004). Individual cognitive and emotional responses
to recurrent GI symptoms and associated life events may also affect
the therapeutical efficacy of anti-IBS treatments (Kennedy et al.,
2012).
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Fichna and Storr Brain-gut interactions in IBS
CENTRAL MECHANISMS
Abnormal activity within higher-order brain systems may alter
cognitive and affective processes and contribute to both abnormal
pain regulation and higher levels of anxiety and depression,
typically reported in chronic pain conditions (Ribeiro et al.,
2005) and IBS (Piche et al., 2011, and citations therein). The
cognitive-behavioral model of IBS is focused particularly on emo-
tional arousal and organism response to stress and the integrated
network of structures, which include the hypothalamus, amyg-
dala, and periaqueductal gray (PAG), as well as a number of
neuromodulators and hormones.
Greenwood-Van et al. (2001) showed in animal models that
there is a link between the central pathways mediating stress and
anxiety and the mechanisms regulating the GI sensitivity. A key
component of this link is the amygdala, which is known for its role
in the regulation of emotional behavior and the expression of fear
and anxiety. Further studies in rodents demonstrated that colonic
sensitivity and motility are increased following fear conditioning
(Gue et al., 1991; Tyler et al., 2007). In accordance, studies on IBS
patients showed substantial activation of the hypothalamus and
amygdala, as well as decreased activity of the antinociceptive PAG
(Naliboff et al., 2001). More recent investigations employing rec-
tosigmoid balloon distension in IBS patients have shown increased
activity in the amygdala, insula, cingulate, and prefrontal cortex,
which form a network of brain structures involved in regulating
affective and sensory processes (Naliboff et al., 2003; Wilder-Smith
et al., 2004; Myers and Greenwood-Van, 2009).
ROLE OF ANS AND HPA AXIS
The autonomic nervous system (ANS) and the hypothalamus-
pituitary-adrenal (HPA) axis are commonly regarded as the major
components of the stress response system in the vertebrates. Alter-
ations of this complex system have been linked to a variety of
anxiety-related psychiatric disorders and stress-sensitive pain syn-
dromes. Stress and stress-related psychosocial factors have also
been proposed to act in IBS, particularly its post-infectious variety
(PI-IBS), by overarching inflammation and the BGA (Arborelius
et al., 1999; Gwee et al., 1999; Fukudo, 2007; Spiller and Garsed,
2009).
The correct function of the ANS and its cross-talk with CNS are
important factors preventing from IBS. Disturbances at the ANS
level, indicated by decreased parasympathetic and increased sym-
pathetic activity and altered autonomic reflexes often occur in the
IBS patients and account for the level of perception to GI stimuli
and extra-intestinal symptoms (Azpiroz, 2002; Jarrett et al., 2003;
Spaziani et al., 2008).
The key activator of the HPA axis is corticotrophin-releasing
factor (CRF), an endogenous 41-amino acid neuropeptide secreted
from endocrine cells in the paraventricular nucleus (PVN) of the
hypothalamus (Aguilera et al., 2008). The action of CRF is medi-
ated by the CRF1 and CRF2 receptors, which belong to the G
protein-coupled receptor family (Kostich et al., 1998). CRF recep-
tor activity can also be modulated by other peptides,likeurocortins
(UCN; Bale and Vale, 2004; Tache and Brunnhuber, 2008). In the
mammalian brain three urocortins have been identified: UCN I,
which binds to both receptors, and UCN II and UCN III, selectively
binding to CRF2 receptor (Morin et al., 1999; Hsu and Hsueh,
2001; Lewis et al., 2001; Reyes et al., 2001; Bale and Vale, 2004;
Dautzenberg et al., 2004). However, the neuroendocrine, auto-
nomic, and behavioral responses to fear and stress are mediated
exclusively by CRF and UCN I, which are selective CRF1 receptor
ligands (Vale et al., 1981; Bale and Vale, 2004; Tache et al., 2009;
Chen et al., 2011).
Corticotrophin-releasing factor and UCN I initiate the signal-
ing cascade in the HPA axis by stimulating the anterior pitu-
itary to secrete adrenocorticotropic hormone (ACTH), which in
turn induces synthesis and secretion of glucocorticoids from the
adrenal cortex. Growing evidence suggests that also the extra-
hypothalamic CRF system is poised to play a critical role in both
psychiatric and the BGA disorders (Lowry and Moore, 2006; Bravo
et al., 2011).
In rodents, stress-induced release or exogenous administration
of CRF and UCN I increased anxiety-like behaviors and stimu-
lated colonic secretion, intestinal motility, and visceral sensitivity
(Moreau et al., 1997; Slawecki et al., 1999; Saunders et al., 2002;
Vetter et al., 2002; Million et al., 2003; Martinez et al., 2004;
Tache et al., 2004, 2009). Johnson et al. (2010) provided evi-
dence that elevated corticosterone levels affected the amygdala
and significantly increased brain activation in response to colorec-
tal distension (CRD) compared to that seen in cholesterol-treated
controls.Elevated CRF expression was found in the thalamus of the
rats exposed to neonatal maternal separation (Tjong et al., 2010).
Deletion of the CRF1 gene using transgenic models or intraven-
tricularly administered CRF1 antagonists had anxiolytic effects
and attenuated stress- and CRF-induced alterations in gastric and
colonic motor function (Smith et al., 1998; Million et al., 2003;
Martinez and Tache, 2006; Trimble et al., 2007).
Only a limited number of studies in IBS patients measured
basal and stimulated HPA axis hormone levels in response to meal,
hormone challenge, or mental stress (Chang et al., 2009, and cita-
tions therein) and some of them demonstrated increased HPA
axis responses in IBS compared to controls. Fukudo et al. (1998)
observed that the intravenous injection of CRF in IBS patients
induced exaggerated motility of the colon and increased visceral
pain sensitivity compared with healthy controls, whereas admin-
istration of a non-selective CRF receptor antagonist ameliorated
these responses (Lembo et al., 1996; Sagami et al., 2004). The recent
study by Chang et al. (2009) showed that basal levels of plasma
ACTH were significantly decreased, while both 24 h basal plasma
cortisol levels and stress-induced cortisol levels were mildly ele-
vated upon visceral stimulation in female IBS patients compared
to controls, suggesting a dysregulation of the HPA axis in IBS.
However, the role of the observed dysregulation of HPA axis in
modulating IBS severity or abdominal pain remained unclear.
A meta-analysis performed by Tillisch et al. (2011) revealed that
the central nucleus of amygdala indirectly activates the HPA axis
and increases ACTH and glucocorticoid secretion via subcorti-
cal regions, which relay on PVN (Redgate and Fahringer, 1973;
Feldman and Weidenfeld, 1998; Herman et al., 2003; Shepard
et al., 2003). The CRF-dependent involvement of the amygdala
in the induction of anxiety-like behavior, visceral hypersensi-
tivity, altered bowel habits and other common feature of IBS
has been later confirmed in animal studies (Tache et al., 2002;
Myers and Greenwood-Van, 2007, 2010; Venkova et al., 2010).
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Fichna and Storr Brain-gut interactions in IBS
The hippocampus may also be involved in several aspects relevant
to the IBS symptomatology, e.g., pain, anxiety, and stress (Prado
and Roberts, 1985; Bannerman et al., 2004; Kwan et al., 2005;
McEwen, 2007; Niddam et al., 2011). Saito et al. (2002) demon-
strated that the induction of visceral pain by CRD increased the
release of hippocampal noradrenaline in animal models. Niddam
et al. (2011) observed abnormal hippocampal glutamatergic neu-
rotransmission in IBS patients and inverse correlation between
glutamate-glutamine concentrations and emotional stress indica-
tors,which was not observed in healthy individuals. It remains pos-
sible that the observed hippocampal glutamatergic hypofunction
could result from a generally impaired HPA axis tone or it could
represent compensatory mechanisms of adaption to enhanced
glucocorticoid feedback.
PSYCHOSOCIAL FACTORS AND IBS
According to the cognitive-behavioral model, a history of abuse
and other psychosocial factors may induce and aggravate symp-
toms of IBS, influence illness experience, and affect treatment
outcome.
Ringel et al. (2008) showed that patients with IBS and a his-
tory of abuse had a significantly lower pain and urge thresholds
and a greater tendency to report pain in response to aversive rec-
tal distentions compared with patients with IBS or abuse history
alone. However, neuro-sensory sensitivity remained unchanged.
These observations suggest that the abuse history in IBS patients
may affect central mechanisms of pain amplification or regional
brain activation at sites linked to affect and attention, resulting in
heightened awareness to visceral and somatic symptoms, greater
pain reports, and greater clinical behavioral responses to painful
visceral stimuli. Nevertheless, changes in peripheral signaling by
nociceptive DRG neurons, including those innervating the colon
cannot be excluded, as suggested by several animal studies (Khasar
et al., 2008; Winston et al., 2010).
It was also observed that there is a higher prevalence of psy-
chological and psychiatric disorders observed in IBS patients:
depression, somatization disorder, generalized anxiety disorder,
panic, and phobic disorders and coping difficulties (for review see,
Arebi et al., 2008). Drossman et al. (1999) estimated that up to 70%
of the patients referred to tertiary centers with IBS meet diagnos-
tic criteria for anxiety or depression. However, Elsenbruch et al.
(2006) revealed that women with IBS were characterized by an
exaggerated anticipatory anxiety response at baseline, but essen-
tially unaltered anxiety and neuroendocrine responses to a public
speaking stressor. These results would suggest that IBS patients
show essentially normal emotional responses when faced with
challenging psychosocial situations.
Although well-evidenced, the impact of psychosocial factors on
the neurochemical responsiveness of visceral nociceptive pathways
and the physiological function of the GI remains unclear. It is pos-
sible that the psychosocial stressors and/or stressful early life events
modulate the immune response of the gut to infectious agents
and cause low level inflammation and mast cell infiltration and
degranulation in the bowel (Barbara et al., 2004; Ohman and Sim-
ren, 2010; Chen et al., 2011; Philpott et al., 2011). This is supported
by questionnaire-based studies indicating an increased prevalence
of atopic diseases among IBS patients (Philpott et al., 2011, and
citations therein) and a report published by Barbara et al. (2004),
demonstrating that there is an increased number of degranulating
MC in patients with IBS compared to that in the healthy con-
trols. Increased mucosal immune activation and elevated blood
concentrations in pro-inflammatory cytokines are also believed to
impact the CNS functioning (for review see; Kennedy et al., 2012).
Although these large molecules do not freely pass the blood-brain
barrier, a number of studies have provided substantial evidence
for their central mechanisms of action, sympathetic arousal and
the HPA axis activation (Dinan et al., 2006).
In rodents, early life stress in the form of separation of neonates
from the mother results in permanent changes in the CNS, which
include unrestrained secretion of CRF and increased expression of
its receptors (Owens and Nemeroff, 1993), increased regional nor-
epinephrine release (Southwick et al., 1999), downregulation of β-
receptors,decreased benzodiazepine receptor,and γ-aminobutryic
acid type A receptor (Caldji et al., 2000). A significant increase in
5-HT-positive cell number and 5-HT content after CRD stimula-
tion was also observed in the colon of animals, which experienced
maternal separation (Ren et al., 2007). Videlock et al. (2009)
demonstrated that IBS patients and controls with a history of
early adverse life events (EAL) have a greater cortisol response to a
visceral stressor compared to individuals without EAL, suggesting
the involvement of the HPA axis.
CURRENT AND FUTURE MOLECULAR TARGETS FOR IBS
TREATMENT
Various classes of drugs, like 5-HT3 antagonists, tricyclic antide-
pressants (TCAs), selective serotonin reuptake inhibitors (SSRIs),
gabapentinoids, CRF-1 antagonists, β3 adrenoceptor agonists,
somatostatin,N -methyl d-aspartate receptor antagonists,or mela-
tonin are currently in use for the treatment of visceral analgesia
and other symptoms of IBS. However, new molecular targets for
the future IBS therapeutics are also being investigated.
SEROTONIN RECEPTORS
Serotonin (5-HT) is a key neurotransmitter and a signaling mol-
ecule that plays an important role in sensation, secretion, and
absorption (for review see, Gershon and Tack, 2007; Garvin and
Wiley, 2008). A number of studies reported altered serotonergic
signaling activity in the brain and gut in IBS, including increase
in plasma 5-HT in IBS-D (diarrhea-predominant) and PI-IBS,
reduced levels in IBS-C (constipation-predominant) and changes
in plasma and tissue levels of serotonin transporter protein (SERT;
Dunlop et al., 2005; Atkinson et al., 2006; Zou et al., 2007; Camil-
leri, 2011). Drugs aimed at selective modulation of the 5-HT
activity (SSRIs,5-HT3,and 5-HT4 receptor antagonists) or both 5-
HT and norepinephrine (NE) systems (serotonin-norepinephrine
reuptake inhibitors, SNRIs, and tricyclic antidepressants, TCAs)
have been used in the treatment of functional GI disorders, as
well as in other chronic pain conditions, and psychiatric syn-
dromes. New generation drugs with similar pharmacological pro-
file may soon become novel efficient therapeutics in the treatment
of IBS.
Several large clinical trials have demonstrated that serotonin
receptor 5-HT3R antagonists, like alosetron, cilansetron, and
ramosetron are among the most effective therapeutic options
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Fichna and Storr Brain-gut interactions in IBS
to date for both male and female IBS-D patients (Jarcho et al.,
2008,and citations therein). The 5-HT3R antagonists alleviate spe-
cific IBS symptoms, such as frequent bowel movements, feelings
of urgency, and chronic abdominal pain and discomfort, acting
through central and peripheral mechanisms. Although the precise
mechanisms underlying their effectiveness remain incompletely
understood, symptom improvement associated with an interac-
tion with dopamine, cholecystokinin, glutamate, acetylcholine,
and GABA (for review see, Barnes et al., 2009) and a reduction
in amygdala and emotional arousal circuit activity (Berman et al.,
2002) have been suggested. Inhibition of the spinal cord c-fos
expression by 5-HT3R antagonists in response to noxious CRD
(Kozlowski et al., 2000) suggests that 5-HT3R plays a role in the
transmission of noxious information within the spinal cord. Excess
5-HT released from enterochromaffin cells (EC) in the colonic
mucosa of both unselected and PI-IBS patients (Spiller, 2007)
and decreased expression of SERT (Coates et al., 2004) may also
account to this phenomenon.
5-HT3 antagonist-based therapies require the implementation
of a risk management plan, as ischemic colitis and complica-
tions of constipation may occur (Chang et al., 2010). Therefore, a
novel class of compounds (of which the prototype is LX-1031) is
being developed that directly inhibits 5-HT synthesis in EC cells,
potentially reversing the underlying pathogenetic factor in con-
ditions like IBS-D. Such compounds could become an alternative
to the application of classical 5-HT3 receptor antagonists in the
treatment of IBS.
Recently, partial 5-HT1 receptor agonists, like buspirone, and
antagonists, like robalzotan tartrate monohydrate (AZD7371),
attracted much attention as they displayed a potent analgesic effect
in the CRD-induced visceral pain model in rats (Sivarao et al.,
2004; Lindstrom et al., 2009). However, the clinical development
of AZD7371 has been discontinued due to severe adverse events,
including hallucinations and the inability to demonstrate signif-
icant efficacy in IBS patients compared with placebo (Drossman
et al., 2008).
The 5-HT4 receptors in the GI tract are found on enteric neu-
rons and smooth muscle cells. Stimulation of 5-HT4 receptors
leads to acetylcholine release and prokinetic effects (Gershon and
Tack, 2007). The early generation 5-HT4 receptor agonists, such
as cisapride and tegaserod, reversed slow motility and relieved
constipation, but they have been withdrawn because of cardiac
or vascular adverse effects (Gershon and Tack, 2007). A number
of novel 5-HT4 agonists have recently been obtained as potential
treatments for patients with IBS-C and appear to be safer than
earlier generation agents in these classes (Camilleri et al., 2008;
Manini et al., 2010).
The 5-HT7 and 5-HT2B receptors are yet another potential
serotonergic target for future IBS treatment. The 5-HT7 recep-
tors are present in humans and other animals and are linked with
depression, circadian rhythm, neuroendocrine function, affective
behavior and body temperature regulation (for review see, Van-
hoenacker et al., 2000). They play an important role in regulating
smooth muscle relaxation in the GI and nociceptive pathways
(Carter et al., 1995; Meuser et al., 2002) and may thus be involved
in the pathological mechanisms of GI dyskinesia, abdominal pain,
and visceral paresthesia in IBS. It was demonstrated that 5-HT7
receptors also mediate stress and glucocorticoid-induced effects on
hippocampal neurogenesis, which have been implicated in mood.
Meanwhile, 5-HT2B receptor blockade was shown to reduce sig-
nificantly pain behaviors in response to CRD (O’Mahony et al.,
2010a).
Recent studies demonstrated that serotonergic neurotransmis-
sion can be markedly affected by CRF acting in a CRF receptor-
dependent manner (Cryan et al., 2005; Valentino and Commons,
2005). The injection of low doses of CRF in the dorsal raphe
nucleus (DRN) reduced the discharge rate of serotonergic neurons
in the striatum (Kirby et al., 2000) and the nucleus accumbens
(Lukkes et al., 2008) and at a higher dose increased striatal 5-
HT release (Price et al., 1998). Additionally, 5-HT levels in the
hippocampus were increased by i.c.v. administration of low and
high doses of CRF (Penalva et al., 2002). These data suggest a
close correlation between the serotonergic system and CRF, which
may be taken into consideration when novel anti-IBS therapies are
designed.
BENZODIAZEPINE RECEPTORS
One of the newly targeted classes of drugs for the treatment of vis-
ceral pain are benzodiazepine (BZD) receptor modulators. BZD
receptors are located in subcortical and hypothalamic regions
and appear important in controlling autonomic function, such
as motor and sensory activity of the gut (for review see, Salari
and Abdollahi, 2011). In addition, activation of the central BZD
receptors affects GABA interaction with central GABA-A recep-
tors and may influence the ANS, dorsal vagal nuclei, and the ENS.
Peripheral BZD receptors were identified on immune cells and
other peripheral tissues and may be involved in cell proliferation
and immunomodulation (for review see, Zisterer and Williams,
1997).
The BZD receptors and their ligands, which belong to an impor-
tant regulatory network between the CNS, behavior, and immune
response,may thus become an attractive target for future IBS treat-
ments. Recently, a novel BZD receptor ligand dextofisopam was
developed for the management of IBS-D (Grundmann et al., 2010)
and is currently under investigation.
NEUROKININ RECEPTORS
Substance P (SP) and the neurokinin-1 receptors (NK1R)
are located throughout the BGA, including peripheral, spinal,
supraspinal, and cortical sites of visceral afferent pathways, as
well as brain regions involved in emotional arousal and auto-
nomic function (Tillisch et al., 2012, and citations therein). It
was observed that SP and NK1R signaling play an important role
in nociceptive responses (hyperalgesia) and the autonomic and
behavioral responses to stress in animals and humans.
Recent study by Tillisch et al. (2012) revealed that a 3-week
treatment with a novel NK1R antagonist reduced activation of
key regions of both the interoceptive afferent and emotional
arousal network in response to noxious and non-noxious vis-
ceral stimulus in female IBS patients, causing a large decrease
in pain-induced negative affect and decreased anxiety and pain
ratings. This positive correlation suggests a potential for use
of NK1R antagonists in IBS patients to decrease pain related
distress.
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Fichna and Storr Brain-gut interactions in IBS
BRAIN-DERIVED NEUROTROPHIC FACTOR
Neurotrophins promote neuronal survival along with the growth
and differentiation of new neurons and synapses. Brain-derived
neurotrophic factor (BDNF) may be involved in the integration
of excitatory and inhibitory neurotransmission and emerging evi-
dence suggests that amygdaloid BDNF can regulate anxiety-like
behaviors (Slack et al., 2004; Pandey et al., 2006).
Yu et al. (2012) recently observed a significant upregulation of
BDNF in the colonic mucosa and structural alterations of mucosal
innervation in biopsies from patients with IBS, as compared with
controls. The enhanced expression of BDNF was closely correlated
with the degree of abdominal pain in IBS. These results suggest
that endogenous BDNF released in response to inflammation con-
tributes to the development of central sensitization and thus plays
a pathophysiological role in the altered gut sensation in IBS. Fur-
thermore, the upregulation of BDNF may also play a role in the
structural alterations of mucosal nerve fibers in patients with IBS.
Inhibition of the BDNF system could therefore be beneficial for
the alleviation of symptoms in the IBS patients.
SEX STEROID RECEPTORS
Because of the sex differences in perceptual responses and a female
predominance of the disorder, attention has been drawn to the
role of sex steroids, in particular ovarian hormones, in the devel-
opment of IBS. Previous reports revealed that women with IBS
often report exacerbation of symptoms, including visceral and
somatic sensitivity during menses (Kane et al., 1998; Mayer et al.,
1999; Houghton et al., 2002; Chang et al., 2006; Gustafsson and
Greenwood-Van, 2011) and show greater, compared to men, acti-
vation of brain areas associated with affective responses including
the amygdala and cingulate cortex (Berman et al., 2000; Naliboff
et al., 2003). In contrast, male IBS patients show less visceral
hypersensitivity than female patients, but have greater sympa-
thetic nervous system responses measured by skin conductance,
and decreased cardiovagal activity measured by heart rate vari-
ability compared to female IBS patients (Tillisch et al., 2005) and
male controls.
Although ovarian steroid receptor levels are higher in some
regions of the female brain (Greco et al., 2001; Milner et al., 2008),
progesterone and estradiol-induced visceral hypersensitivity does
not appear to be sex specific, as males also showed increased vis-
ceral sensitivity following hormone implantation on the amygdala
(Myers et al., 2011). However, the amygdala may still represent the
key supraspinal site mediating the actions of ovarian hormones
on visceral pain in both males and females and account for dif-
ferences in symptom generation in male and female IBS patients
(Naliboff et al., 2003; Labus et al., 2008; Kilpatrick et al., 2010).
The amygdala may thus become an interesting target for the IBS
treatment and alleviation of pain.
TOLL-LIKE RECEPTORS
Toll-like receptors (TLRs) have been localized on mucosal sur-
faces, including the colonic epithelial cells, and their expression is
increased in the colonic mucosa of rat models of visceral hypersen-
sitivity and mucosal biopsies from IBS patients (McKernan et al.,
2009; Brint et al., 2011). TLRs are activated by various bacter-
ial and viral cell components (Takeuchi and Akira, 2010), which
stimulate transcription of inflammatory cytokines, like IL-1b,IL-6,
and TNFa and affect transmission in the spinal cord, resulting in
central sensitization and hyperalgesia (for review seel, Akira and
Takeda, 2004; Arebi et al., 2008). Cytokines are also known to cross
the blood-brain barrier, to affect the HPA axis and stress response
and to stimulate secretion of CRH in rat, as well as in humans (for
review see, John and Buckingham, 2003; Dantzer et al., 2008).
Recently, McKernan et al. (2011) demonstrated that TLR
agonist-induced cytokine and cortisol release was markedly
enhanced in stimulated whole blood from IBS patients compared
with healthy controls. These results point out at the TLR as possible
targets in the treatment of IBS.
RECEPTORS FOR ACETYLCHOLINE AND CATECHOLAMINES
There is an increasing evidence for the beneficiary role of cholin-
ergic, dopaminergic, and noradrenergic pathways in regulating
immunity and cytokine production in IBS, suggesting a posi-
tive influence of acetylcholine and catecholamines on the IBS
symptoms (Dinan et al., 2008; Rosas-Ballina and Tracey, 2009).
However, adrenaline was shown to act directly through adrener-
gic receptors on DRG neurons or indirectly by increasing levels
of pronociceptive mediators following immune activation in the
colon or repeated stress, thus increasing the excitability of the neu-
rons and exacerbating pain sensation (Khasar et al., 2008; Winston
et al., 2010; Ibeakanma et al., 2011). In contrast, no significant
differences in NE responses to sigmoidoscopy were observed in
women with IBS-D compared to healthy women (Chang et al.,
2009).
These conflicting results point at the necessity of further studies
on the involvement of cholinergic, dopaminergic, and adrener-
gic receptors and their ligands in development of IBS and their
possible therapeutical application.
PAST, PRESENT, AND FUTURE OF ANTI-IBS DRUGS
TARGETING THE BRAIN-GUT AXIS
For most IBS patients with mild symptoms, lifestyle, and dietary
changes may be sufficient; for more moderate symptoms, medica-
tions that act on the gut (e.g., anticholinergics, peripheral 5-HT
agents) can be considered. However, patients who suffer from
severe IBS, characterized by increased levels of pain, poorer quality
of life, psychosocial difficulties, or co-morbidity with mood dis-
turbances are usually refractory to first- and second-line therapies
(Drossman et al., 2000; Grover and Drossman, 2011). The bi-
directional communication between the brain and the gut opens
up new treatment possibilities for these patients and directs us to
novel pharmacological targets for the anti-IBS drugs.
Almost all IBS patients could benefit from centrally acting
treatments, like therapies focused on teaching better stress cop-
ing strategies, both at a cognitive and behavioral level (for review
see, Larauche et al., 2012), or psychotropic agents. Some of the
TCAs, SSRIs, SNRIs, or BZDs have already been employed in the
treatment of IBS and proved effective in symptom relief via mood
stabilization, modulation of pain perception and amelioration of
GI motility and secretion (Ford et al., 2009; Grover and Drossman
(2011) estimate that at least every one in eight patients with IBS
is offered an antidepressant). However, the effects of psychotropic
agents on bowel symptoms and visceral hypersensitivity in IBS
Frontiers in Pharmacology | Gastrointestinal Pharmacology July 2012 | Volume 3 | Article 127 | 6
Fichna and Storr Brain-gut interactions in IBS
patients have been less robust and less consistent than the benefits
reported for global symptoms and abdominal pain/discomfort
(Chey et al., 2011). Furthermore, psychotropic agents are not free
from undesired side effects. TCAs display anticholinergic prop-
erties, including constipation, tachycardia, urinary retention, and
xerostomia;patients may also encounter central side effects includ-
ing sedation, insomnia, agitation, and nightmares (Chey et al.,
2011). Compared to TCAs, SSRIs have fewer side effects, but do
not improve bloating or visceral pain (Tack et al., 2006). BZDs
are used routinely in anxiety disorders, but their efficacy in symp-
tom relief of IBS is under debate (Drossman et al., 2002). New
generation of psychotropic agents is therefore anticipated.
Efficacious and safe serotonergic agents may also become future
drugs in the treatment of IBS. Recently, novel mixed 5-HT1A
agonists/5-HT3 antagonists, 5-HT1B/D agonists, and 5-HT2B
antagonists have been proposed as new therapeutics for IBS (Tack
et al., 2000; Mulak and Paradowski, 2006; Vera-Portocarrero et al.,
2008; Asagarasu et al., 2009; O’Mahony et al., 2010b).
Other endogenous systems, which may become possible new
targets in the IBS therapy, include GABA-B, CRF, NK, cannabi-
noid, and opioid receptors and their ligands. Preliminary data
suggest that anxiolytic activity of GABA-ergic agent, gabapentin
may be efficient in reducing central sensitization in hyperalge-
sia (for review see, Camilleri and Andresen, 2009). CRF receptor
antagonists have also been proposed as a potential treatment of
IBS (Martinez and Tache, 2006; Tache et al., 2009). However, due
the failure of treatment with a CRFR1 antagonists to alter colonic
transit and the global improvement scale in IBS patients (Sweetser
et al., 2009), further studies are required.
The potential use of cannabinoid and opioid receptor ligands
as anti-IBS agents has also been considered and has been reviewed
in detail elsewhere (Fichna et al., 2009; Izzo and Sharkey, 2010).
CONCLUSION
In summary, there is striking evidence of a crucial involvement
of the BGA in the development of IBS and IBS like symptoms.
Though the role of the BGA is not fully understood, some con-
cepts are at an advanced stage and allow speculation on possi-
ble future treatment options. Future research needs to identify
the exact involvement of the discussed neurotransmitter systems
and to identify at which level pharmacological treatment may be
beneficial to patients with IBS.
ACKNOWLEDGMENTS
This work was supported by the grant from the Deutsche
Forschungsgemeinschaft (STO 645/6-1 to Martin A. Storr), and
the Iuventus Plus program of the Polish Ministry of Science and
Higher Education (0119/IP1/2011/71 to Jakub Fichna).
REFERENCES
Adeyemo, M. A., Spiegel, B. M., and
Chang, L. (2010). Meta-analysis: do
irritable bowel syndrome symptoms
vary between men and women? Ali-
ment. Pharmacol. Ther. 32, 738–755.
Aguilera, G., Subburaju, S., Young, S.,
and Chen, J. (2008). The parvo-
cellular vasopressinergic system and
responsiveness of the hypothalamic
pituitary adrenal axis during chronic
stress. Prog. Brain Res. 170, 29–39.
Akira, S., and Takeda, K. (2004). Toll-
like receptor signalling. Nat. Rev.
Immunol. 4, 499–511.
Arborelius, L., Owens, M. J., Plotsky, P.
M., and Nemeroff, C. B. (1999). The
role of corticotropin-releasing factor
in depression and anxiety disorders.
J. Endocrinol. 160, 1–12.
Arebi, N., Gurmany, S., Bullas, D.,
Hobson, A., Stagg, A., and Kamm,
M. (2008). Review article: the psy-
choneuroimmunology of irritable
bowel syndrome an exploration
of interactions between psycholog-
ical, neurological and immunologi-
cal observations. Aliment. Pharma-
col. Ther. 28, 830–840.
Asagarasu, A., Matsui, T., Hayashi, H.,
Tamaoki, S., Yamauchi, Y., and Sato,
M. (2009). Design and synthesis
of piperazinylpyridine derivatives
as novel 5-HT1A agonists/5-HT3
antagonists for the treatment of irri-
table bowel syndrome (IBS). Chem.
Pharm. Bull. 57, 34–42.
Atkinson, W., Lockhart, S., Whor-
well, P. J., Keevil, B., and
Houghton, L. A. (2006). Altered
5-hydroxytryptamine signaling in
patients with constipation- and
diarrhea-predominant irritable
bowel syndrome. Gastroenterology
130, 34–43.
Atkinson, W., Sheldon, T. A., Shaath,
N., and Whorwell, P. J. (2004). Food
elimination based on IgG antibod-
ies in irritable bowel syndrome: a
randomised controlled trial. Gut 53,
1459–1464.
Azpiroz, F. (2002). Gastrointestinal per-
ception: pathophysiological impli-
cations. Neurogastroenterol. Motil.
14, 229–239.
Azpiroz, F., Bouin, M., Camilleri, M.,
Mayer, E. A., Poitras, P., Serra, J., and
Spiller, R. C. (2007). Mechanisms
of hypersensitivity in IBS and func-
tional disorders. Neurogastroenterol.
Motil. 19(1 Suppl.), 62–88.
Bale, T. L., and Vale, W. W. (2004).
CRF and CRF receptors: role in stress
responsivity and other behaviors.
Annu. Rev. Pharmacol. Toxicol. 44,
525–557.
Bannerman, D. M., Rawlins, J. N.,
McHugh, S. B., Deacon, R. M.,
Yee, B. K., Bast, T., Zhang, W.
N., Pothuizen, H. H., and Feldon,
J. (2004). Regional dissociations
within the hippocampus memory
and anxiety. Neurosci. Biobehav. Rev.
28, 273–283.
Barbara, G., Cremon, C., De Giorgio,
R., Dothel, G., Zecchi, L., Bellacosa,
L., Carini, G., Stanghellini, V., and
Corinaldesi, R. (2011). Mechanisms
underlying visceral hypersensitivity
in irritable bowel syndrome. Curr.
Gastroenterol. Rep. 13, 308–315.
Barbara, G., Stanghellini, V., De Gior-
gio, R., Cremon, C., Cottrell, G. S.,
Santini, D., Pasquinelli, G., Morselli-
Labate, A. M., Grady, E. F., Bun-
nett, N. W., Collins, S. M., and Cori-
naldesi, R. (2004). Activated mast
cells in proximity to colonic nerves
correlate with abdominal pain in
irritable bowel syndrome. Gastroen-
terology 126, 693–702.
Barnes, N. M., Hales, T. G., Lum-
mis, S. C., and Peters, J. A. (2009).
The 5-HT3 receptor the relation-
ship between structure and function.
Neuropharmacology 56, 273–284.
Berman, S., Munakata, J., Naliboff, B.
D., Chang, L., Mandelkern, M., Sil-
verman, D., Kovalik, E., and Mayer,
E. A. (2000). Gender differences in
regional brain response to visceral
pressure in IBS patients. Eur. J. Pain
4, 157–172.
Berman, S. M., Chang, L., Suyenobu, B.,
Derbyshire, S. W., Stains, J., Fitzger-
ald, L., Mandelkern, M., Hamm, L.,
Vogt, B., Naliboff, B. D., and Mayer,
E. A. (2002). Condition-specific
deactivation of brain regions by 5-
HT3 receptor antagonist alosetron.
Gastroenterology 123, 969–977.
Blankstein, U., Chen, J., Diamant,
N. E., and Davis, K. D. (2010).
Altered brain structure in irritable
bowel syndrome: potential contri-
butions of pre-existing and disease-
driven factors. Gastroenterology 138,
1783–1789.
Bravo, J. A., Dinan, T. G., and Cryan,
J. F. (2011). Alterations in the cen-
tral CRF system of two different
rat models of comorbid depression
and functional gastrointestinal dis-
orders. Int. J. Neuropsychopharma-
col. 14, 666–683.
Brint, E. K., MacSharry, J., Fanning,
A., Shanahan, F., and Quigley, E.
M. (2011). Differential expres-
sion of toll-like receptors in
patients with irritable bowel syn-
drome. Am. J. Gastroenterol. 106,
329–336.
Caldji, C., Diorio, J., and Meaney, M. J.
(2000). Variations in maternal care
in infancy regulate the development
of stress reactivity. Biol. Psychiatry
48, 1164–1174.
Camilleri, M. (2011). LX-1031, a
tryptophan 5-hydroxylase inhibitor,
and its potential in chronic diar-
rhea associated with increased sero-
tonin. Neurogastroenterol. Motil. 23,
193–200.
Camilleri, M., and Andresen, V. (2009).
Current and novel therapeutic
options for irritable bowel syndrome
management. Dig. Liver Dis. 41,
854–862.
www.frontiersin.org July 2012 | Volume 3 | Article 127 | 7
Fichna and Storr Brain-gut interactions in IBS
Camilleri, M., and Choi, M. G. (1997).
Review article: irritable bowel syn-
drome. Aliment. Pharmacol. Ther.
11, 3–15.
Camilleri, M., Kerstens, R., Rykx, A., and
Vandeplassche, L. (2008). A placebo-
controlled trial of prucalopride for
severe chronic constipation. N. Engl.
J. Med. 358, 2344–2354.
Carter, D., Champney, M., Hwang, B.,
and Eglen, R. M. (1995). Char-
acterization of a postjunctional 5-
HT receptor mediating relaxation
of guinea-pig isolated ileum. Eur. J.
Pharmacol. 280, 243–250.
Chang, L., Mayer, E. A., Labus, J. S.,
Schmulson, M., Lee, O. Y., Olivas,
T. I., Stains, J., and Naliboff, B. D.
(2006). Effect of sex on perception
of rectosigmoid stimuli in irrita-
ble bowel syndrome. Am. J. Phys-
iol. Regul. Integr. Comp. Physiol. 291,
R277–R284.
Chang, L., Sundaresh, S., Elliott, J.,
Anton, P. A., Baldi, P., Licudine,
A., Mayer, M., Vuong, T., Hirano,
M., Naliboff, B. D., Ameen, V. Z.,
and Mayer, E. A. (2009). Dys-
regulation of the hypothalamic-
pituitary-adrenal (HPA) axis in irri-
table bowel syndrome. Neurogas-
troenterol. Motil. 21, 149–159.
Chang, L., Tong, K., and Ameen, V.
(2010). Ischemic colitis and com-
plications of constipation associated
with the use of alosetron under a risk
management plan: clinical charac-
teristics, outcomes, and incidences.
Am. J. Gastroenterol. 105, 866–875.
Chen, J. Y., Blankstein, U., Diamant,
N. E., and Davis, K. D. (2011).
White matter abnormalities in irrita-
ble bowel syndrome and relation to
individual factors. Brain Res. 1392,
121–131.
Chey, W. D., Maneerattaporn, M.,
and Saad, R. (2011). Pharmaco-
logic and complementary and alter-
native medicine therapies for irri-
table bowel syndrome. Gut Liver 5,
253–266.
Clarke, G., Quigley, E. M., Cryan, J. F.,
and Dinan, T. G. (2009). Irritable
bowel syndrome: towards biomarker
identification. Trends Mol. Med. 15,
478–489.
Coates, M. D., Mahoney, C. R., Lin-
den, D. R., Sampson, J. E., Chen, J.,
Blaszyk, H., Crowell, M. D., Sharkey,
K. A., Gershon, M. D., Mawe, G. M.,
and Moses, P. L. (2004). Molecular
defects in mucosal serotonin con-
tent and decreased serotonin reup-
take transporter in ulcerative col-
itis and irritable bowel syndrome.
Gastroenterology 126, 1657–1664.
Collins, S. M., and Bercik, P. (2009).
The relationship between intestinal
microbiota and the central nervous
system in normal gastrointestinal
function and disease. Gastroente rol-
ogy 136, 2003–2014.
Cryan, J. F., Valentino, R. J., and
Lucki, I. (2005). Assessing substrates
underlying the behavioral effects of
antidepressants using the modified
rat forced swimming test. Neurosci.
Biobehav. Rev. 29, 547–569.
Dantzer, R., O’Connor, J. C., Freund,
G. G., Johnson, R. W., and Kelley,
K. W. (2008). From inflammation
to sickness and depression: when
the immune system subjugates the
brain. Nat. Rev. Neurosci. 9, 46–56.
Dautzenberg, F. M., Higelin, J., Wille,
S., and Brauns, O. (2004). Molecular
cloning and functional expression of
the mouse CRF2(a) receptor splice
variant. Regul. Pept. 121, 89–97.
Davis, K. D., Pope, G., Chen, J., Kwan, C.
L., Crawley, A. P., and Diamant, N.
E. (2008). Cortical thinning in IBS:
implications for homeostatic, atten-
tion, and pain processing. Neurology
70, 153–154.
Dinan, T. G., Clarke, G., Quigley,
E. M., Scott, L. V., Shanahan, F.,
Cryan, J., Cooney, J., and Keeling,
P. W. (2008). Enhanced cholinergic-
mediated increase in the pro-
inflammatory cytokine IL-6 in irri-
table bowel syndrome: role of mus-
carinic receptors. Am. J. Gastroen-
terol. 103, 2570–2576.
Dinan, T. G., Quigley, E. M., Ahmed,
S. M., Scully, P., O’Brien, S.,
O’Mahony, L., O’Mahony, S.,
Shanahan, F., and Keeling,
P. W. (2006). Hypothalamic-
pituitary-gut axis dysregulation in
irritable bowel syndrome: plasma
cytokines as a potential biomarker?
Gastroenterology 130, 304–311.
Dorn, S. D., Palsson, O. S., Thiwan, S.
I., Kanazawa, M., Clark, W. C., van
Tilburg, M. A., Drossman, D. A.,
Scarlett, Y., Levy, R. L., Ringel, Y.,
Crowell, M. D., Olden, K. W., and
Whitehead, W. E. (2007). Increased
colonic pain sensitivity in irritable
bowel syndrome is the result of an
increased tendency to report pain
rather than increased neurosensory
sensitivity. Gut 56, 1202–1209.
Drossman, D. A. (1998). Presidential
address: gastrointestinal illness and
the biopsychosocial model. Psycho-
som. Med. 60, 258–267.
Drossman, D. A., Camilleri, M., Mayer,
E. A., and Whitehead, W. E. (2002).
AGA technical review on irritable
bowel syndrome. Gastroenterology
123, 2108–2131.
Drossman, D. A., Creed, F. H., Olden,
K. W., Svedlund, J., Toner, B.
B., and Whitehead, W. E. (1999).
Psychosocial aspects of the func-
tional gastrointestinal disorders. Gut
45(Suppl. 2), II25–II30.
Drossman, D. A., Danilewitz, M.,
Naesdal, J., Hwang, C., Adler, J.,
and Silberg, D. G. (2008). Ran-
domized, double-blind, placebo-
controlled trial of the 5-HT1A recep-
tor antagonist AZD7371 tartrate
monohydrate (robalzotan tartrate
monohydrate) in patients with irri-
table bowel syndrome. Am. J. Gas-
troenterol. 103, 2562–2569.
Drossman, D. A., and Dumitrascu, D.
L. (2006). Rome III new standard
for functional gastrointestinal disor-
ders. J. Gastrointestin. Liver Dis. 15,
237–241.
Drossman, D. A., Whitehead, W. E.,
Toner, B. B., Diamant, N., Hu, Y.
J., Bangdiwala, S. I., and Jia, H.
(2000). What determines severity
among patients with painful func-
tional bowel disorders? Am. J. Gas-
troenterol. 95, 974–980.
Dunlop, S. P., Coleman, N. S., Black-
shaw, E., Perkins, A. C., Singh,
G., Marsden, C. A., and Spiller,
R. C. (2005). Abnormalities of 5-
hydroxytryptamine metabolism in
irritable bowel syndrome. Clin. Gas-
troenterol. Hepatol. 3, 349–357.
Elsenbruch, S., Lucas, A., Holtmann,
G., Haag, S., Gerken, G., Riemen-
schneider, N., Langhorst, J., Kave-
laars, A., Heijnen, C. J., and Sched-
lowski, M. (2006). Public speak-
ing stress-induced neuroendocrine
responses and circulating immune
cell redistribution in irritable bowel
syndrome. Am. J. Gastroenterol. 101,
2300–2307.
Engel, G. L. (1977). The need for a
new medical model: a challenge for
biomedicine. Science 196, 129–136.
Feldman, S., and Weidenfeld, J.
(1998). The excitatory effects of
the amygdala on hypothalamo-
pituitary-adrenocortical responses
are mediated by hypothalamic nor-
epinephrine, serotonin, and CRF-41.
Brain Res. Bull. 45, 389–393.
Fichna, J., Schicho, R., Janecka,A., Zjaw-
iony, J. K., and Storr, M. (2009).
Selective natural kappa opioid and
cannabinoid receptor agonists with
a potential role in the treatment of
gastrointestinal dysfunction. Drug
News Perspect. 22, 383–392.
Ford, A. C., Talley, N. J., Schoenfeld, P.
S., Quigley, E. M., and Moayyedi, P.
(2009). Efficacy of antidepressants
and psychological therapies in irri-
table bowel syndrome: systematic
review and meta-analysis. Gut 58,
367–378.
Fukudo, S. (2007). Role of
corticotropin-releasing hormone
in irritable bowel syndrome
and intestinal inflammation. J.
Gastroenterol. 42(Suppl. 17), 48–51.
Fukudo, S., and Kanazawa, M. (2011).
Gene, environment, and brain-gut
interactions in irritable bowel syn-
drome. J. Gastroenterol. Hepatol.
26(Suppl. 3), 110–115.
Fukudo, S., Nomura, T., and Hongo,
M. (1998). Impact of corticotropin-
releasing hormone on gastrointesti-
nal motility and adrenocorticotropic
hormone in normal controls and
patients with irritable bowel syn-
drome. Gut 42, 845–849.
Gaman, A., and Kuo, B. (2008).
Neuromodulatory processes of the
brain-gut axis. Neuromodulation 11,
249–259.
Garvin, B., and Wiley, J. W. (2008). The
role of serotonin in irritable bowel
syndrome: implications for manage-
ment. Curr. Gastroenterol. Rep. 10,
363–368.
Gershon, M. D., and Tack, J. (2007).
The serotonin signaling system:
from basic understanding to drug
development for functional GI
disorders. Gastroenterology 132,
397–414.
Greco, B., Allegretto, E. A., Tetel, M. J.,
and Blaustein, J. D. (2001). Coex-
pression of ER beta with ER alpha
and progestin receptor proteins in
the female rat forebrain: effects of
estradiol treatment. Endocrinology
142, 5172–5181.
Greenwood-Van, M. B., Gibson, M.,
Gunter, W., Shepard, J., Foreman,
R., and Myers, D. (2001). Stereo-
taxic delivery of corticosterone to
the amygdala modulates colonic
sensitivity in rats. Brain Res. 893,
135–142.
Gros, D. F., Antony, M. M., McCabe, R.
E., and Swinson, R. P. (2009). Fre-
quency and severity of the symp-
toms of irritable bowel syndrome
across the anxiety disorders and
depression. J. Anxiety Disord. 23,
290–296.
Grover, M., and Drossman, D. A.
(2011). Centrally acting therapies
for irritable bowel syndrome. Gas-
troenterol. Clin. North Am. 40,
183–206.
Grundmann, O., Yoon, S. L., and
Moshiree, B. (2010). Current devel-
opments for the diagnosis and treat-
ment of irritable bowel syndrome.
Curr. Pharm. Des. 16, 3638–3645.
Gue, M., Junien, J. L., and Bueno,
L. (1991). Conditioned emo-
tional response in rats enhances
colonic motility through the central
release of corticotropin-releasing
factor. Gastroenterology 100,
964–970.
Frontiers in Pharmacology | Gastrointestinal Pharmacology July 2012 | Volume 3 | Article 127 | 8
Fichna and Storr Brain-gut interactions in IBS
Gustafsson, J. K., and Greenwood-Van,
M. B. (2011). Amygdala activation
by corticosterone alters visceral and
somatic pain in cycling female rats.
Am. J. Physiol. Gastrointest. Liver
Physiol. 300, G1080–G1085.
Gwee, K. A., Leong, Y. L., Graham, C.,
McKendrick, M. W., Collins, S. M.,
Walters, S. J., Underwood, J. E., and
Read, N. W. (1999). The role of psy-
chological and biological factors in
postinfective gut dysfunction. Gut
44, 400–406.
Hall, G. B., Kamath, M. V., Collins, S.,
Ganguli, S., Spaziani, R., Miranda,
K. L., Bayati, A., and Bienenstock,
J. (2010). Heightened central affec-
tive response to visceral sensa-
tions of pain and discomfort in
IBS. Neurogastroenterol. Motil. 22,
276-e80.
Herman, J. P., Figueiredo, H., Mueller,
N. K., Ulrich-Lai, Y., Ostrander,
M. M., Choi, D. C., and Cullinan,
W. E. (2003). Central mechanisms
of stress integration: hierarchical
circuitry controlling hypothalamo-
pituitary-adrenocortical responsive-
ness. Front. Neuroendocrinol. 24:7.
doi:10.1016/j.yfrne.2003.07.001
Houghton, L. A., Lea, R., Jackson, N.,
and Whorwell, P. J. (2002). The men-
strual cycle affects rectal sensitivity
in patients with irritable bowel syn-
drome but not healthy volunteers.
Gut 50, 471–474.
Hsu, S. Y., and Hsueh, A. J. (2001).
Human stresscopin and stresscopin-
related peptide are selective lig-
ands for the type 2 corticotropin-
releasing hormone receptor. Nat.
Med. 7, 605–611.
Ibeakanma, C., Ochoa-Cortes, F.,
Miranda-Morales, M., McDon-
ald, T., Spreadbury, I., Cenac, N.,
Ibeakanma, C., Ochoa-Cortes, F.,
Miranda-Morales, M., McDonald,
T., Spreadbury, I., Cenac, N., Cat-
taruzza, F., Hurlbut, D., Vanner,
S., Bunnett, N., Vergnolle, N., and
Vanner, S. (2011). Brain-gut interac-
tions increase peripheral nociceptive
signaling in mice with postinfec-
tious irritable bowel syndrome.
Gastroenterology 141, 2098–2108.
Izzo, A. A., and Sharkey, K. A.
(2010). Cannabinoids and the gut:
new developments and emerging
concepts. Pharmacol. Ther. 126,
21–38.
Jarcho, J. M., Chang, L., Berman, M.,
Suyenobu, B., Naliboff, B. D., Lieber-
man, M. D., Ameen, V. Z., Mandelk-
ern, M. A., and Mayer, E. A. (2008).
Neural and psychological predic-
tors of treatment response in irri-
table bowel syndrome patients with
a 5-HT3 receptor antagonist: a pilot
study. Aliment. Pharmacol. Ther. 28,
344–352.
Jarrett, M. E., Burr, R. L., Cain, K.
C., Hertig, V., Weisman, P., and
Heitkemper, M. M. (2003). Anxi-
ety and depression are related to
autonomic nervous system function
in women with irritable bowel syn-
drome. Dig. Dis. Sci. 48, 386–394.
John, C. D., and Buckingham, J.
C. (2003). Cytokines: regulation
of the hypothalamo-pituitary-
adrenocortical axis. Curr. Opin.
Pharmacol. 3, 78–84.
Johnson, A. C., Myers, B., Lazovic,
J., Towner, R., and Greenwood-
Van, M. B. (2010). Brain acti-
vation in response to visceral
stimulation in rats with amyg-
dala implants of corticosterone: an
FMRI study. PLoS ONE 5, e8573.
doi:10.1371/journal.pone.0008573
Kane, S. V., Sable, K., and Hanauer, S.
B. (1998). The menstrual cycle and
its effect on inflammatory bowel dis-
ease and irritable bowel syndrome:
a prevalence study. Am. J. Gastroen-
terol. 93, 1867–1872.
Kennedy, P. J., Clarke, G., Quigley,
E. M., Groeger, J. A., Dinan, T.
G., and Cryan, J. F. (2012). Gut
memories: towards a cognitive neu-
robiology of irritable bowel syn-
drome. Neurosci. Biobehav. Rev. 36,
310–340.
Khasar, S. G., Burkham, J., Dina, O. A.,
Brown, A. S., Bogen, O., Alessandri-
Haber, N., Green, P. G., Reichling, D.
B., and Levine, J. D. (2008). Stress
induces a switch of intracellular sig-
naling in sensory neurons in a model
of generalized pain. J. Neurosci. 28,
5721–5730.
Kilpatrick, L. A., Ornitz, E., Ibrahi-
movic, H., Treanor, M., Craske,
M., Nazarian, M., Kilpatrick, L. A.,
Ornitz, E., Ibrahimovic, H., Treanor,
M., Craske, M., Nazarian, M., Labus,
J. S., Mayer, E. A., and Naliboff, B.
D. (2010). Sex-related differences in
prepulse inhibition of startle in irri-
table bowel syndrome (IBS). Biol.
Psychol. 84, 272–278.
Kirby, L. G., Rice, K. C., and Valentino,
R. J. (2000). Effects of corticotropin-
releasing factor on neuronal activ-
ity in the serotonergic dorsal raphe
nucleus. Neuropsychopharmacology
22, 148–162.
Kostich, W. A., Chen, A., Sperle, K.,
and Largent, B. L. (1998). Mol-
ecular identification and analysis
of a novel human corticotropin-
releasing factor (CRF) receptor:
the CRF2gamma receptor. Mol.
Endocrinol. 12, 1077–1085.
Kozlowski, C. M., Green, A., Grundy,
D., Boissonade, F. M., and Bountra,
C. (2000). The 5-HT(3) receptor
antagonist alosetron inhibits the col-
orectal distention induced depressor
response and spinal c-fos expres-
sion in the anaesthetised rat. Gut 46,
474–480.
Kwan, C. L., Diamant, N. E., Pope,
G., Mikula, K., Mikulis, D. J., and
Davis, K. D. (2005). Abnormal fore-
brain activity in functional bowel
disorder patients with chronic pain.
Neurology 65, 1268–1277.
Labus, J. S., Naliboff, B. N., Fallon,
J., Berman, S. M., Suyenobu, B.,
Bueller, J. A., Mandelkern, M., and
Mayer, E. A. (2008). Sex differences
in brain activity during aversive vis-
ceral stimulation and its expectation
in patients with chronic abdominal
pain: a network analysis. Neuroimage
41, 1032–1043.
Lackner, J. M., Lou, C. M., Mertz, H. R.,
Wack, D. S., Katz,L. A., Krasner, S. S.,
Firth, R., Mahl, T. C.,and Lockwood,
A. H. (2006). Cognitive therapy for
irritable bowel syndrome is associ-
ated with reduced limbic activity, GI
symptoms, and anxiety. Behav. Res.
Ther. 44, 621–638.
Larauche, M., Mulak, A., and Tache, Y.
(2012). Stress and visceral pain: from
animal models to clinical therapies.
Exp. Neurol. 233, 49–67.
Lawal, A., Kern, M., Sidhu, H., Hof-
mann, C., and Shaker, R. (2006).
Novel evidence for hypersensitivity
of visceral sensory neural cir-
cuitry in irritable bowel syndrome
patients. Gastroenterology 130,
26–33.
Lee, S. Y., Kim, J. H., Sung, I. K., Park,
H. S., Jin, C. J., Choe, W. H., Kwon,
S. Y., Lee, C. H., and Choi, K. W.
(2007). Irritable bowel syndrome is
more common in women regardless
of the menstrual phase: a Rome II-
based survey. J. Korean Med. Sci. 22,
851–854.
Lembo, T., Plourde, V., Shui, Z.,
Fullerton, S., Mertz, H., Tache,
Y., Sytnik, B., Munakata, J., and
Mayer, E. (1996). Effects of the
corticotropin-releasing factor (CRF)
on rectal afferent nerves in humans.
Neurogastroenterol. Motil. 8,
9–18.
Lewis, K., Li, C., Perrin, M. H.,
Blount, A., Kunitake, K., Donald-
son, C., Vaughan, J., Reyes, T. M.,
Gulyas, J., Fischer, W., Bilezikjian,
L., Rivier, J., Sawchenko, P. E.,
and Vale, W. W. (2001). Identifi-
cation of urocortin III, an addi-
tional member of the corticotropin-
releasing factor (CRF) family with
high affinity for the CRF2 recep-
tor. Proc. Natl. Acad. Sci. U.S.A. 98,
7570–7575.
Lindstrom, E., Ravnefjord, A., Brus-
berg, M., Hjorth, S., Larsson, H.,
and Martinez, V. (2009). The
selective 5-hydroxytryptamine
1A antagonist, AZD7371 [3(R)-
(N,N-dicyclobutylamino)-8-fluoro-
3,4-dihydro-2H-1-benzopyran-
5-carboxamide (R,R)-tartrate
monohydrate] (robalzotan tartrate
monohydrate), inhibits visceral
pain-related visceromotor, but
not autonomic cardiovascular,
responses to colorectal distension in
rats. J. Pharmacol. Exp. Ther. 329,
1048–1055.
Lowry, C. A., and Moore, F. L.
(2006). Regulation of behavioral
responses by corticotropin-releasing
factor. Gen. Comp. Endocrinol. 146,
19–27.
Lukkes, J. L., Forster, G. L., Renner,
K. J., and Summers, C. H. (2008).
Corticotropin-releasing factor 1 and
2 receptors in the dorsal raphe dif-
ferentially affect serotonin release
in the nucleus accumbens. Eur. J.
Pharmacol. 578, 185–193.
Mach, T. (2004). The brain-gut axis
in irritable bowel syndrome clin-
ical aspects. Med. Sci. Monit. 10,
RA125–RA131.
Manini, M. L., Camilleri, M., Gold-
berg, M., Sweetser, S., McKinzie, S.,
Burton, D., Wong, S., Kitt, M. M.,
Li, Y. P., and Zinsmeister, A. R.
(2010). Effects of Velusetrag (TD-
5108) on gastrointestinal transit and
bowel function in health and phar-
macokinetics in health and constipa-
tion. Neurogastroenterol. Motil. 22,
42–48.
Martinez, V., and Tache, Y. (2006).
CRF1 receptors as a therapeu-
tic target for irritable bowel syn-
drome. Curr. Pharm. Des. 12,
4071–4088.
Martinez, V., Wang, L., Rivier, J., Grigo-
riadis, D., and Tache, Y. (2004).
Central CRF, urocortins and stress
increase colonic transit via CRF1
receptors while activation of CRF2
receptors delays gastric transit in
mice. J. Physiol. (Lond.) 556(Pt 1),
221–234.
Mayer, E. A., and Collins, S. M.
(2002). Evolving pathophysiologic
models of functional gastrointesti-
nal disorders. Gastroenterology 122,
2032–2048.
Mayer, E. A., Naliboff, B., Lee, O.,
Munakata, J., and Chang, L. (1999).
Review article: gender-related
differences in functional gas-
trointestinal disorders. Aliment.
Pharmacol. Ther. 13(Suppl. 2),
65–69.
Mayer, E. A., Naliboff, B. D., and Craig,
A. D. (2006). Neuroimaging of the
www.frontiersin.org July 2012 | Volume 3 | Article 127 | 9
Fichna and Storr Brain-gut interactions in IBS
brain-gut axis: from basic under-
standing to treatment of functional
GI disorders. Gastroenterology 131,
1925–1942.
McEwen, B. S. (2007). Physiol-
ogy and neurobiology of stress
and adaptation: central role
of the brain. Physiol. Rev. 87,
873–904.
McKernan, D. P., Gaszner, G., Quigley,
E. M., Cryan, J. F., and Dinan,
T. G. (2011). Altered peripheral
toll-like receptor responses in
the irritable bowel syndrome.
Aliment. Pharmacol. Ther. 33,
1045–1052.
McKernan, D. P., Nolan, A., Brint, E.
K., O’Mahony, S. M., Hyland, N.
P., Cryan, J. F., and Dinan, T. G.
(2009). Toll-like receptor mRNA
expression is selectively increased in
the colonic mucosa of two animal
models relevant to irritable bowel
syndrome. PLoS ONE 4, e8226.
doi:10.1371/journal.pone.0008226
Mertz, H., Morgan, V., Tanner, G., Pick-
ens, D., Price, R., Shyr, Y., and
Kessler, R. (2000). Regional cere-
bral activation in irritable bowel
syndrome and control subjects
with painful and nonpainful rec-
tal distention. Gastroenterology 118,
842–848.
Meuser, T., Pietruck, C., Gabriel,
A., Xie, G. X., Lim, K. J., and
Pierce, P. P. (2002). 5-HT7 recep-
tors are involved in mediating 5-
HT-induced activation of rat pri-
mary afferent neurons. Life Sci. 71,
2279–2289.
Million, M., Grigoriadis, D. E., Sulli-
van, S., Crowe, P. D., McRoberts, J.
A., Zhou, H., Saunders, P. R., Mail-
lot, C., Mayer, E. A., and Taché, Y.
(2003). A novel water-soluble selec-
tive CRF1 receptor antagonist, NBI
35965, blunts stress-induced vis-
ceral hyperalgesia and colonic motor
function in rats. Brain Res. 985,
32–42.
Milner, T. A., Lubbers, L. S., Alves, S. E.,
and McEwen, B. S. (2008). Nuclear
and extranuclear estrogen binding
sites in the rat forebrain and auto-
nomic medullary areas. Endocrinol-
ogy 149, 3306–3312.
Moreau, J. L., Kilpatrick, G., and
Jenck, F. (1997). Urocortin, a novel
neuropeptide with anxiogenic-
like properties. Neuroreport 8,
1697–1701.
Morin, S. M., Ling, N., Liu, X. J., Kahl,
S. D., and Gehlert, D. R. (1999). Dif-
ferential distribution of urocortin-
and corticotropin-releasing
factor-like immunoreactivities
in the rat brain. Neuroscience 92,
281–291.
Mulak, A., and Bonaz, B. (2004). Irri-
table bowel syndrome: a model of
the brain-gut interactions. Med. Sci.
Monit. 10, RA55–RA62.
Mulak, A., and Paradowski, L.
(2006). Effect of 5-HT1 agonist
(sumatriptan) on anorectal func-
tion in irritable bowel syndrome
patients. World J. Gastroenterol. 12,
1591–1596.
Myers, B., and Greenwood-Van, M.
B. (2007). Corticosteroid receptor-
mediated mechanisms in the amyg-
dala regulate anxiety and colonic
sensitivity. Am. J. Physiol. Gastroin-
test. Liver Physiol. 292, G1622–
G1629.
Myers, B., and Greenwood-Van, M.
B. (2009). Role of anxiety in
the pathophysiology of irritable
bowel syndrome: importance of
the amygdala. Front. Neurosci. 3:47.
doi:10.3389/neuro.21.002.2009
Myers, B., and Greenwood-Van, M.
B. (2010). Elevated corticosterone
in the amygdala leads to persis-
tent increases in anxiety-like behav-
ior and pain sensitivity. Behav. Brain
Res. 214, 465–469.
Myers, B., Schulkin, J., and Greenwood-
Van, M. B. (2011). Sex steroids
localized to the amygdala increase
pain responses to visceral stim-
ulation in rats. J. Pain. 12,
486–494.
Naliboff, B. D., Berman, S., Chang,
L., Derbyshire, S. W., Suyenobu,
B., Vogt, B. A., Mandelkern, M.,
and Mayer, E. A. (2003). Sex-
related differences in IBS patients:
central processing of visceral
stimuli. Gastroenterology 124,
1738–1747.
Naliboff, B. D., Derbyshire, S. W.,
Munakata, J., Berman, S., Mandelk-
ern, M., Chang, L., and Mayer, E.
A. (2001). Cerebral activation in
patients with irritable bowel syn-
drome and control subjects dur-
ing rectosigmoid stimulation. Psy-
chosom. Med. 63, 365–375.
Niddam, D. M., Tsai, S. Y., Lu,
C. L., Ko, C. W., and Hsieh, J.
C. (2011). Reduced hippocampal
glutamate-glutamine levels in irri-
table bowel syndrome: preliminary
findings using magnetic resonance
spectroscopy. Am. J. Gastroenterol.
106, 1503–1511.
Ohman, L., and Simren, M. (2010).
Pathogenesis of IBS: role of
inflammation, immunity and
neuroimmune interactions. Nat.
Rev. Gastroenterol. Hepatol. 7,
163–173.
O’Mahony, S. M., Bulmer, D. C., Coelho,
A. M., Fitzgerald, P., Bongiovanni,
C., Lee, K., Winchester, W., Dinan,
T. G., and Cryan, J. F. (2010a). 5-
HT(2B) receptors modulate visceral
hypersensitivity in a stress-sensitive
animal model of brain-gut axis dys-
function. Neurogastroenterol. Motil.
22, 573–578, e124.
O’Mahony, S. M., Bulmer, D. C., Coelho,
A. M., Fitzgerald, P., Bongiovanni,
C., Lee, K., Winchester, W., Dinan,
T. G., and Cryan, J. F. (2010b). 5-
HT(2B) receptors modulate visceral
hypersensitivity in a stress-sensitive
animal model of brain-gut axis dys-
function. Neurogastroenterol. Motil.
22, 573–578, e124.
O’Mahony, S. M., Hyland, N. P., Dinan,
T. G., and Cryan, J. F. (2011).
Maternal separation as a model
of brain-gut axis dysfunction.
Psychopharmacology (Berl.) 214,
71–88.
Owens, M. J., and Nemeroff, C. B.
(1993). The role of corticotropin-
releasing factor in the pathophys-
iology of affective and anxiety
disorders: laboratory and clinical
studies. Ciba Found. Symp. 172,
296–308.
Pandey, S. C., Zhang, H., Roy, A.,
and Misra, K. (2006). Central and
medial amygdaloid brain-derived
neurotrophic factor signaling plays a
critical role in alcohol-drinking and
anxiety-like behaviors. J. Neurosci.
26, 8320–8331.
Penalva, R. G., Flachskamm, C., Zim-
mermann, S., Wurst, W., Holsboer,
F., Reul, J. M., and Linthorst,
A. C. (2002). Corticotropin-
releasing hormone receptor type
1-deficiency enhances hippocampal
serotonergic neurotransmission:
an in vivo microdialysis study in
mutant mice. Neuroscience 109,
253–266.
Philpott, H., Gibson, P., and Thien, F.
(2011). Irritable bowel syndrome
an inflammatory disease involving
mast cells. Asia Pac. Allergy 1,
36–42.
Piche, M., Bouin, M., Arsenault, M.,
Poitras, P., and Rainville, P. (2011).
Decreased pain inhibition in irri-
table bowel syndrome depends on
altered descending modulation and
higher-order brain processes. Neuro-
science 195, 166–175.
Prado, W. A., and Roberts, M. H. (1985).
An assessment of the antinociceptive
and aversive effects of stimulating
identified sites in the rat brain. Brain
Res. 340, 219–228.
Price, M. L., Curtis, A. L., Kirby, L.
G., Valentino, R. J., and Lucki,
I. (1998). Effects of corticotropin-
releasing factor on brain serotoner-
gic activity. Neuropsychopharmacol-
ogy 18, 492–502.
Rapps, N., van Oudenhove, L., Enck,
P., and Aziz, Q. (2008). Brain
imaging of visceral functions
in healthy volunteers and IBS
patients. J. Psychosom. Res. 64,
599–604.
Redgate, E. S., and Fahringer, E. E.
(1973). A comparison of the pitu-
itary adrenal activity elicited by elec-
trical stimulation of preoptic, amyg-
daloid and hypothalamic sites in
the rat brain. Neuroendocrinology 12,
334–343.
Ren, T. H., Wu, J., Yew, D., Ziea, E., Lao,
L., Leung, W. K., Berman, B., Hu,
P. J., and Sung, J. J. (2007). Effects
of neonatal maternal separation on
neurochemicaland sensory response
to colonic distension in a rat model
of irritable bowel syndrome. Am. J.
Physiol. Gastrointest. Liver Physiol.
292, G849–G856.
Reyes, T. M., Lewis, K., Perrin, M. H.,
Kunitake, K. S.,Vaughan, J., Arias, C.
A., Hogenesch, J. B., Gulyas, J., Riv-
ier, J., Vale, W. W., and Sawchenko,
P. E. (2001). Urocortin II: a mem-
ber of the corticotropin-releasing
factor (CRF) neuropeptide family
that is selectively bound by type 2
CRF receptors. Proc. Natl. Acad. Sci.
U.S.A. 98, 2843–2848.
Ribeiro, S. C., Kennedy, S. E., Smith,
Y. R., Stohler, C. S., and Zubi-
eta, J. K. (2005). Interface of
physical and emotional stress reg-
ulation through the endogenous
opioid system and mu-opioid
receptors. Prog. Neuropsy-
chopharmacol. Biol. Psychiatry 29,
1264–1280.
Ringel,Y. (2002). Brain research in func-
tional gastrointestinal disorders. J.
Clin. Gastroenterol. 35(1 Suppl.),
S23–S25.
Ringel, Y., Drossman, D. A., Leserman,
J. L., Suyenobu, B. Y., Wilber, K.,
Lin, W., Whitehead, W. E., Naliboff,
B. D., Berman, S., and Mayer, E.
A. (2008). Effect of abuse history
on pain reports and brain responses
to aversive visceral stimulation: an
FMRI study. Gastroenterology 134,
396–404.
Rosas-Ballina, M., and Tracey, K.
J. (2009). The neurology of the
immune system: neural reflexes
regulate immunity. Neuron 64,
28–32.
Sagami, Y., Shimada, Y., Tayama, J.,
Nomura, T., Satake, M., Endo, Y.,
Shoji, T., Karahashi, K., Hongo, M.,
and Fukudo, S. (2004). Effect of
a corticotropin releasing hormone
receptor antagonist on colonic sen-
sory and motor function in patients
with irritable bowel syndrome. Gut
53, 958–964.
Frontiers in Pharmacology | Gastrointestinal Pharmacology July 2012 | Volume 3 | Article 127 | 10
Fichna and Storr Brain-gut interactions in IBS
Saito, K., Kanazawa, M., and Fukudo,
S. (2002). Colorectal distention
induces hippocampal noradrenaline
release in rats: an in vivo microdial-
ysis study. Brain Res. 947, 146–149.
Salari, P., and Abdollahi, M. (2011).
Systematic review of modulators of
benzodiazepine receptors in irri-
table bowel syndrome: is there
hope? World J. Gastroenterol. 17,
4251–4257.
Sandler, R. S., Everhart, J. E., Donowitz,
M., Adams, E., Cronin, K., Good-
man, C., Gemmen, E., Shah, S.,
Avdic, A., and Rubin, R. (2002). The
burden of selected digestive diseases
in the United States. Gastroe nterol-
ogy 122, 1500–1511.
Saunders, P. R., Maillot, C., Million,
M., and Tache, Y. (2002). Periph-
eral corticotropin-releasing factor
induces diarrhea in rats: role of
CRF1 receptor in fecal watery
excretion. Eur. J. Pharmacol. 435,
231–235.
Seminowicz, D. A., Labus, J. S., Bueller,
J. A., Tillisch, K., Naliboff, B. D.,
Bushnell, M. C., and Mayer, E. A.
(2010). Regional gray matter density
changes in brains of patients with
irritable bowel syndrome. Gastroen-
terology 139, 48–57.
Shepard, J. D.,Barron, K. W., and Myers,
D. A. (2003). Stereotaxic localization
of corticosterone to the amygdala
enhances hypothalamo-pituitary-
adrenal responses to behavioral
stress. Brain Res. 963, 203–213.
Sivarao, D. V., Newberry, K., and
Lodge, N. J. (2004). Effect of the
5HT1A receptor partial agonist bus-
pirone on colorectal distension-
induced pseudoaffective and behav-
ioral responses in the female Wis-
tar rat. Eur. J. Pharmacol. 494,
23–29.
Slack, S. E., Pezet, S., McMahon, S.
B., Thompson, S. W., and Mal-
cangio, M. (2004). Brain-derived
neurotrophic factor induces NMDA
receptor subunit one phosphoryla-
tion via ERK and PKC in the rat
spinal cord. Eur. J. Neurosci. 20,
1769–1778.
Slawecki, C. J., Somes, C., Rivier, J. E.,
and Ehlers, C. L. (1999). Neurophys-
iological effects of intracerebroven-
tricular administration of urocortin.
Peptides 20, 211–218.
Smith, G. W., Aubry, J. M., Dellu, F.,
Contarino, A., Bilezikjian, L. M.,
Gold, L. H., Chen, R., Marchuk,
Y., Hauser, C., Bentley, C. A.,
Sawchenko, P. E., Koob, G. F.,
Vale, W., and Lee, K. F. (1998).
Corticotropin releasing factor
receptor 1-deficient mice display
decreased anxiety, impaired stress
response, and aberrant neuroen-
docrine development. Neuron 20,
1093–1102.
Southwick, S. M., Bremner, J. D., Ras-
musson, A., Morgan, C. A. III,
Arnsten, A., and Charney, D. S.
(1999). Role of norepinephrine in
the pathophysiology and treatment
of posttraumatic stress disorder.
Biol. Psychiatry 46, 1192–1204.
Spaziani, R., Bayati, A., Redmond, K.,
Bajaj, H., Mazzadi, S., Bienenstock,
J., Collins, S. M., and Kamath, M. V.
(2008).Vagal dysfunction in irritable
bowel syndrome assessed by rectal
distension and baroreceptor sensi-
tivity. Neurogastroenterol. Motil. 20,
336–342.
Spiller, R. (2007). Recent advances in
understanding the role of serotonin
in gastrointestinal motility in func-
tional bowel disorders: alterations in
5-HT signalling and metabolism in
human disease. Neurogastroenterol.
Motil. 19(Suppl. 2), 25–31.
Spiller, R., and Garsed, K. (2009). Infec-
tion, inflammation, and the irritable
bowel syndrome. Dig. Liver D is. 41,
844–849.
Sweetser, S., Camilleri, M., Linker Nord,
S. J., Burton, D. D., Castenada, L.,
Croop, R., Tong, G., Dockens, R.,and
Zinsmeister, A. R. (2009). Do cor-
ticotropin releasing factor-1 recep-
tors influence colonic transit and
bowel function in women with irri-
table bowel syndrome? Am. J. Phys-
iol. Gastrointest. Liver Physiol. 296,
G1299–G1306.
Tache, Y., and Brunnhuber, S. (2008).
From Hans Selye’s discovery of
biological stress to the identifica-
tion of corticotropin-releasing fac-
tor signaling pathways: implication
in stress-related functional bowel
diseases. Ann. N. Y. Acad. Sci. 1148,
29–41.
Tache, Y., Kiank, C., and Sten-
gel, A. (2009). A role for
corticotropin-releasing factor
in functional gastrointestinal disor-
ders. Curr. Gastroenterol. Rep. 11,
270–277.
Tache, Y., Martinez, V., Million, M.,
and Maillot, C. (2002). Role of cor-
ticotropin releasing factor receptor
subtype 1 in stress-related functional
colonic alterations: implications in
irritable bowel syndrome. Eur. J.
Surg. 168 (Suppl. 1), 16–22.
Tache, Y., Martinez, V., Wang, L.,
and Million, M. (2004). CRF1
receptor signaling pathways are
involved in stress-related alterations
of colonic function and viscerosen-
sitivity: implications for irritable
bowel syndrome. Br. J. Pharmacol.
141, 1321–1330.
Tack, J., Broekaert, D., Fischler, B., van
Oudenhove, L., Gevers, A. M., and
Janssens, J. (2006). A controlled
crossover study of the selective sero-
tonin reuptake inhibitor citalopram
in irritable bowel syndrome. Gut 55,
1095–1103.
Tack, J., Coulie, B., Wilmer, A., Andri-
oli, A., and Janssens, J. (2000). Influ-
ence of sumatriptan on gastric fun-
dus tone and on the perception of
gastric distension in man. Gut 46,
468–473.
Takeuchi, O., and Akira, S. (2010).
Pattern recognition receptors
and inflammation. Cell 140,
805–820.
Thompson, W. G., Heaton, K. W.,
Smyth, G. T., and Smyth, C.
(2000). Irritable bowel syndrome in
general practice: prevalence, char-
acteristics, and referral. Gut 46,
78–82.
Tillisch, K., Labus, J., Nam, B., Bueller,
J., Smith, S., Suyenobu, B., Sif-
fert, J., McKelvy, J., Naliboff, B.,
and Mayer, E. (2012). Neurokinin-1-
receptor antagonism decreases anx-
iety and emotional arousal circuit
response to noxious visceral disten-
sion in women with irritable bowel
syndrome: a pilot study. Aliment.
Pharmacol. Ther. 35, 360–367.
Tillisch, K., Mayer, E. A., and Labus, J. S.
(2011). Quantitative meta-analysis
identifies brain regions activated
during rectal distension in irritable
bowel syndrome. Gastroenterology
140, 91–100.
Tillisch, K., Mayer, E. A., Labus, J. S.,
Stains, J., Chang, L., and Naliboff, B.
D. (2005). Sex specific alterations in
autonomic function among patients
with irritable bowel syndrome. Gut
54, 1396–1401.
Tjong, Y. W., Ip, S. P., Lao, L.,
Wu, J., Fong, H. H., Sung, J. J.,
Berman, B., and Che, C. T. (2010).
Neonatal maternal separation ele-
vates thalamic corticotrophin releas-
ing factor type 1 receptor expres-
sion response to colonic distension
in rat. Neuro Endocrinol. Lett. 31,
215–220.
Toner, B. B., Segal, Z. V., Emmott,
S., Myran, D., Ali, A., DiGas-
barro, I., and Stuckless, N. (1998).
Cognitive-behavioral group therapy
for patients with irritable bowel syn-
drome. Int. J. Group Psychother. 48,
215–243.
Trimble, N., Johnson, A. C., Foster,
A., and Greenwood-Van, M. B.
(2007). Corticotropin-releasing fac-
tor receptor 1-deficient mice show
decreased anxiety and colonic sensi-
tivity. Neurogastroenterol. Motil. 19,
754–760.
Tyler, K., Moriceau, S., Sullivan, R.
M., and Greenwood-Van, M. B.
(2007). Long-term colonic hyper-
sensitivity in adult rats induced
by neonatal unpredictable vs pre-
dictable shock. Neurogastroenterol.
Motil. 19, 761–768.
Vale, W., Spiess, J., Rivier, C., and Riv-
ier, J. (1981). Characterization of a
41-residue ovine hypothalamic pep-
tide that stimulates secretion of cor-
ticotropin and beta-endorphin. Sci-
ence 213, 1394–1397.
Valentino, R. J., and Commons, K. G.
(2005). Peptides that fine-tune the
serotonin system. Neuropeptides 39,
1–8.
Vanhoenacker, P., Haegeman, G., and
Leysen, J. E. (2000). 5-HT7 recep-
tors: current knowledge and future
prospects. Trends Pharmacol. Sci. 21,
70–77.
Venkova, K., Johnson, A. C., Myers,
B., and Greenwood-Van, M. B.
(2010). Exposure of the amyg-
dala to elevated levels of corti-
costerone alters colonic motility
in response to acute psychologi-
cal stress. Neuropharmacology 58,
1161–1167.
Vera-Portocarrero, L. P., Ossipov, M.
H., King, T., and Porreca, F.
(2008). Reversal of inflammatory
and noninflammatory visceral pain
by central or peripheral actions of
sumatriptan. Gastroenterology 135,
1369–1378.
Vetter, D. E., Li, C., Zhao, L., Con-
tarino, A., Liberman, M. C., Smith,
G. W., Marchuk, Y., Koob, G. F.,
Heinemann, S. F., Vale, W., and
Lee,K. F. (2002). Urocortin-deficient
mice show hearing impairment and
increased anxiety-like behavior. Nat.
Genet. 31, 363–369.
Videlock, E. J., Adeyemo, M., Licudine,
A., Hirano, M., Ohning, G., Mayer,
M., Mayer, E. A., and Chang, L.
(2009). Childhood trauma is asso-
ciated with hypothalamic-pituitary-
adrenal axis responsiveness in irrita-
ble bowel syndrome. Gastroenterol-
ogy 137, 1954–1962.
Wilder-Smith, C. H., Schindler, D.,
Lovblad, K., Redmond, S. M., and
Nirkko, A. (2004). Brain functional
magnetic resonance imaging of rec-
tal pain and activation of endoge-
nous inhibitory mechanisms in irri-
table bowel syndrome patient sub-
groups and healthy controls. Gut 53,
1595–1601.
Winston, J. H., Xu, G. Y., and Sarna,
S. K. (2010). Adrenergic stimula-
tion mediates visceral hypersensitiv-
ity to colorectal distension following
heterotypic chronic stress. Gastroen-
terology 138, 294–304.
www.frontiersin.org July 2012 | Volume 3 | Article 127 | 11
Fichna and Storr Brain-gut interactions in IBS
Yu, Y. B., Zuo, X. L., Zhao, Q. J.,
Chen, F. X., Yang, J., Dong, Y.
Y., Wang, P., and Li, Y.-Q. (2012).
Brain-derived neurotrophic factor
contributes to abdominal pain in
irritable bowel syndrome. Gut 61,
685–694.
Zisterer, D. M., and Williams, D.
C. (1997). Peripheral-type benzodi-
azepine receptors. Gen. Pharmacol.
29, 305–314.
Zou, B. C., Dong, L., Wang, Y.,
Wang, S. H., and Cao, M. B.
(2007). Expression and role of 5-
HT7 receptor in brain and intes-
tine in rats with irritable bowel
syndrome. Chin. Med. J. 120,
2069–2074.
Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any
commercial or financial relationships
that could be construed as a potential
conflict of interest.
Received: 16 March 2012; pape r pend-
ing published: 28 April 2012; accepted: 15
June 2012; published online: 05 July 2012.
Citation: Fichna J and Storr MA
(2012) Brain-gut interactions in
IBS. Front. P harmacol. 3:127. doi:
10.3389/fphar.2012.00127
This article was submitted to Frontiers
in Gastrointestinal Pharmacology, a spe-
cialty of Frontiers in Pharmacology.
Copyright © 2012 Fichna and Storr. This
is an open-access article distributed under
the terms of the Creative Commons Attri-
bution Non Commercial License, which
permits non-commercial use, distribu-
tion, and reproduction in other forums,
provided the original authors and source
are credited.
Frontiers in Pharmacology | Gastrointestinal Pharmacology July 2012 | Volume 3 | Article 127 | 12
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Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders. Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples. Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls. These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.
Conference Paper
Background-Corticotropin-releasing hormone (CRH) plays a key role in modulating intestinal motility in stressed animals. Aims-To evaluate the effect of CRH on intestinal motility in humans and to determine whether patients with irritable bowel syndrome (IBS) have an exaggerated response to CRH. Subjects-Ten IBS patients diagnosed by Rome criteria and 10 healthy controls. Methods-CRH (2 mu g/kg) was intravenously administered during duodenal and colonic manometry and plasma adrenocorticotropic hormone (ACTH) was measured by radioimmunoassay. Results-CRH induced motility of the descending colon in both groups (p<0.001) and induced greater motility indexes in IBS patients than in controls (p<0.05). CRH produced duodenal phase III motor Methods activity in 80% of the subjects and duodenal dysmotility in 40% of IBS patients. Abdominal symptoms evoked by CRH in IBS patients lasted significantly longer than those in controls (p<0.05). CRH induced significant increases in plasma ACTH levels in both groups (p<0.001) and produced significantly higher plasma ACTH levels in IBS patients than in controls (p<0.001). Conclusion-Human intestinal motility is probably modulated by exogenous CRH. The brain-gut in IBS patients may have an exaggerated response to CRH.