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Psychoneuroendocrinology (2011) xxx, xxx—xxx
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y n e u e n
REVIEW
Stress and animal models of inflammatory
bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis
S.O. Reber *
Department of Behavioral and Molecular Neuroendocrinology, University of Regensburg, Universitätsstraße 31,
93053 Regensburg, Germany
Received 11 March 2011; received in revised form 28 April 2011; accepted 26 May 2011
KEYWORDS
Chronic psychosocial
stress;
HPA axis;
Corticosterone;
Colitis;
IBD;
Glucocorticoids;
Colonic barrier function
Summary Chronic psychosocial stress has been repeatedly shown in humans to be a risk factor
for the development of several affective and somatic disorders, including inflammatory bowel
diseases (IBD). There is also a large body of evidence from rodent studies indicating a link between
stress and gastrointestinal dysfunction, resembling IBD in humans. Despite this knowledge, the
detailed underlying neuroendocrine mechanisms are not sufficiently understood. This is due, in
part, to a lack of appropriate animal models, as most commonly used rodent stress paradigms do
not adequately resemble the human situation and/or do not cause the development of spontaneous colitis. Therefore, our knowledge regarding the link between stress and IBD is largely based
on rodent models with low face and predictive validity, investigating the effects of unnatural
stressors on chemically induced colitis. These studies have consistently reported that hypothalamo—pituitary—adrenal (HPA) axis activation during stressor exposure has an ameliorating effect
on the severity of a chemically induced colitis. However, to show the biological importance of this
finding, it needs to be replicated in animal models employing more clinically relevant stressors,
themselves triggering the development of spontaneous colitis.
Important in view of this, recent studies employing chronic/repeated psychosocial stressors
were able to demonstrate that such stressors indeed cause the development of spontaneous
Abbreviations: AA, acetic acid; ACTH, adrenocorticotrope hormone; ADX, adrenalectomy; ANS, autonomic nervous system; AVP, arginine
vasopressin; CD, Crohn’s disease; CD, cluster of differentiation; CRC, colorectal cancer; CRH, corticotrophin releasing hormone; CSC, chronic
subordinate colony housing; d, day/s; DNBS, dinitrobenzene sulphonic acid; DSS, dextran sulphate sodium; ES, electric shock; GC, glucocorticoids; GR, glucocorticoid receptor; h, hour/s; HPA, hypothalamo—pituitary—adrenal axis; IBD, inflammatory bowel disease; IBS, irritable
bowel syndrome; ICV, intracerebroventricular; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LPMC, lamina propria mononuclear cells;
min, minute/s; MPO, myeloperoxidase; MR, mineralocorticoid receptor; mRNA, messenger RNA; MS, maternal separation; n.a., not assessed;
NE, norepinephrine; OC, overcrowding; PND, postnatal day; PRS, partial restraint stress; PVN, paraventricular nucleus; resp., respective; SD,
social defeat; SD/OC, social defeat/overcrowding; SDR, social disruption stress; SNS, sympathetic nervous system; TGF, tumor growth factor;
Th, T helper; TNBS, trinitrobenzene sulphonic acid; TNF, tumor necrosis factor; TLR, toll-like receptor; UC, ulcerative colitis; VEH, vehicle; vs.,
versus; WAS, water avoidance stress; wk, week/s.
* Corresponding author. Tel.: +49 941 943 3050; fax: +49 941 943 3052.
E-mail address: [email protected].
0306-4530/$ — see front matter # 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.psyneuen.2011.05.014
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
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S.O. Reber
colitis and, thus, represent promising tools to uncover the mechanisms underlying stress-induced
development of IBD.
Interestingly, in these models the development of spontaneous colitis was paralleled by
decreased anti-inflammatory glucocorticoid (GC) signaling, whereas adrenalectomy (ADX) prior
to stressor exposure prevented its development. These findings suggest a more complex role of
the HPA axis in the development of spontaneous colitis.
In the present review I summarize the available human and rodent data in order to provide a
comprehensive understanding of the biphasic role of the HPA axis and/or the GC signaling during
stressor exposure in terms of spontaneous colitis development.
# 2011 Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
7.
General introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
IBD in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
Risk factors for IBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
The stress concept. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
Evidence for chronic stress to be a risk factor for IBD in human and non-human primates . . . . . . . . . . . . . . . . . . 000
Rodent data supporting stress to be a risk factor for IBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.1. Rodent models for IBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2. Rodent data supporting (or at least not contradicting) the concept that stress-induced HPA axis activation has
ameliorating effects on experimentally induced or spontaneous colitis (for summary see Table 1) . . . . . . . 000
6.2.1. Stress-induced reactivation of chemically induced colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2.2. Stress-induced aggravation of chemically induced colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2.3. Stress-induced amelioration of chemically induced colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2.4. Stress-induced development of spontaneous colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2.5. Conclusions to be drawn from these studies on the underlying HPA axis-dependent mechanisms . . 000
6.3. Rodent data supporting the concept that stress-induced HPA axis activation has colitis-promoting effects (for
summary see Table 1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.4. HPA axis-independent mechanisms underlying colitis-promoting effects of stress . . . . . . . . . . . . . . . . . . . . 000
Summary (see Fig. 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
1. General introduction
Inflammatory disorders, such as Crohn’s disease (CD) and
ulcerative colitis (UC) represent a major health concern,
particularly in Western societies, with a life-time prevalence
of approximately 0.1% (for review see Singh et al., 2001). In
addition to limiting quality of life due to abdominal cramps
and pain, diarrhea, bloody stools, ulceration, fever, tiredness
and other socially unacceptable symptoms, inflammatory
bowel disorders (IBD) are further linked to an increased risk
for developing inflammation-related colorectal cancer (CRC)
(for review see Yang et al., 2009). Furthermore, early-onset
IBD (i.e. in childhood) has been shown to cause growth
problems and even to delay puberty, as an appropriate
uptake of nutrients is not guarantied during periods of severe
gut inflammation (for review see Mamula et al., 2008).
The pathogenesis of IBD is still not completely understood.
It is generally accepted that IBD has a complex and multifactorial aetiology, involving genetic and environmental factors (for review see Andus and Gross, 2000; MacDonald and
Monteleone, 2005), which are in turn associated with a dysregulation of the mucosal immune system. One environmental
factor that is often discussed in this context during the last
decades is the perceived level of life stress (Salem and Shubair,
1967; Duffy et al., 1991; Bernstein et al., 2010). A similar link
between stress and IBD has been suggested also by a large body
of rodent data (Collins et al., 1996; Gue et al., 1997; Million
et al., 1999; Qiu et al., 1999; Milde and Murison, 2002; Cakir
et al., 2004; Gulpinar et al., 2004; Saunders et al., 2006;
Melgar et al., 2008). However, the face and predictive validity
of most animal models have to be valued with caution, as they
often employ unnatural- and short-term-stressors and investigate their effects on artificially (chemically)-induced colitis.
In contrast relevant human stressors in modern societies that
are discussed as risk factors for the development of several
affective and somatic disorders are mostly chronic and psychosocial in nature (Salem and Shubair, 1967; Duffy et al.,
1991; Kiecolt-Glaser and Glaser, 1995; Kiecolt-Glaser et al.,
1995, 1996, 1998; Agid et al., 1999; Coker et al., 2000;
Herrmann et al., 2000; Buske-Kirschbaum et al., 2001; Heim
and Nemeroff, 2001; Bitton et al., 2003; Wright et al., 2004;
Amat et al., 2005; Post et al., 2005; Heim et al., 2009). It is,
therefore, not surprising that, except from the generally
reported colitis-ameliorating role of HPA axis activation during
stressor exposure, there is a paucity of detailed neuroendocrine mechanisms underlying stress-induced development/
aggravation of IBD. Recent studies employing chronic psychosocial stressors to investigate the aetiology of stress-induced
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
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Stress and animal models of inflammatory bowel disease
spontaneous colitis (Reber et al., 2007, 2008, 2011; Savignac
et al., 2011), which are believed to be more clinically relevant
(for review see Cryan and Slattery, 2007, 2010) have begun to
address this dearth of knowledge. Interestingly, they suggest
that while activation of the HPA axis in the initial phase of
stressor exposure promotes the development of spontaneous
colitis, its activation in the later phases of stressor exposure
can actually be beneficial.
Therefore, the main aim of this review is to summarize
available human and animal data linking stress and spontaneous or chemically induced colitis, and what we can deduce
from these studies about the possible underlying neuroendocrine mechanisms. The focus will be put on the biphasic role
of HPA axis activity and glucocorticoid (GC) signaling during
stressor exposure on chemically induced and/or spontaneous
colitis.
2. IBD in humans
In humans IBD classically includes two distinct disease patterns, UC and CD (for review see Blumberg et al., 1999;
Lichtenstein, 2000; Blumberg and Strober, 2001; Brandtzaeg,
2001; Podolsky, 2002; MacDonald and Monteleone, 2005;
Mawdsley and Rampton, 2006). Briefly, IBD can be classified
as a chronic relapsing inflammatory condition of the intestinal tract and is characterized by mucosal ulceration.
Patients suffer from chronic diarrhea, weight loss, abdominal
pain, fever, and fatigue. Extra-intestinal manifestations can
also occur, including skin ulcers, arthritis, and bile-duct
inflammation, the last especially in UC. On top, patients
suffering from IBD have also an increased risk for developing
inflammation-related CRC (for review see Yang et al., 2009).
Epidemiologic studies showed that approximately 0.1% of the
western population suffer from IBD (Singh et al., 2001) and
that world wide, each year 5—18 out of 100,000 individuals
additionally develop IBD (Yang et al., 2009). The peak incidence of IBD occurs in the third decade of life (Yang et al.,
2009).
The salient features of UC and CD have been recognized
for many years and are in detail described in a number of
excellent review articles (for review see Podolsky, 1991a,b;
Mawdsley and Rampton, 2006). Briefly, inflammation in UC is
confined to the mucosa and superficial submucosa of the
large bowel, with deeper layers of the bowel being not
affected. This is reflected by a dense infiltration of the
lamina propria by neutrophils and lymphocytes which produce extensive amounts of inflammatory mediators, finally
driving development of superficial mucosal ulceration.
In contrast, active disease in CD is characterized by an
infiltration of predominantly macrophages and lymphocytes
into deeper layers of the bowel wall, often resulting in deep
linear or even transmural ulcers. Inflammatory processes can
even extend beyond the gastrointestinal tract, resulting in
the development of fistulas.
Furthermore, mucosal ulceration in UC patients is continuous and restricted to the colon but patchy and possibly
spread through the whole intestinal tract in CD (for review
see MacDonald and Monteleone, 2005). Both UC and CD
patients suffer from diarrhea and weight loss, abdominal
pain, fever, and fatigue (Mawdsley and Rampton, 2006).
Importantly, in UC patients loose stools are slimy and bloody,
3
whereas in excrements from CS patients generally no blood is
detected (Podolsky, 1991a; Fiocchi, 1998).
Substantial progress has been further made in characterizing immune-cell populations and inflammatory mediators in
patients with IBD (for review see Podolsky, 2002; Mawdsley
and Rampton, 2006). Briefly, the mucosa of CD patients is
dominated by CD4+ lymphocytes and a typical and strong T
helper type 1 (Th1) cytokine profile (increased secretion of
tumor necrosis factor (TNF), interleukin (IL)-2, interferon
(IFN)-g, IL-12, IL-18). In contrast, the mucosa in patients with
ulcerative colitis is dominated by CD4+ lymphocytes with an
atypical Th2 phenotype, characterized by the production of
transforming growth factor b (TGF-b) and IL-5. The presence
of auto-antibodies, such as the anti-neutrophil cytoplasmatic
antibody, also is suggestive of a Th2 pathogenesis in UC (for
review see Singh et al., 2001).
Current treatments for IBD consist of TNF antibodies, IL-10
(Dejaco et al., 2000) and IL-11, and substances blocking
specific gut-homing molecules for activated CD4+ Th cells
(antibody against the a4 subunit of the a4b1 and a4b7 integrin
or antisense against intercellular adhesion molecule-1) (for
review see Singh et al., 2001). However, 5-aminosalicylates
and steroids constitute still a cornerstone of medical therapy
in patients with IBD (Dejaco et al., 2006).
3. Risk factors for IBD
IBD has a complex and multi-factorial aetiology, comprising
genetic and environmental factors (for review see Andus and
Gross, 2000; MacDonald and Monteleone, 2005; Mawdsley
and Rampton, 2006). IBD is predominantly associated with
industrialized societies and temperate climates, and is rare
in tropical countries with poor sanitation and a low level of
overcrowding (for review see Elliott et al., 2000). The fact
that migration to developed countries increases the risk for
development of IBD (Probert et al., 1992, 1995) further
supports the hypothesis that genetic factors are not solely
responsible for the disease. Various environmental factors
have been proposed to contribute to the enhanced risk of IBD
in industrialized countries, including nutrition, infections,
smoking status (Tan et al., 1992; Shapira and Tamir, 1994;
Klein et al., 1998; Russel et al., 1998; Neurath and Schurmann, 2000; Khan et al., 2002), and the level of perceived
life stress (Salem and Shubair, 1967; Mitchell and Drossman,
1987; Robertson et al., 1989; Duffy et al., 1991; Levenstein
et al., 1998, 2000; Bitton et al., 2003, 2008). As the latter
finding is of central importance for the present review it will
be outlined in more detail after introducing the reader to the
‘‘stress concept’’ and the adaptive physiological response of
an organism to an acute stressor.
4. The stress concept
In the 19th century the French physiologist Claude Bernard
(1813—1878) noticed that the relative constancy of the
internal environment is critical for the functional integrity
of an organism. Later, Walter Cannon (1871—1945) coined the
term homeostasis for this internal equilibrium and described
the disruption of it by fear- or rage-induced ‘‘fight or flight’’
reactions in his ‘‘emergency concept’’ (Cannon, 1939). In
1936 it was Hans Selye (1907—1982), who first defined stress
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
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and the stress response as ‘‘the non-specific response of the
body to any physical demand’’ (Selye, 1936) and distinguished between ‘‘stress’’ and the ‘‘stressor’’ (Selye,
1975). According to him, stressors are defined as the specific
challenges that cause the physiological stress response
(Selye, 1975). Since then, an overwhelming number of studies have focussed on the physiological, in particular neuroendocrine, and also behavioural consequences of an acute
stress response, which are, in general, well understood
(Sapolsky, 1992; Rabin, 1999; Sapolsky et al., 2000).
It is generally accepted that the physiological and behavioural responses to acute stressors are adaptive and important to reinstate the homeostasis of the body (Sapolsky et al.,
1986b; Dhabhar and McEwen, 1996; McEwen and Seeman,
1999; Dhabhar, 2002; McEwen, 2004). In contrast, repeated
or chronic exposure to stressors over several weeks or months
are thought to result in mal-adaptive alterations of numerous
body and brain systems, which are less well understood partly
due to the lack of appropriate and clinically relevant animal
models.
In response to an acute stressor of any given quality, two
major stress systems become activated, namely the autonomic nervous system (ANS), especially its sympathetic (SNS)
tree, and the hypothalamo—pituitary—adrenocortical (HPA)
axis. Stimulation of these emergency systems reflects the
stress response of the organism with the major aim to
reinstate the homeostasis of the body, a process referred
to as allostasis (for review see Goldstein and Kopin, 2007).
Rapid, within seconds, activation of the SNS via exclusively
neuronal pathways originating in the thoracolumbal regions
of the spinal cord (splanchnic nerve) results in the release of
adrenalin from the chromaffin cells of the adrenal medulla
into the blood. Elevated levels of adrenaline in the circulation act in synergism with an increased sympathetic noradrenergic innervation of essentially all organs in the body (for
more details see Lewis, 1975; for brief summary see review
Bartolomucci, 2007). As a result, cardiovascular and catabolic functions are promoted, and anabolic processes and
digestion, for example, are inhibited.
In contrast to the very fast-acting SNS, induction of endorgan effects elicited by HPA axis activation, which is exclusively driven by hormones, takes longer to develop. The
stimulation of the HPA axis is triggered by the secretion of
corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) from the paraventricular nucleus (PVN) of the
hypothalamus into the portal blood stream of the pituitary
stalk. CRH promotes the synthesis and the secretion of adrenocorticotropic hormone (ACTH) into the peripheral blood,
which, in turn, stimulates the adrenal cortical cells to produce
and secrete glucocorticoids (GC; cortisol in humans, corticosterone in rodents) into the blood. Within minutes, termination
of the acute stress response of the HPA axis is achieved by
efficient negative feedback inhibition via GC acting at glucocorticoid (GR) and mineralocorticoid receptors (MR) at several
brain levels (Reul and de Kloet, 1985). The degree and the time
course of HPA axis activation are, and this is in contrast to what
was proposed by Selye (1975), strongly dependent on the
quality, intensity and duration of the acute stressor (for review
see Koolhaas et al., 2011). For instance, exposure of adult male
Wistar rats to different types of stressors for 15 min elicits
totally different plasma GC responses, most pronounced following social stressors and least pronounced following noise
stress or handling. In line, the group around Dhabhar showed
that 2 h of combined restraint and shaking (severe) stress
resulted in higher plasma corticosterone levels than 2 h of
restraint (moderate) stress alone (Dhabhar and McEwen,
1997). In addition, they showed that in contrast to the immune
stimulatory effects of plasma corticosterone released during
2 h of restraint stress, the repeated release of plasma corticosterone seen during daily 5 h exposures (3—5 weeks) to
restraint stress (Dhabhar and McEwen, 1997) or chronic corticosterone administration (via drinking water) (Dhabhar and
McEwen, 1999) have immunosuppressive effects. Stressinduced HPA axis activation is further dependent on prior
experiences, resulting for instance in adaptation of the HPA
axis response to repeated homotypic stressor exposure (Dhabhar and McEwen, 1997) and sensitisation to a novel heterotypic
stressor (Berton et al., 1999; Chen et al., 2008; Reber et al.,
2008). In addition, the acute neuroendocrine stress response
was shown to be age-dependent (Sapolsky et al., 1986a; Meijer
et al., 2005), altered under various physiological conditions
(e.g. in the peripartum period (Neumann et al., 2000; Torner
and Neumann, 2002; Torner et al., 2002)), and strongly influenced by the genetic background (Sternberg et al., 1989;
Landgraf et al., 1999; Ohta et al., 1999; Touma et al.,
2008). Moreover, the HPA axis response to acute challenges
in genetically susceptible individuals (Alexander et al., 2009)
can become dys-regulated by several factors including somatic
and affective diseases as well as chronic stressor exposure
(Wigger and Neumann, 1999; Veenema et al., 2008; Elzinga
et al., 2010).
5. Evidence for chronic stress to be a risk
factor for IBD in human and non-human
primates
In contrast to the so far reported adaptive and, thus, positive
effects of the acute stress response, chronic stress and
especially chronic psychosocial stress is a burden of modern
societies and as such an acknowledged risk factor for numerous bodily and affective disorders, including stomach ulcers
(Coker et al., 2000), diarrhea and digestive problems (Coker
et al., 2000; Campbell et al., 2002), chronic pelvic and
abdominal pain (Coker et al., 2000; Campbell et al.,
2002), infections (Cohen et al., 1991; Kiecolt-Glaser et al.,
1996; Coker et al., 2000; Campbell et al., 2002), impaired
wound healing (Kiecolt-Glaser et al., 1995, 1998; Marucha
et al., 1998), cancer (Kiecolt-Glaser and Glaser, 1995), irritable bowel syndrome (IBS), and IBD (for review see Mawdsley
and Rampton, 2005, 2006).
Evidence for a role of stress in the modulation of disease
onset and severity in IBD comes from numerous studies done
in human and non-human primates. In 1958, Porter et al.
(1958) reported the development of gastrointestinal lesions
in 11/19 rhesus monkeys who were either restrained in chairs
or placed in a conditioned anxiety situation (Drossman,
1985). Most of these were gastroduodenal erosions, but
two of the monkeys, which were conditioned for anxiety,
developed a wasting syndrome and chronic colitis (Drossman,
1985). The first hint for a link between stress and human IBD
was provided by Salem and Shubair in 1967 who showed that
Arab Bedouins frequently developed UC after they were
forced to leave their familiar environment in the desert
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
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Stress and animal models of inflammatory bowel disease
and live in houses provided by the government (Salem and
Shubair, 1967). Two years later, Stout and Snyder (1969)
described extensive colonic ulceration in Siamong gibbons
that died within a few weeks after the death of their mating
pair (Stout and Snyder, 1969). The development of spontaneous colonic inflammation and carcinomas in different
tamarin species (New World primates; Saguinus oedipus = cotton-top tamarin; Saguinus mystax = moustached tamarin) during captivity (Drossman, 1985; Gozalo and Montoya, 1992;
Wood et al., 2000) further supports a possible link between
stress and the development of colonic inflammation. Interestingly, the absence of colonic inflammations in the wild population (Wood et al., 1998) as well as in tamarins caged in the
conditions of their natural habitat in Columbia (Wood et al.,
1995) suggests that spontaneous coltiis is caused by temperature-induced metabolic stress during captivity when caged in
temperate climates throughout the world (Wood et al., 2000).
In 1991, Duffy and coworkers clearly demonstrated in a large
prospective study, performed with 124 patients (UC and CD)
over 6 month, an increased risk of IBD symptom exacerbation
following severe, sustained life stress (Duffy et al., 1991).
Furthermore, in 1998 Levenstein and coworkers showed
that among a group of patients with previously diagnosed UC
who were currently in complete clinical remission, those with
endoscopically visible rectal mucosal abnormalities reported
higher levels of perceived life stress (Levenstein et al.,
1998). A comparable study done by Bitton et al. (2003) also
described that among 60 patients with UC in remission phase,
those who relapsed showed significantly more severe life
events during the time span prior to relapsing compared with
patients that did not relapse. In a prospective follow up study
they further showed that among patients with quiescent CD,
those were least likely to relapse whose life was least
stressful and who were least engaged in social diversion or
distraction (Bitton et al., 2008). Further support for an
impact of psychological factors and, thus, brain activity on
intestinal disease state comes from the relatively high success rate of treating human colitis with placebo drugs (Thomas, 1994; Ilnyckyi et al., 1997). In line Bernstein and
coworkers just recently showed that only high-perceived
stress was associated with an increased risk of flare in IBD
patients (Bernstein et al., 2010). Evidence described so far
showing that adverse life events, chronic stress, and depression are risk factors for IBD, is also supported by human
studies employing experimental stressors. For further
detailed information on the link between stress and IBD in
humans the interested reader is directed to an excellent
review articles done by Mawdsley and Rampton (for review
see Mawdsley and Rampton, 2005).
With respect to the underlying neuroendocrine mechanisms
only little is known so far from human studies. Available data
suggest IBD, similar to rheumatoid arthritis, to be rather
associated with hypocortisolism than hypercortisolism (for
review see Mayer, 2000a; Mawdsley and Rampton, 2006).
The prolonged lack of adequate levels of anti-inflammatory
GC thereby might contribute to the generation of a proinflammatory milieu in the intestinal tract, finally favoring
the development of IBD. Support for this hypothesis comes
from the group around R. Straub. They showed that the
positive correlation of the sympathetic tone and activation
of the HPA axis found in healthy controls is shifted towards a
more pronounced SNS and decreased HPA axis activation in UC
5
patients (Straub et al., 2002). In addition, it has been reported
that the release of GC in response to inflammatory cytokines
becomes blunted in IBD patients (Straub et al., 1998).
Importantly, it has to be at least briefly mentioned in this
context that besides IBD also IBS is discussed to be a consequence of physical and psychosocial stressor exposure (for
review see Mayer, 2000a; Cumberland et al., 2003). In line,
Bennett et al. (1998) provided evidence in a longitudinal
human study that the presence of a highly threatening
chronic stressor inhibits improvement from IBS, while its
reduction or absence may be a prerequisite for a significant
improvement of the disease. Furthermore, an increased rate
of sexual and physical abuse during childhood together with
high perceived life stress has been reported for IBS patients
(Gaynes and Drossman, 1999). Interestingly, over the past
years it became more and more clear that IBS does not solely
represent a functional gastrointestinal disorder but is also
linked with low-grade mucosal inflammation and innate and
adaptive immune system activation (Ohman and Simren,
2010). The increased risk for developing IBS after infectious
gastroenteritis and in patients with IBD in remission supports
this hypothesis. In line with what has been so far reported for
IBD, a disturbed HPA-axis activity has been found also in
patients suffering from IBS (Patacchioli et al., 2001).
However, the role of psychosocial factors in the development and modulation of common gastrointestinal disorders,
such as IBS and IBD, remains controversial (for review see
Mayer, 2000b). For example Campbell et al. (1986) investigated in a prospective study whether there is a link between
stressful life events and symptoms of pain or diarrhea and
failed to find any significant correlations. In line, North et al.
(1990) reported in their review article that only 8 out of 15
studies, done in patients with UC, support a link between
stressful life events and the etiopathology of the disease,
whereas the other 7 studies failed. In their own study they
also failed to provide evidence for a link between stressful life
events and disease activity in 24 patients with CD and 8
patients with UC (North et al., 1991). Furthermore, Riley
et al. (1990) and Garrett et al. (1991) were not able to
determine a clear correlation between stress and the pathogenesis of IBD. The existence of these contrary findings is
particularly surprising in view of the unique well established
bidirectional interactions between brain and gut, the prominent role of the gut associated lymphoid tissue in this brain—
gut interaction, and in view of the common clinical impression
that certain stressful life events frequently precede exacerbation of symptoms in all of these disorders (for review see
Mayer, 2000b). As many of these studies investigating the
effects of a defined stressor on IBD pathology do not explicitly
distinguish between UC and CD patients (Duffy et al., 1991;
North et al., 1991; Bernstein et al., 2010) or do only investigate
stress effects on either UC (Salem and Shubair, 1967; Campbell
et al., 1986; Levenstein et al., 1998; Bitton et al., 2003) or CD
(Bitton et al., 2008) it is not possible to draw reliable conclusions on whether UC or CD is more heavily influenced by stress.
6. Rodent data supporting stress to be a risk
factor for IBD
In addition to the already mentioned studies done in human
and non-human primates, a growing number of rodent studies
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
Plasma GC levels
Further findings
describing HPA
axis activity
References
Effects of stressor exposure on prior chemically induced and already healed colitis
TNBS
Restraint
6 wk before
Rats (male)
Reactivation
(3 h/d; 3 d)
No
After last stressor
Increased
(vs. non-stressed)
Collins
et al. (1996)
DNBS
Restraint + sound
(2 2 h/d; 5 d)
7—8 wk before
Mice (male)
Reactivation when
combined with
sub-threshold dose
of DNBS
Yes
After last stressor
Increased
(vs. non-stressed)
DSS
WAS (1 h/d; 7 d)
4 wk before
Mice (female)
Reactivation
Yes
After last stressor
Increased
(vs. non-stressed)
DSS
WAS (1 h/d; 7 d)
4 wk before
Mice (female)
Yes
After last stressor
Unaffected
(vs. non-stressed)
DNBS
Restraint
(3 h/d; 3 d)
6 wk before
Rats
Reactivation when
combined with
sub-threshold dose
of DSS
Reactivation when
combined with
sub-threshold dose
of DNB
Plasma GC not
different from
VEH-treated rats
exposed to the
stressor
Plasma GC not
different from
VEH-treated rats
exposed to the
stressor
Adrenal weight
was increased
(vs. non-stressed)
Adrenal weight
was increased
(vs. non-stressed)
Yes
—
n.a.
Start of colitis
induction relative
to stressor
exposure
Species (sex)
Stress effects
on colitis
Effects of stressor exposure on acute chemically induced colitis
TNBS
PRS (2 h/d; 4 d)
1 d after
Rats (male)
Aggravation
Yes
—
n.a.
TNBS
PRS (2 h/d; 4 d)
1 d before
Rats (male)
Aggravation
Yes
—
n.a.
TNBS
WAS or PRS
(alternatively;
3 h/d; 6 d)
24 h before
Rats (female)
Aggravation (more
pronounced in Lewis
than Fischer rats)
Yes
20 min after
1st, 3rd, and
6th stressor
Increased in
Fischer after
1st and 2nd
stressor
(vs. non-stressed)
Qiu
et al. (1999)
Melgar
et al. (2008)
Melgar
et al. (2008)
Saunders
et al. (2006)
ICV injection of CRH
or AVP antagonists
before each
stressor worsened
outcome
Gue
et al. (1997)
Gue
et al. (1997)
Million
et al. (1999)
S.O. Reber
-Daily (6 d) ICV
injection of CRH
reduced TNBS
colitis in Lewis
and Fischer rats
-ICV CRH antagonist
10 min before each
stressor worsened
outcome in both
strains
+ Models
Time of killing/
blood drawing
for determining
plasma GC
Type of
stressor
(duration)
PNEC-1996; No. of Pages 19
Stressor
effects
on histol.
damage
Drug to
induce
colitis
6
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
Table 1 Summary of studies investigating the effects of different stressors on either reactivation of prior chemically induced colitis, aggravation/amelioration of chemically
induced colitis, or development of spontaneous colitis.
Rats (male)
Faster symptom
development
Yes
After the 1st and 4th
stressor
DSS
Restraint
(2 h/d; 4 d)
Before (until
fecal blood
was detected)
Rats (male)
No effect
No
After the 1st and 4th
stressor
DSS
SD (2 h/d) or OC
(24 h/d) over 19 d
1 d after
Mice (male)
Aggravation and
impairment of
regeneration
Yes
1 d after last stressor
(A) and after 7 d of
DSS (B)
Increased after
1st and 4th
stressor
(vs. non-stressed)
Increased after
1st and 4th
stressor
(vs. non-stressed)
-Unaffected
(morning)
-Decreased (evening)
(A; vs. non-stressed)
-Increased (morning)
(B; vs. non-stressed)
DSS
CSC (19 d)
1 d after
Mice (male)
Aggravation
Yes
d2, 4 and 8 of DSS
d2: not affected; d4:
not affected; d8:
increased
(vs. non-stressed)
DSS
MS (3 h/d;
PND1—14)
9 wk after
Mice (male)
Aggravation
Yes
Morning before start
of DSS
Unaffected
(vs. non-stressed)
DSS
MS (3 h/d;
PND1—14)
and CSC
(19 d; wk8—11)
1 d after
termination
of CSC
Mice (male)
Aggravation
(vs. both resp.
non-MS and
non-CSC mice)
Yes
(vs. resp.
non-CSC)
Morning before start
of DSS
Decreased
(vs. resp. both
non-MS and non-CSC)
AA
WAS (30 min)
6 h before
Rats (male and
female)
Amelioration
Yes
—
n.a.
TNBS
PRS (2 h)
4 h after
Rats (male)
Amelioration
No
—
n.a.
Milde and
Murison (2002)
Milde and
Murison (2002)
-Adrenal weight
was increased
-Adrenal ACTH
responsiveness
was decreased
-CRH mRNA in the
PVN was unaffected
(all A; vs. non-stressed)
-Plasma ACTH was
increased (B; vs.
non-stressed)
Although cytokine
secretion was increased
on d2 and d4 of DSS
treatment in stressed
mice, plasma GC was
not -ADX prior to CSC
ameliorated CSC-induced
aggravation of DSS colitis
-Adrenal weight was not
affected
-CRH and AVP mRNA in
the PVN was unaffected
(vs. non-stressed)
-Adrenal weight
was increased
-CRH mRNA in the
PVN was increased
-AVP mRNA in the
PVN was decreased
(all vs. resp. non-CSC)
RU-486 (10 min before
stressor) reversed
stressor effects
Reber
et al. (2006)
Reber
et al. (2008)
Veenema
et al. (2008)
Veenema
et al. (2008)
Cakir
et al. (2004)
Gulpinar
et al. (2004)
+ Models
1 d after
PNEC-1996; No. of Pages 19
Restraint
(2 h/d; 4 d)
Stress and animal models of inflammatory bowel disease
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
DSS
7
Type of
stressor
(duration)
Start of colitis
induction relative
to stressor
exposure
Species (sex)
Stress effects
on colitis
Stressor
effects
on histol.
damage
Time of killing/
blood drawing
for determining
plasma GC
Plasma GC levels
Further findings
describing HPA
axis activity
References
TNBS
Controllable
ES (30 min)
4 h after
Rats (male)
Amelioration
Yes
—
n.a.
Injection of RU-486
(ip; 12 + 1 h before and
24 h after stressor) or
CRH receptor antagonists
(ICV; 10 min before
stressor) reversed
stressor effects
Gulpinar
et al. (2004)
TNBS
Controllable
ES (30 min; d0)
+ shock box
(30 min/d; d1—3)
Controllable
ES (30 min;d0)
+ shock box
(30 min/d; d1—3)
+ PRS (2 h; d4)
4 h after
last stressor
Rats (male)
No effect
No
—
n.a.
Gulpinar
et al. (2004)
4 h after
last stressor
Rats (male)
Amelioration
Yes
—
n.a.
Gulpinar
et al. (2004)
Effects of stressor exposure on the development of spontaneous colitis
—
CSC (19 d)
—
Mice (male)
Induction of
spontaneous colitis
Yes
d2, 3, 7, 14, 20 of
stressor exposure
-Increased only
on d2 (morning)
-Decreased on
d20 (evening)
(all vs. non-stressed)
—
Crowding (15 d)
—
Rats (male)
Induction of colonic
inflammation
No
d1, 3, 7, 12, 15 of
stressor exposure
Increased at every
time point assessed
(vs. non-stressed)
—
CSC (19 d)
—
Mice (male)
n.a.
—
n.a.
—
SDR (2 h/d; 6 d)
—
Mice (male)
Yes
SDR (2 h)
—
Mice (male)
2 h after last
stressor
2 h after last
stressor
Not affected
—
Induction of
spontaneous colitis
Induction of
spontaneous colitis
No effect
TNBS
Increased
(vs. non-stressed)
Reber
et al. (2007)
Vicario
et al. (2010)
Reber
et al. (2011)
Savignac
et al. (2011)
Savignac
et al. (2011)
S.O. Reber
No
-Adrenal weight was
increased (d2, 3, 7, 14, 20)
-Adrenal ACTH
responsiveness was
decreased (d20)
-CRH mRNA in the PVN
was only increased on
d2 (vs. non-stressed)
-ADX prior to CSC
ameliorated
spontaneous colitis
CRH-induced (ip;
30 min before killing)
corticosterone
production following
15 d of crowding
was unaffected
(vs. non-stressed)
+ Models
Drug to
induce
colitis
PNEC-1996; No. of Pages 19
8
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
Table 1 (Continued )
+ Models
PNEC-1996; No. of Pages 19
Stress and animal models of inflammatory bowel disease
provide evidence for a link between exposure to different
types of stress procedures and the pathogenesis of an experimentally induced and/or spontaneous colitis. In the current
review the term colitis is used when animals developed
cellular infiltration and/or histopathology, whereas more
subtle indications of colonic inflammation as for instance
increased cytokine production or myeloperoxidase (MPO)
activity are referred to as colonic inflammatory processes.
However, before enlightening the effects of stressor exposure on gut inflammation, relevant rodent models for the
induction of IBD-like pathology will be introduced briefly. For
further details on these models and on additional models the
reader is directed to a recent review article by Singh and
coworkers from 2001 (for review see Singh et al., 2001).
6.1. Rodent models for IBD
Besides adoptive transfer models in which colonic inflammation is induced in immunodeficient animals by the transfer of
CD4+ Tcell subpopulations, and immune models in which colitis
is induced by the generation of a single deletion of a target
gene (knockout animals) or increased expression of a particular gene (transgenic animals) (for review see Singh et al.,
2001), there is also a variety of chemically induced colitis
models. Colitis thereby is induced by oral or rectal administration of different chemicals (inducible models). Although
rectal administration of dinitrobenzene sulphonic acid (DNBS)
(Qiu et al., 1999), trinitrobenzene sulphonic acid (TNBS)
(Morris et al., 1989; Elson et al., 1996), acetic acid (AA), or
oxazolone (Boirivant et al., 1998) reliably induces colitis, the
application procedure itself poses an additional and uncontrollable stressor for the rodent and, thus, seems not to be the gold
standard for investigating the effects of a defined stress
procedure on the pathogenesis or severity of colonic inflammation. Despite of that disadvantage chemically induced
colitis models so far are the only ones that have been used
in this context in rodents. However, this is different for colitis
induction by the oral administration of the sodium salt of a
sulphated polysaccharide, dextran sulphate sodium (DSS), via
the drinking water, which has been described for mice
(Okayasu et al., 1990), rats (Kishimoto et al., 1992; Kimura
et al., 1995), and hamsters (Ohkusa, 1985; Yamada et al.,
1992). DSS colitis is restricted mainly to the large intestine
and, therefore, was considered to be a useful animal model for
human UC (Okayasu et al., 1990; Kitajima et al., 1999).
Interestingly, the finding of a Th1 shifted immune response
in animals treated with DSS also suggests a similarity to human
CD (Strober et al., 2002). In general, animals treated with DSS
show a marked loss of body weight, rectal bleeding, reduction
of colonic length, and destruction of the epithelial layer and
glandular architecture of the large intestine (Okayasu et al.,
1990; Cooper et al., 1993; Kitajima et al., 1999).
As stated by Singh and coworkers (for review see Singh
et al., 2001) spontaneous animal models of IBD are uncommon, with the most studied being the already mentioned
non-human primate tamarin model (Drossman, 1985; Madara
et al., 1985; Podolsky et al., 1985; Gozalo and Montoya, 1992;
Elson et al., 1995). However, recently we and others could
show that also repeated/chronic psychosocial stressors are
able to cause the development of spontaneous colitis (Reber
et al., 2007, 2008, 2011; Savignac et al., 2011). Besides
9
offering a new way of inducing spontaneous colitis in male
mice, these findings provide important evidence for a link
between repeated/chronic psychosocial stress and the development of IBD and, thus, will be discussed in more detail
below.
6.2. Rodent data supporting (or at least not
contradicting) the concept that stress-induced
HPA axis activation has ameliorating effects on
experimentally induced or spontaneous colitis
(for summary see Table 1)
6.2.1. Stress-induced reactivation of chemically
induced colitis
Collins et al. (1996) showed in rats that a previous colitis,
which was induced by TNBS administration 6 weeks prior to
stressor exposure, was reactivated by repeated restraint
stress (3 h/d for 3 consecutive days). This was indicated by
a significant increase in MPO activity. However, stressinduced inflammatory processes were not accompanied by
tissue damage, suggesting that changes in colonic histology
may take longer to establish (Collins et al., 1996). Restraint
stress thereby had no effect in rats prior treated only with
vehicle (VEH; EtOH). Interestingly, similar plasma corticosterone levels in TNBS and VEH-treated rats immediately
following the third round of restraint stress indicate that
factors different from HPA axis activation probably have
mediated stress-induced reactivation of prior TNBS colitis
(Collins et al., 1996).
In line, Qiu et al. (1999) demonstrated that DNBS colitis in
mice resolves by 6 weeks, but can subsequently be reactivated by stress (2 2 h/d of combined restraint and sonic
stress for 5 consecutive days) plus a sub-threshold dose of
DNBS, but not by a sub-threshold dose of DNBS alone. Here,
the reactivation of colitis was also paralleled by mucosal
inflammation and ulceration and essentially dependent on
the presence of CD4+ lymphocytes (Qiu et al., 1999). In
addition, they have shown that stress impairs the colonic
barrier function by decreasing mucus production and increasing colonic permeability (Qiu et al., 1999). Again, similar
plasma corticosterone levels in DNBS and VEH-treated rats
immediately following stressor termination indicate that the
reactivation of colitis is unlikely to reflect an altered
hypothalamic—pituitary response to stress in animals that
had previous colitis.
It has been further shown that DSS colitis can be reactivated by water avoidance stress in mice (WAS; 1 h/d for 7
consecutive days) (Melgar et al., 2008) and DNBS colitis by
restraint stress (3 h/d for 3 d) (Saunders et al., 2006), both
applied in addition to a sub-threshold dose of the respective
hapten. Interestingly, in the DSS study, plasma corticosterone
levels seem blunted in response to repetitive WAS exposure in
previously DSS-treated compared with VEH-treated mice,
although the adrenal weight was increased in DSS mice. This
suggests that reactivation of DSS colitis might be due to a
functional loss of the adrenal glands and the consequent
reduction in anti-inflammatory GC signaling in these mice
(Melgar et al., 2008). However, it has to be mentioned here
that reactivation of prior DSS colitis, although to a less
pronounced extent, was also possible without adding the
sub-threshold dose of DSS (Melgar et al., 2008). Interestingly,
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
+ Models
PNEC-1996; No. of Pages 19
10
both adrenal weight and plasma corticosterone levels were
increased in WAS compared with non-stressed control mice.
Although a role of the HPA axis cannot be excluded (not
assessed) the DNBS study suggests noradrenergic and cholinergic neural stress pathways to be critical for the stressinduced relapse of colitis (Saunders et al., 2006).
6.2.2. Stress-induced aggravation of chemically
induced colitis
Besides the stress-induced reactivation of resolved colitis,
Gue et al. (1997) further showed that 4 d of partial restraint
stress (PRS; 2 h/d) applied either prior to or after TNBS
instillation, increased the severity of experimental colitis
in rats. Interestingly, this effect was not mediated by
increased brain levels of either CRH or AVP (Gue et al.,
1997), key hormones in the activation of the HPA axis during
stress. In contrast, brain CRH and AVP seemed even to
restrain colitis aggravation during stress, as daily central
injection of either CRH or AVP antagonist before PRS (applied
prior to TNBS instillation) resulted in further enhancement of
colitis severity (Gue et al., 1997). The authors, thus,
hypothesized that mechanisms different from activation of
the immunosuppressive HPA axis during the 4 d of PRS must be
involved in aggravation of a subsequent TNBS colitis (Gue
et al., 1997). In line, daily intracerebroventricular (ICV)
injections of CRH during the 6 consecutive days following
TNBS instillation resulted in a decreased colitis severity in
inbred rat strains with hypo (Lewis/N) and hyper
(Fischer344/N) CRH responsiveness to stress (Million et al.,
1999). Further underlining the protective role of an increased
HPA axis activity during stressor exposure on stress-induced
aggravation of colitis, TNBS colitis was found to be more
severely worsened by subsequent daily intermittent stress
(3 h/d water avoidance stress or wrap restraint alternatively
for 6 d) in CRH hypo-responsive Lewis/N compared with CRH
hyper-responsive Fischer344/N rats (Million et al., 1999).
In 2002, Milde and Murison also showed that restraint
stress (2 h/d for 4 consecutive days) further aggravates
subsequent DSS colitis in rats. In contrast to earlier studies
restraint stress did not aggravate or sustain the inflammatory
condition, when applied following colitis induction (Milde
and Murison, 2002). However, as in the Milde and Musison
study visible bloody stools and not colonic MPO activity were
taken as readouts for colitis severity, comparison with earlier
studies is difficult.
Support for an aggravating effect of a more naturalistic
and clinically relevant stressor, namely repeated/chronic
psychosocial stress, on DSS colitis was recently also provided by our own group. Mice that were exposed for 19 d to
either the social defeat/overcrowding (SD/OC) (Reber
et al., 2006) or the chronic subordinate colony housing
(CSC) (Reber et al., 2007; Veenema et al., 2008) stress
paradigm and subsequently treated with DSS (1%, 7 d)
showed an aggravated colitis compared with non-stressed
single housed control mice. This was indicated by an
increased body weight loss, inflammatory reduction of
colon length, and histological damage score of SD/OC
and CSC mice compared with respective controls on day
8 of DSS treatment (Reber et al., 2006, 2007; Veenema
et al., 2008). Although a causal involvement still has to be
proven, the decreased GC signaling — caused by adrenal
insufficiency (Reber et al., 2006, 2007) and/or GC resis-
S.O. Reber
tance (Reber et al., 2007) — in both SD/OC and CSC mice
following stressor termination is very likely to be involved in
the overshooting immune response in the colon of these mice
during DSS treatment. This is indicated by the lack of an
increase in plasma corticosterone levels on day 2 of DSS
treatment although cytokine secretion from isolated mesenteric lymph node cells was already increased at that time
point. In contrast, an increased cytokine secretion from isolated mesenteric lymph node cells in control mice was first
detected after 7 d of DSS treatment and paralleled by high
plasma corticosterone concentrations (Reber et al., 2008).
Activation of the immunosuppressive HPA axis caused by
inflammatory stimuli thereby can occur at various levels,
including hypothalamic CRH/AVP neurons, pituitary corticotrophs, and the adrenal cortex (Sapolsky et al., 1987; Gue
et al., 1997; for review see Tracey, 2002). As AVP, instead of
CRH, has been suggested to be the main activator of the HPA
axis during chronic inflammatory conditions like adjuvantinduced arthritis (Chowdrey et al., 1995; Harbuz et al.,
1995), the decreased AVP mRNA expression in the PVN of
CSC mice (Reber and Neumann, 2008) might additionally contribute to the generation of the overall pro-inflammatory
milieu following CSC exposure. Further support for colitis
aggravating/promoting effects of decreased GC signaling following chronic stress comes from our recent data showing that
combination of early life stress (maternal separation, MS; 3 h/
d, from postnatal days (PND) 1—14) and 19 d of CSC during
adulthood have additive effects on DSS colitis. In contrast to
CSC mice which just cannot adequately generate the diurnal
rise in plasma GC, mice exposed to both MS and CSC suffer from
hypocorticism even during the morning hours, although their
adrenals are significantly enlarged (Veenema et al., 2008).
6.2.3. Stress-induced amelioration of chemically
induced colitis
Besides studies providing evidence for stress exacerbating
the severity and/or causing reactivation of an experimentally
induced colitis, there are also studies showing contrasting
effects. For example, Cakir et al. (2004) showed that 30 min
of water avoidance stress, applied during the 6th hour after
colitis induction by acetic acid (AA) infusion, ameliorated
colitis severity. Interestingly, by the injection of the GR
antagonist RU486 1 h before stressor exposure, they could
demonstrate that this effect was mediated by GCs, the most
potent endogenous inhibitors of inflammation (Cakir et al.,
2004). In addition, Gulpinar et al. (2004) showed that acute
controllable electric shock (ES) and to a lesser extent also
PRS prior to colitis induction by TNBS reduced its severity,
possibly via the stimulation of the HPA axis and/or the SNS.
This was suggested by a more pronounced stress-induced
aggravation of colitis severity in rats which were injected
ICV with a CRH receptor antagonist or ip with the GC receptor
antagonist RU-486 or the ganglion blocker hexamethonium
10 min prior to ES exposure (Gulpinar et al., 2004). They
further hypothesized that the colitis aggravating effect of
prior repeated restraint stress (restraint; 2 h/d for 4 d)
described by Gue et al. (1997) and the colitis ameliorating
effect of their repeated stress paradigm (PRS after repeated
ES exposure; day 1: exposure to ES; days 2, 3: exposure to the
same boxes but receiving no shock; day 4: 2 h of PRS) might
be due to a difference in stressor controllability (Gulpinar
et al., 2004). However, based on the above reported colitis
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
+ Models
PNEC-1996; No. of Pages 19
Stress and animal models of inflammatory bowel disease
ameliorating effects of HPA axis activation during stressor
exposure, another explanation seems to be more likely. Daily
homotypic stressor exposure — restraint stress (Gue et al.,
1997) or ES/shock box exposure (Gulpinar et al., 2004) —
might have resulted in an adaptation of the HPA axis and,
thus, equal or just slightly increased GCs levels in comparison
to unstressed control animals. In contrast to the Gue study,
the additional exposure to the heterotypic PRS in the Gülpinar study before colitis induction (Gulpinar et al., 2004),
probably has dramatically increased the levels of anti-inflammatory corticosterone at the time of colitis induction.
6.2.4. Stress-induced development of spontaneous
colitis
As already mentioned, 19 d of CSC aggravate the severity of
subsequent DSS colitis (Reber et al., 2008). Interestingly, in
contrast to non-stressed controls, CSC mice, already on the
second day of DSS treatment, showed an increased cytokine
secretion from isolated mesenteric lymph node cells. This
finding indicated that chronic psychosocial stressors themselves might trigger the development of spontaneous colitis. In
agreement, CSC mice not subsequently treated with DSS also
showed an increased cytokine secretion from isolated mesenteric lymph node cells 8 d following CSC termination (Reber
et al., 2008). Furthermore, exposure to CSC caused an
increase in the histological damage score, which is first detectable after 14 d of CSC (Reber et al., 2007), in the number of
colonic macrophages, dendritic and Th cells (Reber et al.,
2011), and in the cytokine secretion from isolated mesenteric
lymph node (Reber et al., 2007) and lamina propria mononuclear (Reber et al., 2011) cells. Together, these findings
clearly indicated, for the first time, that clinically relevant
chronic psychosocial stressors in male mice cause the development of mild spontaneous colitis. Further evidence that
psychosocial stress exposure can lead to spontaneous colitis in
rodents comes from the group of John Cryan. These groups
have demonstrated that a modified version of the socialdisruption stress paradigm (SDR) (Avitsur et al., 2001; Bailey
et al., 2006, 2007; Engler et al., 2008) caused increased
plasma levels of pro-inflammatory cytokines and mild histological damage in the colon (Savignac et al., 2011) of male
mice. Similar to CSC exposure (Reber et al., 2007, 2011;
Schmidt et al., 2010), SDR stress has been repeatedly shown
to result in decreased GC signaling (Avitsur et al., 2003; Engler
et al., 2005, 2008), increased bacterial translocation into the
host (Bailey et al., 2006), and changes in the structure of the
intestinal microbiota (Bailey et al., 2011).
Support comes also from a recent study done by Vicario
et al. (2010). They showed that 15 d of crowding stress causes
mild colonic inflammation, indicated by an increased MPO
activity, and increased mast cell degranulation and mucosal
content/luminal release of mast cell protease-II. However,
whether or not the lack of histological damage following 15 d
of crowding stress is due to a pronounced immunosuppression
by the continuously increased plasma GC levels still remains
elusive. It might also be possible that crowing stress is less
severe than for instance CSC and, therefore, histological
damage might not be detectable after 2 week of stressor
exposure but might take longer to develop.
It is, therefore, very likely that during conditions of
repeated/chronic psychosocial stress a reduction in the
11
immunosuppressive signaling capacity of GC and increased
number or changed community structure of intestinal/translocated bacteria contribute to an overall pro-inflammatory
milieu, which in turn promotes the development of mild
colitis.
6.2.5. Conclusions to be drawn from these studies on
the underlying HPA axis-dependent mechanisms
While it appears at first glance that the effects of stress on
the pathogenesis of experimentally induced colitis in rodents
are contrasting, closer inspection reveals that stress-induced
HPA axis activity and, thus, anti-inflammatory GC signaling is
beneficial rather than detrimental. Although the face and
predictive validity of many of these animal models have to be
viewed with caution, these findings seem to be in line with
the limited human data available (see above; for review see
Mawdsley and Rampton, 2006). Support comes also from the
fact that adrenocorticotropic hormone and corticosteroids
are not just commonly used for treatment of IBD but have also
been proven to be highly effective (for review see Singh
et al., 2001; Sands, 2007). However, although the ameliorating effect of HPA axis activation on stress-induced colitis
aggravation/development seems to be generally accepted,
recent evidence suggests that an increase in GC signaling,
especially during the initial phase of chronic stressor exposure, might also have opposite effects.
6.3. Rodent data supporting the concept that
stress-induced HPA axis activation has colitispromoting effects (for summary see Table 1)
A detrimental role of HPA axis activation on experimentally
induced colitis, at least during the initial stress phase, is
suggested by our recent finding that adrenalectomy (ADX)
prior to CSC exposure results in amelioration of subsequent
DSS colitis (Reber et al., 2008). Furthermore, ADX mice
exposed to chronic psychosocial stress only showed a slight
increase in cytokine secretion from isolated mesenteric
lymph node cells and no histological abnormalities (Reber
et al., 2007). Thus, given that ADX prior to CSC ameliorates
the CSC-induced aggravation of DSS colitis (Reber et al.,
2008) and prevents the development of a full-blown spontaneous colitis (Reber et al., 2007), activation of the HPA axis
during the initial phase of chronic psychosocial stress, while
the adrenals are still fully functional and the target cells are
still responsive to GC, seems to have a colitis-promoting
effect (Reber et al., 2007).
Assessment of several functional levels of the colon during
the initial stress phase (10 h of CSC) revealed a pronounced,
adrenal hormone-mediated, local immune suppression in the
colonic tissue; probably allowing luminal- and translocatedbacteria to proliferate without constraint (Reber et al.,
2011). Immune suppression was indicated by a reduced
cytokine and immunoglobulin (Ig) A secretion from isolated
and anti-CD3/IL-2-stimulated lamina propria mononuclear
cells (LPMC), a decreased percentage of CD3+ cells within
all isolated LPMC, a decreased pro-inflammatory colonic
cytokine mRNA expression, and a lower number of F4/80+
macrophages, CD11c+ dendritic cells, CD3+ Tcells, and CD4+ T
helper (Th) cells in colonic tissue of CSC compared with nonstressed mice. Whether or not this effect is mediated by
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
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12
cortical GC or medullary catecholamines still needs further
investigation. However, given the well documented immunosuppressive effects of prolonged high doses of GC (Dhabhar
and McEwen, 1999) it is very likely that this initial immunosuppression is mediated by cortical GC and, thus, the activation of the HPA axis, instead of medullary catecholamines.
6.4. HPA axis-independent mechanisms
underlying colitis-promoting effects of stress
It is known from clinical studies that during IBD, excessive
penetration of antigens through a leaky epithelial barrier
results in an inappropriate immune stimulation, which leads
in turn to chronic gastrointestinal inflammation (Hollander,
1992; Wyatt et al., 1993). For instance, increased epithelial
permeability has been shown to play a role in the onset
(Hollander et al., 1986; May et al., 1993; Yacyshyn and
Meddings, 1995), and relapse, of CD (Wyatt et al., 1993).
Support in this direction is also provided from animal studies.
For example, injecting luminal bacterial wall extracts
directly into the sub-mucosa of rats, thus bypassing the
epithelial barrier, initiates a chronic relapsing inflammatory
syndrome similar to CD (Yamada et al., 1993; Meddings and
Swain, 2000). Furthermore, simply decreasing epithelial
barrier function in mice, by altering the expression of intracellular adhesion molecules, prompts the spontaneous generation of intestinal inflammation (Hermiston and Gordon,
1995; Meddings and Swain, 2000). Altering luminal constituents by housing these animals in a germ free environment can
delay, or even prevent, disease onset (Rath et al., 1996).
Interestingly, experiments employing prolonged antibiotic
treatment revealed also a causal role of such bacterial
translocation/proliferation during the initial phase of CSC
in initiating colonic inflammation (Reber et al., 2011). In line,
exposure to SDR failed to increase for instance circulating IL6 levels when mice were treated with an antibiotic cocktail
(Bailey et al., 2011). However, in contrast to SDR causing
bacterial translocation into secondary lymphoid organs (Bailey et al., 2006) 10 h of CSC only increased the number of
bacteria in the stool and colonic tissue (Reber et al., 2011).
This suggests that stress-induced changes in the composition
of colonic microbiota and/or adhesion to/translocation into
the lamina propria of the colon might be enough for induction
of inflammatory processes. However, many stressors have
been shown to change the composition of the intestinal
microbiota in both humans and laboratory animals (Holdeman et al., 1976; Everson and Toth, 2000; Bailey et al., 2004,
2010, 2011) but do not cause development of spontaneous
colitis. This suggests additional factors to be vital in developing these stress-induced changes in the colonic microbiota
into a full-blown colitis. In support, the above mentioned
ADX-CSC data (Reber et al., 2007) clearly indicate an important role for the immune-modulatory effects of fluctuating
levels of adrenal hormones, i.e. the pronounced immunosuppression during the initial and the over-reactive immune
system during the late CSC phase, in spontaneous colitis
development (Reber et al., 2011). This overshooting immune
response to bacterial antigens during later stressor exposure
might further be promoted by a chronic stress-induced upregulation of Toll-like receptor 4 (TLR4) expression in the
colonic mucosa (McKernan et al., 2009), which is one of the
S.O. Reber
pattern recognition receptors of the innate immune system
activated by bacterial cell wall products.
Importantly, all different compartments of the intestinal
barrier, i.e. physical-diffusion barriers, regulated physiological and enzymatic barriers, and immunological barriers, are
under neuro-hormonal control and, thus, possible targets for
the inflammation-inducing influence of stress (for review see
Söderholm and Perdue, 2001). Therefore, it is not surprising
that both animal and human studies demonstrate that various
stressors affect the functional integrity of the gastrointestinal tract, resulting in an altered mucin production (Castagliuolo et al., 1996, 1998; Pfeiffer et al., 2001), secretion of
ions and water (Barclay and Turnberg, 1987, 1988; Santos
et al., 1998), and intestinal permeability (Saunders et al.,
1994, 1997; Kiliaan et al., 1998; Santos et al., 1999, 2000;
Ferrier et al., 2003; Vicario et al., 2010). Furthermore,
Meddings and Swain (2000) showed that two very different
forms of stress exposure, namely 3 h of immobilization or
20 min of forced swimming, both increased intestinal permeability of all segments of the gastrointestinal tract (Meddings
and Gibbons, 1998; Meddings and Swain, 2000).
Although there is limited evidence in rats showing endogenous GC (Meddings and Swain, 2000) and dexamethasone
(Spitz et al., 1996) to be involved in the stress-induced
decrease in colonic-barrier function, ADX mice exposed to
10 h of CSC still display signs of leaky barrier function, which
argues against this hypothesis. Therefore, it is more likely
that the initial decrease in colonic sulphomucins and development of an obsolescent mucosa during CSC exposure
(Reber et al., 2011) are mediated by mechanisms different
from HPA axis activation.
As activation of the noradrenergic and cholinergic pathways were already suggested to be involved in the stressinduced relapse of colitis (Saunders et al., 2006), it should be
mentioned in this context that tyrosine hydroxylase mRNA
expression is significantly up-regulated in the colonic tissue
of CSC mice during the initial stress phase (Reber et al.,
2007). Tyrosine hydroxylase is the rate-limiting enzyme in the
production of catecholamines, which suggests that CSCinduced barrier defects might be mediated by a local activation of the sympathetic nervous system instead of the HPA
axis. In support, elevated plasma norepinephrine (NE) levels
were observed after 19 d of CSC exposure, which suggests
that, in contrast to the HPA axis, the SNS is still able to
respond when challenged. This uncoupling of the HPA axis and
the SNS during chronic psychosocial stressor exposure may
also promote pro-inflammatory processes, since the synergism between steroid hormones and SNS neurotransmitters
will be dissipated (Straub et al., 2002).
Increased basal plasma NE levels following 19 d of CSC are
in line with the general accepted idea that during conditions
of stress predominantly the sympathetic/catecholaminergic
tree of the ANS is activated and the parasympathetic/cholinergic tree is inhibited (for review see Goldstein and Kopin,
2007; Tracey, 2009). It has been further shown that, besides
tonic inhibition of heart rate and cardiac contractility during
resting conditions, the cholinergic ANS maintains homeostasis by limiting pro-inflammatory responses within a healthy,
protective, and non-toxic range (for review see Tracey, 2002,
2009). Thus, inhibition of this cholinergic anti-inflammatory
reflex following/during 19 d of CSC might further contribute
to the development of an overall pro-inflammatory milieu,
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
+ Models
PNEC-1996; No. of Pages 19
Stress and animal models of inflammatory bowel disease
7. Summary (see Fig. 1)
Independent of how the above described barrier defects are
induced by stress, they have been repeatedly shown to result
in increased bacterial translocation from the gut lumen into
colonic tissue (see Fig. 1, grey line), mesenteric lymph nodes,
the liver, and the spleen (Ando et al., 2000; Everson and Toth,
2000; Ding et al., 2004; Wang et al., 2004; Bailey et al., 2006;
Reber et al., 2011). A pronounced adrenal-hormone
mediated suppression of the local gut immune system (see
Fig. 1, green line) allows unhindered proliferation of luminal
and trans-located bacteria, which leads to a further increase
in the antigen load found in colonic tissue (Reber et al., 2011)
during the initial phase of stressor exposure. It is further very
likely that stressor-induced alterations in the structure of
intestinal microbiota (Bailey et al., 2010, 2011) are mediated
by such pronounced local immunosuppression.
As most stress paradigms initially result in a pronounced
activation of all stress-relevant neuroendocrine systems, the
above described scenario, i.e. local immunosuppression,
barrier defects, and bacterial translocation, is likely to be
a common feature of stressor exposure, independent of the
type of stressor.
However, whether or not this finally results in a full-blown
spontaneous colitis strongly depends on the type and duration of the stressor and the activity/response patterns of the
neuroendocrine systems. In detail, these responses include
the regulation of plasma corticosterone by the HPA axis
activity (see Fig. 1, blue line), regulation of plasma and
colonic NE levels (for colonic TH mRNA levels see Fig. 1,
turquoise line) by the SNS, and the GC sensitivity of target
cells (see Fig. 1, purple line) during stressor exposure.
Stressors that result in an overall decrease in GC signaling,
induced by either adrenal insufficiency (Reber et al., 2007,
acute
stress
phase
arbitrary units
finally resulting in spontaneous colitis (Reber et al., 2007,
2008, 2011).
Several studies also suggest an important role for mast
cells, peripheral CRH, and cholinergic/parasympathetic
mechanisms in the pathophysiology of stress-mediated barrier
disturbances (Castagliuolo et al., 1996; Saunders et al., 1997;
Kiliaan et al., 1998; Santos et al., 1999, 2000). It is hypothesized that mast cells may be activated in parallel with various
other factors for instance by CRH and/or acetylcholine
released by peripheral gut neurons. As mechanisms different
from HPA axis activation underlying stress-induced break down
of colonic barrier function are not in the focus of the current
review, the interested reader is directed to excellent studies
done by the groups around Santos, Sauders, Söderholm, Tache,
and Perdue (Perdue et al., 1991; Santos et al., 1999, 2000,
2001; Söderholm and Perdue, 2001; Saunders et al., 2002a,b;
Söderholm et al., 2002a,b; Tache et al., 2002, 2004). In line,
just recently a role of mast cells in chronic stress-induced
development of spontaneous colonic inflammation has been
suggested by an increase in colonic MPO activity and mast cellmediated barrier dysfunction in the rat bowel following 15 d of
crowding stress (Vicario et al., 2010).
Stress-induced opening of colonic epithelial tight junctions might also be mediated by a stress-induced increase in
IFN-g secretion from CD4+/CD8+ T cells, which in turn activates myosin light chain kinase (Ferrier et al., 2003).
13
colonic TH mRNA
plasma corticosterone
GC sensitivity of target cells
bacterial proliferation/ translocation
barrier function
histological damage score
local gut immune function
adrenal insufficiency
GC resistance
CHRONIC PSYCHOSOCIAL STRESSOR EXPOSURE
START
hours/
days
TERMINATION
Figure 1 Schematic representation of the hypothesis on the
mechanisms underlying chronic psychosocial stress-induced
spontaneous colitis. The initial rise in plasma corticosterone
(Engler et al., 2005; Reber et al., 2007, 2011) [blue line] in
combination with normal GC sensitivity of target cells (Engler
et al., 2005) [purple line] causes suppression of the local colonic
immune system (Reber et al., 2011) [green line]. Immune suppression and the decrease in colonic epithelial barrier function
[brown line] promote proliferation (Reber et al., 2011) and/or
changes in the structure of commensal flora bacteria in the gut
lumen (stool) (Bailey et al., 2010, 2011), as well as after they
have translocated into colonic tissue (Reber et al., 2011),
mesenteric lymph nodes, liver, and spleen (leaky barrier) (Bailey
et al., 2006), resulting in an increased number of colonic bacterial antigens [grey line]. Barrier deficits are likely to be mediated
by activation of the sympathetic nervous system, here indicated
by a stress-induced increase in colonic tyrosine hydroxylase (TH)
mRNA levels (Reber et al., 2007) [turquoise line]. With the
continuation of stressor exposure, the increased number of
bacterial antigens in the colonic tissue are targeted by an
over-reactive local gut immune-system (Reber et al., 2011)
[green line], caused by a decrease in immune suppressive glucocorticoid signaling [purple line] due to adrenal insufficiency
(Reber et al., 2007, 2008; Veenema et al., 2008) [blue line] and
GC resistance (Avitsur et al., 2001, 2002; Reber et al., 2007;
Schmidt et al., 2010) [purple line]. As a consequence, histological abnormalities and leukocyte infiltration, described by an
increase in the histological damage score (Reber et al., 2007,
2011; Savignac et al., 2011) [red line] and indicative of an acute
full-blown colitis, develop after prolonged stressor exposure.
2008; Veenema et al., 2008) or GC resistance (Avitsur et al.,
2001, 2002; Engler et al., 2005; Reber et al., 2007; Schmidt
et al., 2010), have been shown to promote the development
of a full blown spontaneous colitis in this context (Reber
et al., 2007, 2008, 2011; Savignac et al., 2011), characterized by histological damage and leukocyte infiltration (see
Fig. 1, red line). HPA axis activation during stressor exposure
has been consistently reported to have ameliorating effects
on chemically induced colitis. Thus, the colitis-promoting
effect of decreased GC signaling during repeated/chronic
psychosocial stressors is probably due to a lack of immunosuppression and a consequent overshooting of the immune
response (see Fig. 1, green line) to the increased antigen load
(see Fig. 1, grey line) in the colonic tissue. Importantly,
Please cite this article in press as: Reber, S.O., Stress and animal models of inflammatory bowel disease–—An update on the role of the
hypothalamo—pituitary—adrenal axis. Psychoneuroendocrinology (2011), doi:10.1016/j.psyneuen.2011.05.014
+ Models
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14
animal models of stressor exposure that result in this
decrease in GC signaling mainly seem to be repeated/chronic
and psychosocial in nature (Reber et al., 2007, 2011; Savignac
et al., 2011), like human stressors that are discussed to be
risk factors for the development of many affective and
somatic disorders, including IBD. Repeated/chronic psychosocial stress paradigms, thus, seem to represent the most
promising tools to learn more about the mechanism underlying stress-induced development of IBD. As colitis induced by
these chronic social stressors in general is very mild, and as
IBS over the last years has been repeatedly shown to go along
with low-grade mucosal inflammation, I finally just want to
raise the possibility that CSC and SDR might also pose adequate models for IBS instead of or in addition to IBD-like
pathology. Investigation of IBS key symptoms, as for instance
visceral pain sensitivity using the colorectal distension
model, would help to clarify this aspect.
Taken together, these animal and human studies have
greatly increased our understanding on the neuroendocrine
mechanisms underlying stress and IBD. Further, they substantiate the recently phrased hypothesis by Karin and coworkers (for review see Karin et al., 2006) that an aberrant
epithelial barrier instigated not only by genetic and microbial, but also stress factors and followed by microbial invasion and the failure to control leukocyte activation, might
indeed be central to the pathogenesis of IBD.
Role of the funding source
Most of our studies described in this review article were
funded by the German Research Foundation.
Conflict of interest
None.
Acknowledgements
The author is grateful to Prof. Dr. I.D. Neumann and P.D. Dr. F.
Obermeier for all their help and fruitful and inspiring scientific discussions during the time that the CSC studies were
performed in their labs and to Dr. D.A. Slattery for his helpful
comments regarding the manuscript.
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