THEMES
Stress and the Gastrointestinal Tract
V. Stress
and irritable bowel syndrome
Emeran A.
Mayer,
Bruce D.
Naliboff,
Lin
Chang, and
Santosh V.
Coutinho
UCLA/CURE Neuroenteric Disease Program, Departments of Medicine,
Physiology, and Biobehavioral Sciences, UCLA School of Medicine, Los
Angeles, California 90024
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ABSTRACT |
Different types of stress play important roles in the
onset and modulation of irritable bowel syndrome (IBS) symptoms. The physiological effects of psychological and physical stressors on gut
function and brain-gut interactions are mediated by outputs of the
emotional motor system in terms of autonomic, neuroendocrine, attentional, and pain modulatory responses. IBS patients show an
enhanced responsiveness of this system manifesting in altered modulation of gastrointestinal motility and secretion and in
alterations in the perception of visceral events. Functional brain
imaging techniques are beginning to identify brain circuits involved in the perceptual alterations. Animal models have recently been proposed that mimic key features of the human syndrome.
corticotropin-releasing factor; emotional motor system; visceral
pain; hypothalamic-pituitary-adrenal axis; functional brain imaging; animal models
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INTRODUCTION |
A VARIETY OF STRESSOR TYPES play a
role in the development of irritable bowel syndrome (IBS). Stress,
defined as an acute threat to the homeostasis of an organism, real
(physical) or perceived (psychological) and posed by events in the
outside world or from within, evokes adaptive responses that serve to
defend the stability of the internal environment and to ensure the
survival of the organism. Numerous reports in the literature provide
evidence for a prominent role of stress in the pathophysiology
(38) and clinical presentation of IBS symptoms (Refs.
23, 24, 27 and detailed
references therein). A model that summarizes the possible role of
different types of stressors in the development and modulation of IBS
symptoms is shown in Fig. 1. According to this model, different types of stressors play a role in 1)
permanent enhancement of stress responsiveness (pathological stress),
2) transient symptom exacerbation, and 3) symptom
perpetuation (symptom-generated stress). Early life stress and trauma,
in the form of abuse, neglect, or loss of the primary caregiver, play a
major role in the vulnerability of individuals to develop functional
gastrointestinal (GI) disorders later in life. Acute, life-threatening
stress episodes in adult life (rape, posttraumatic stress syndrome) are
also important risk factors in the development of functional GI
disorders. In the genetically predisposed individual, both early life
stress and severe life-threatening stress (referred in this article as "pathological stressors") can result in permanent, irreversible enhancement of the responsiveness of central stress circuits and therefore vulnerability to development of functional (as well as
affective) disorders later in life. Other types of stressors occurring
throughout the life of an individual, which may result only in
transient changes in stress responsiveness, clearly play a role in
symptom exacerbation. For example, psychosocial stressors in the form
of sustained, threatening life events have been associated with onset
and symptom exacerbation in IBS. "Physical" or interoceptive stressors of the digestive system, such as enteric infections, trauma,
and surgery, may play a similar role in symptom exacerbation in the
predisposed individual. Finally, in the affected patient, fear
conditioning and interoceptive conditioning are likely to play
important roles in triggering stress responses to situations and
contexts that by themselves are not threatening or stressful (14). For a large number of IBS patients, the
positive-feedback loop of conditioned fear responses to interoceptive
stimuli or contextually conditioned stimuli of symptom-generated
stressors may play a primary role in symptom chronicity.

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Fig. 1.
Role of stress in development and modulation of irritable bowel
syndrome (IBS) symptoms. Different types of stressors may play a role
in the permanent biasing of stress responsiveness, in transient
activation of the stress response, and in the persistence of
symptoms.
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HOW ARE STRESSORS TRANSLATED INTO INTEGRATIVE PHYSIOLOGICAL
RESPONSES RELEVANT FOR GI FUNCTION? |
The traditional concept of stress has focused on the subjective
conscious feelings, thoughts, beliefs, and memories reported by some
individuals in association with stressful life events. However, the
major breakthroughs in this area have occurred through an understanding
of the biological mechanisms that are responsible for the detrimental
effects of certain stressful life events on health (25).
The organism's response to stress is generated by a network comprised
of integrative brain structures, in particular, subregions of the
hypothalamus (paraventricular nucleus, PVN), amygdala, and
periaqueductal gray. These structures receive input from visceral and
somatic afferents and from cortical structures, in particular, the
ventral subdivision of the anterior cingulate and the medial prefrontal
(ventromedial and orbitofrontal) cortex (3, 42). This
integrative network provides outputs to the pituitary and to
pontomedullary nuclei, which in turn mediate the neuroendocrine and
autonomic output to the body, respectively. This central stress
circuitry is under feedback control via ascending monoaminergic
projections from these brain stem nuclei, in particular, serotonergic
(raphe nuclei) and noradrenergic (NA) (including locus ceruleus)
nuclei, and via circulating glucocorticoids, which exert an inhibitory
control via central glucocorticoid receptors located in the medial
prefrontal cortex and hippocampus (37). The parallel
outputs of this central circuitry ("emotional motor system," EMS),
which is activated in response to various stressors, include responses
of the autonomic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, endogenous pain modulatory systems, and ascending aminergic
pathways. These pathways are summarized in Fig.
2.

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Fig. 2.
Inputs and outputs of the emotional motor system (EMS). Output
pathways of the EMS are activated by psychosocial (exteroceptive) and
physical (interoceptive) stressors. Major outputs to the periphery are
autonomic, pain modulatory, and neuroendocrine responses. An important
output to the forebrain occurs in terms of attentional and emotional
modulation. Feedback from the gut to the EMS occurs in form of
neuroendocrine (epinephrine, cortisol) as well as visceral afferent
mechanisms.
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One important chemical mediator of the central stress response is
corticotropin-releasing factor (CRF) (and probably related currently
unknown molecules) located in certain effector neurons of the PVN, the
amygdala, and the locus ceruleus complex (41). CRF
secretion by PVN neurons is under positive-feedback regulation by
central NA pathways (including those originating from locus ceruleus),
thereby forming a bidirectional positive-feedback loop between the CRF
and NA systems. Central injection of CRF can reproduce behavioral and
physiological responses similar to those seen in response to acute
psychological stress (30, 39), and inhibition of
CRF-mediated responses by antagonists (38, 39) or in
knockout animals results in a decrease in the animals' response to
stress (32, 40).
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ENHANCED RESPONSIVENESS OF CENTRAL STRESS CIRCUITS |
The responsiveness of the EMS is likely to be under partial
genetic control, and it shows considerable plasticity in response to
early life events (22) and to certain types of
pathological stress (15). For example, studies in animals
and humans clearly demonstrated that certain types of pathological
stress can alter the responsiveness of feedback systems by
downregulation of pre- and/or postsynaptic receptors [adrenergic,
serotonergic, glucocorticoid receptors (GC)] and, in the most severe
forms, by structural changes in certain brain regions (reviewed in Ref.
23). Thus pathological stress can not only activate but
also fundamentally change the responsiveness and output of the central
stress circuits. These alterations could affect the individual output
pathways of the EMS differentially and in different directions, for
example, an increase or decrease in target-specific sympathetic and
vagal outputs, up- or downregulation of the HPA axis, and up- or
downregulation of pain perception. Some of the best-characterized
alterations in this central adaptation to pathological stress are an
increase in CRF synthesis and secretion (30), an increase
in the activity and sensitivity of central NA systems (22,
33), and downregulation of GC (31) suggestive of an
enhanced HPA response to stress. In contrast, an upregulation of GC has
been found in animals exposed to "early handling" stress and in
patients with posttraumatic stress disorder (PTSD), which supports an
enhanced negative-feedback control of cortisol and a blunted HPA
response to stress (44). As a consequence of these
alterations in the central stress circuitry, secondary changes in
receptor systems can occur in spinal or peripheral target cells of the
output systems. Thus, in cases of pathological stress resulting in
permanent changes in the central stress circuitry, lifelong changes in
peripheral receptor systems may also be expected. In the following
paragraphs, we discuss evidence for alterations in the three output
systems of the EMS in IBS patients.
Changes in autonomic nervous system responses.
In the most common functional GI disorders, IBS and functional
dyspepsia (FD), persistent alterations of autonomic responsiveness are
likely to play a role in altered bowel habits and alterations in
gastric emptying, respectively. Evidence for such enhanced responsiveness of autonomic responses in IBS (reviewed in Ref. 23) includes increased responses of distal colonic
motility in response to laboratory stress and possibly food intake and delayed gastric emptying in a subset of patients.
A model of IBS, taking into account altered autonomic regulation of
gastric and distal colonic function and based on an upregulation of
CRF-containing neurons in Barrington's nucleus (part of the locus
ceruleus complex), was recently reported by Valentino and co-workers
(41). Although descending CRF-containing projections from
this pontine nucleus to the distal colon may mediate increased stress-
and food-induced motor responses of the distal colon, ascending
projections to the locus ceruleus and to the forebrain may be
responsible for mediating arousal and shifting attention to visceral
afferent stimuli. Increased expression of CRF message and release of
CRF in IBS patients, or a subset of patients, is also consistent with
the reported evidence for certain increased sympathetic responses
(12, 21).
Changes in the frequency of high-amplitude propagated contraction
(HAPC) in the colon, presumably via alteration in vagal colonic
regulation, may play an important role in diarrhea and slow-transit
constipation, thereby determining the predominant bowel habit pattern
in IBS (reviewed in Ref. 23). There is evidence that
decreased cardiovagal tone is present in a subset of patients with IBS,
in particular in female patients with constipation-predominant bowel
habit and more severe symptoms (1, 19). The correlation of
changes in cardiovagal tone and vagal regulation of the intestine is
emphasized by the recent demonstration in patients with functional constipation of parallel changes in cardiovagal tone and autonomic regulation of whole gut transit and distal colonic mucosal blood flow
(11).
Thus, although enhanced sacral parasympathetic modulation of the distal
colon, reflecting enhanced responsiveness of neurons within the locus
ceruleus complex, may be shared by all IBS patients, alterations in
vagal output to the small intestine and proximal colon may be variable,
depending on severity and the predominant bowel habit.
Neuroendocrine changes.
Preliminary evidence for alterations in HPA axis function was
demonstrated in diarrhea-predominant IBS patients who showed decreased
24 h plasma cortisols, blunted cortisol responses, and normal ACTH
responses to noxious rectosigmoid distension (26). In
contrast, Heitkemper et al. (20) reported that urine
cortisol levels obtained immediately on rising were significantly
higher in a subgroup of IBS women compared with control women. Even
though a thorough characterization of HPA axis responses in patients with functional gastrointestinal disorders has not been reported, these
preliminary findings suggest the pattern of sensitized GC feedback also
reported in patients with PTSD, fibromyalgia, and chronic fatigue
syndrome. However, HPA responses at baseline and in response to
provocation in these patients have been conflicting, which may be
caused in part by methodological differences and the presence of
comorbid depression in some patients. There is significant overlap in
the epidemiology of all these conditions with IBS. Other evidence for
central alterations in neuroendocrine responses in IBS comes from
reports of abnormal neuroendocrine challenge tests in this patient
population (8, 17). Existing data support
neuroendocrine alterations in IBS and other overlapping syndromes, but
further well-designed studies are needed to fully characterize these alterations.
Possible relevance of autonomic and neuroendocrine changes for
intestinal immune modulation.
Although it is not known currently whether these HPA axis changes are
an epiphenomenon or play a role in symptom generation and
pathophysiology of these syndromes, one may speculate about their
possible role (in conjunction with alterations in autonomic gut
regulation) in the observed findings in postinfectious IBS patients.
The reported persistence of chronic inflammatory mucosal changes after
eradication of the infectious organism (18) and increased
intestinal permeability and hyperplasia of enterochromaffin cells
(34) are consistent with an inadequate physiological
response to acute gut inflammation, in particular an inadequate
cortisol (and possibly an altered sympathetic) response. Stress-related alterations in cytokine networks, in particular a suppression of
cellular immunity and a shift toward humoral immunity [alteration in T
helper (Th)1/Th2 balance], have been reported (10).
Multiple reports in the literature on increased intestinal mast cell
numbers in IBS patients (29) are consistent with such a
Th2 shift.
Changes in pain modulation.
Evidence suggestive of alterations in stress-induced modulation of
viscerosomatic sensitivity comes from human and animal studies.
IBS patients show cutaneous normo- or hypoalgesia combined with
visceral hypersensitivity (27). A similar pattern was also seen in a recently described rat IBS model in response to an acute psychological stressor (5). Preliminary results from the
use of psychological laboratory stressors in healthy volunteers suggest a stress-induced increase in colonic or rectosigmoid sensitivity to
distension (6). Even though all published human studies are open to methodological criticism, they are consistent with reported
findings in animals of a differential viscerosomatic pain modulation.
It is of interest to note that patients with bulimia (who, in contrast
to IBS patients, have a hyperactive HPA axis) show cutaneous
hypoalgesia as well, which precedes symptom exacerbations
(13).
Changes in regional brain activation.
Functional brain imaging studies of IBS patients have shown decreased
activation of ventral subdivisions of the anterior cingulate cortex
(ACC) and increased activation of the dorsal subdivision (28). Because dorsal ACC is inhibited by intense visceral
stimuli in healthy control subjects (unpublished observations),
increased dorsal ACC activation may be related to alterations in
attentional processes in IBS in regard to visceral sensory events.
Decreased ventral cingulate/medial prefrontal cortex activity was also
reported in patients with depression (9) and PTSD
(33), both affective disorders commonly associated with
IBS. Southwick et al. (33) reported a decrease in
prefrontal and orbitofrontal cortical metabolism in patients with PTSD
in response to the
2-antagonist yohimbine. Together with
results from preclinical studies showing decreased metabolism in
cortical regions with high NA release (33), these results
are consistent with enhanced NA release in these brain regions in PTSD
patients. One may speculate that the decreased activation in ventral
anterior cingulate, ventromedial frontal cortex, and hippocampus seen
in IBS patients may also be related to enhanced NA release from locus
ceruleus projections in response to stress, consistent with the
Valentino model (41). Recent evidence suggests that
regional brain activation in response to visceral stimulation may
differ between male and female IBS patients (4, 7).
Although most brain regions showed similar activity patterns in male
and female patients, differences were seen primarily in the insular and
anterior cingulate cortices.
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ANIMAL MODELS OF IBS |
Although early attempts to model different aspects of IBS in
nonhuman animals have met with only limited success, several animal
models utilizing different pathological interoceptive and exteroceptive
stressors (2) that mimic at least some of the pathophysiological features of IBS are now available. For example, Al-Chaer et al. (2) recently demonstrated that colonic
irritation in neonatal rats results in chronic visceral
hypersensitivity that persists into adulthood even after the
inflammation has resolved. More recently, a single experience of foot
shocks in the adult rat has been shown to cause long-term sensitization
of the cardiovascular response to colonic distension (36).
In the rat, neonatal stress in the form of moderate periods of maternal
separation of newborn rats results in permanent changes in the central
nervous system accompanied by a compromised ability to restrain the
synthesis and release of CRF in response to acute laboratory stressors. These neurochemical changes are associated with enhanced fearfulness, increased HPA responsiveness to stressors, and an increased risk of
developing depression-like behaviors. It was demonstrated recently (5) that maternally separated rats also exhibit permanent
alterations in their stress responsiveness that predispose the adult
animals to the development of visceral hyperalgesia and somatic
hypoalgesia in response to psychological stress. Additionally,
colonic motor function in response to stress is also enhanced in these
animals, thereby mimicking all the main features of IBS. Together with knockout technology, these and other animal models (16, 22, 35,
43) will help to determine which components of the altered stress response are epiphenomena and which play a primary role in pathophysiology.
 |
SUMMARY AND CONCLUSIONS |
In summary, an extensive literature is consistent with an
enhanced stress responsiveness in IBS patients, manifested by predicted autonomic, pain modulatory, and attentional responses and a sensitized GC feedback. This response pattern is associated with changes in brain
activity in limbic regions. The blunting of the HPA axis together with
alterations in sympathetic modulation of immune function may predispose
individuals to develop postinfectious IBS. The fact that up to 40% of
IBS patients show evidence for increased anxiety and the fact that the
changes are similar to those reported in a variety of other so-called
"functional" disorders (e.g., fibromyalgia, chronic fatigue
syndrome, and interstitial cystitis) suggest a model in which
alterations in the central stress circuits in predisposed individuals
are triggered by pathological stressors and play a primary role in pathophysiology.
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ACKNOWLEDGEMENTS |
This work was funded by National Institutes of Health Grants
DK-48351 (E. A. Mayer), NR-04881 (BDN), and AR-46122 (LC).
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FOOTNOTES |
Address for reprint requests and other correspondence:
E. A. Mayer, CURE Neuroenteric Disease Program, UCLA Division of
Digestive Diseases, GLA VA HS, Bldg. 115/CURE, 11301 Wilshire Blvd.
Bldg. 115, Rm. 223, Los Angeles, CA 90073 (E-mail
emayer{at}ucla.edu).
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