Stress and animal models of inflammatory bowel disease—An update on the role of the hypothalamo–pituitary–adrenal axis

doi:10.1016/j.psyneuen.2011.05.014

Psychoneuroendocrinology

Volume 37, Issue 1, January 2012, Pages 1-19

https://doi.org/10.1016/j.psyneuen.2011.05.014 Get rights and content

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 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.

Section snippets

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

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.

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 (

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 and the stress

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

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 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

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

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.

References (195)

N. Alexander et al.
Gene–environment interactions predict cortisol responses after acute stress: implications for the etiology of depression
Psychoneuroendocrinology
(2009)
R. Avitsur et al.
Social disruption-induced glucocorticoid resistance: kinetics and site specificity
J. Neuroimmunol.
(2002)
R. Avitsur et al.
Social stress induces glucocorticoid resistance in subordinate animals
Horm. Behav.
(2001)
M.T. Bailey et al.
Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation
Brain Behav. Immun.
(2011)
M.T. Bailey et al.
Stress induces the translocation of cutaneous and gastrointestinal microflora to secondary lymphoid organs of C57BL/6 mice
J. Neuroimmunol.
(2006)
G. Barclay et al.
Effect of psychological stress on salt and water transport in the human jejunum
Gastroenterology
(1987)
G. Barclay et al.
Effect of cold-induced pain on salt and water transport in the human jejunum
Gastroenterology
(1988)
A. Bartolomucci
Social stress, immune functions and disease in rodents
Front. Neuroendocrinol.
(2007)
O. Berton et al.
Behavioral, neuroendocrine and serotonergic consequences of single social defeat and repeated fluoxetine pretreatment in the Lewis rat strain
Neuroscience
(1999)
A. Bitton et al.
Psychosocial determinants of relapse in ulcerative colitis: a longitudinal study
Am. J. Gastroenterol.
(2003)

R.S. Blumberg et al.

Animal models of mucosal inflammation and their relation to human inflammatory bowel disease

Curr. Opin. Immunol.

(1999)

B. Cakir et al.

The anti-inflammatory effect of leptin on experimental colitis: involvement of endogenous glucocorticoids

Peptides

(2004)

S.M. Collins et al.

Previous inflammation alters the response of the rat colon to stress

Gastroenterology

(1996)

J.F. Cryan et al.

GABAB receptors and depression. Current status

Adv. Pharmacol.

(2010)

F.S. Dhabhar

Stress-induced augmentation of immune function—the role of stress hormones, leukocyte trafficking, and cytokines

Brain Behav. Immun.

(2002)

F.S. Dhabhar et al.

Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking

Brain Behav. Immun.

(1997)

C.O. Elson et al.

Experimental models of inflammatory bowel disease

Gastroenterology

(1995)

B.M. Elzinga et al.

The role of childhood abuse in HPA-axis reactivity in social anxiety disorder: a pilot study

Biol. Psychol.

(2010)

H. Engler et al.

Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen

Psychoneuroendocrinology

(2008)

H. Engler et al.

Tissue-specific alterations in the glucocorticoid sensitivity of immune cells following repeated social defeat in mice

J. Neuroimmunol.

(2005)

L. Ferrier et al.

Stress-induced disruption of colonic epithelial barrier: role of interferon-gamma and myosin light chain kinase in mice

Gastroenterology

(2003)

C. Fiocchi

Inflammatory bowel disease: etiology and pathogenesis

Gastroenterology

(1998)

B.N. Gaynes et al.

The role of psychosocial factors in irritable bowel syndrome

Baillieres Best Pract. Res. Clin. Gastroenterol.

(1999)

M.A. Gulpinar et al.

Anti-inflammatory effect of acute stress on experimental colitis is mediated by cholecystokinin-B receptors

Life Sci.

(2004)

C. Heim et al.

The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies

Biol. Psychiatry

(2001)

M. Herrmann et al.

Stress and rheumatic diseases

Rheum. Dis. Clin. North Am.

(2000)

M. Karin et al.

Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer

Cell

(2006)

J.K. Kiecolt-Glaser et al.

Slowing of wound healing by psychological stress

Lancet

(1995)

S. Levenstein et al.

Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission

Am. J. Gastroenterol.

(2000)

J.L. Madara et al.

Characterization of spontaneous colitis in cotton-top tamarins (Saguinus oedipus) and its response to sulfasalazine

Gastroenterology

(1985)

G.R. May et al.

Is small intestinal permeability really increased in relatives of patients with Crohn's disease?

Gastroenterology

(1993)

O. Agid et al.

Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia

Mol. Psychiatry

(1999)

J. Amat et al.

Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus

Nat. Neurosci.

(2005)

T. Ando et al.

Bacterial translocation can increase plasma corticosterone and brain catecholamine and indoleamine metabolism

Am. J. Physiol. Regul. Integr. Comp. Physiol.

(2000)

T. Andus et al.

Etiology and pathophysiology of inflammatory bowel disease-environmental factors

Hepatogastroenterology

(2000)

R. Avitsur et al.

Expression of glucocorticoid resistance following social stress requires a second signal

J. Leukoc. Biol.

(2003)

M.T. Bailey et al.

Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by citrobacter rodentium

Infect. Immun.

(2010)

M.T. Bailey et al.

Repeated social defeat increases the bactericidal activity of splenic macrophages through a toll-like receptor dependent pathway

Am. J. Physiol. Regul. Integr. Comp. Physiol.

(2007)

M.T. Bailey et al.

Prenatal stress alters bacterial colonization of the gut in infant monkeys

J. Pediatr. Gastroenterol. Nutr.

(2004)

E.J. Bennett et al.

Level of chronic life stress predicts clinical outcome in irritable bowel syndrome

Gut

(1998)

C.N. Bernstein et al.

A prospective population-based study of triggers of symptomatic flares in IBD

Am. J. Gastroenterol.

(2010)

A. Bitton et al.

Predicting relapse in Crohn's disease: a biopsychosocial model

Gut

(2008)

R.S. Blumberg et al.

Prospects for research in inflammatory bowel disease

JAMA

(2001)

M. Boirivant et al.

Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4

J. Exp. Med.

(1998)

P. Brandtzaeg

Inflammatory bowel disease: clinics and pathology. Do inflammatory bowel disease and periodontal disease have similar immunopathogeneses?

Acta Odontol. Scand.

(2001)

A. Buske-Kirschbaum et al.

Psychobiological aspects of atopic dermatitis: an overview

Psychother. Psychosom.

(2001)

D. Campbell et al.

The relationship between personality, stress and disease activity in ulcerative colitis

Gastroenterology

(1986)

J. Campbell et al.

Intimate partner violence and physical health consequences

Arch. Int. Med.

(2002)

W.B. Cannon

The Wisdom of the Body

(1939)

I. Castagliuolo et al.

Acute stress causes mucin release from rat colon: role of corticotropin releasing factor and mast cells

Am. J. Physiol. Gastrointest. Liver Physiol.

(1996)

Cited by (86)

Subcutaneous Mycobacterium vaccae ameliorates the effects of early life adversity alone or in combination with chronic stress during adulthood in male and female mice
2023, Neurobiology of Stress
Chronic psychosocial stress is a burden of modern society and poses a clear risk factor for a plethora of somatic and affective disorders, of which most are associated with an activated immune status and chronic low-grade inflammation. Preclinical and clinical studies further suggest that a failure in immunoregulation promotes an over-reaction of the inflammatory stress response and, thus, predisposes an individual to the development of stress-related disorders. Therefore, all genetic (i.e., sex) and environmental (i.e., early life adversity; ELA) factors facilitating an adult's inflammatory stress response are likely to increase their stress vulnerability.
In the present study we investigated whether repeated subcutaneous (s.c.) administrations with a heat-killed preparation of Mycobacterium vaccae (M. vaccae; National Collection of Type Cultures (NCTC) 11659), an abundant soil saprophyte with immunoregulatory properties, are protective against negative behavioral, immunological and physiological consequences of ELA alone or of ELA followed by chronic psychosocial stress during adulthood (CAS) in male and female mice. ELA was induced by the maternal separation (MS) paradigm, CAS was induced by 19 days of chronic subordinate colony housing (CSC) in males and by a 7-week exposure to the social instability paradigm (SIP) in females.
Our data indicate that ELA effects in both sexes, although relatively mild, were to a great extent prevented by subsequent s.c. M. vaccae administrations. Moreover, although the use of different paradigms for males and females impedes a direct comparison, male mice seemed to be more susceptible to CAS than females, with only females benefitting slightly from the stress protective effects of s.c. M. vaccae administrations when given prior to CAS alone. Finally, our data support the hypothesis that female mice are more vulnerable to the additive effects of ELA and CAS than male mice and that s.c. M. vaccae administrations subsequent to ELA but prior to CAS are protective in both sexes.
Taken together and considering the limitation that CAS in males and females was induced by different paradigms, our findings are consistent with the hypotheses that murine stress vulnerability during different phases of life is strongly sex dependent and that developing immunoregulatory approaches, such as repeated s.c. administrations with immunoregulatory microorganisms, have potential for prevention/treatment of stress-related disorders.
Tryptophan-kynurenine metabolic characterization in the gut and brain of depressive-like rats induced by chronic restraint stress
2023, Journal of Affective Disorders
Accumulating evidence revealed the role of tryptophan (TRP) metabolism, especially its kynurenine pathway (KP), in the communication along the gut-brain axis. However, the underlying characterization of such interaction was not precise. In the present study, the rat depression model was induced by chronic restraint stress (CRS). After depression behavior tests, seven segments (cortex, hippocampus, striatum, hypothalamus, serum, cecum, and colon) along the gut-brain axis were collected to characterize their KP metabolism. mRNA expression of IL-1β, IFN-γ, IL-10 and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme revealed a general inflammatory response and region-specific activated IDO1 along the gut-brain axis. Determination of KP metabolites and enzymes displayed a general KP activation with region-specificity, especially in the hippocampus and colon, where the changes were more pronounced. KYN and 3-HK were increased dramatically along the gut-brain axis; hippocampal KA revealed a significant decrease while colonic KA showed a notable increase, evidenced by the same alternation trends of the corresponding enzymes. The expression of quinolinic acid phosphoribosyltransferase (QPRT), the crucial enzyme to produce NAD⁺ from QA, was significantly upregulated in the gut but not changed in the brain. Pearson's correlation analysis suggested that kynurenine (KYN), 3-hydroxycaninuric acid (3-HK), serotonin (5-HT), TRP and kynurenic acid (KA) significantly correlated with depressive behaviors in rats. Furthermore, western blot analysis on nod-like receptor protein 3/2 (NLRP3/NLRP2) inflammasome signaling displayed that NLRP3 and cleaved IL-1β/caspase-1 were significantly activated in the hippocampus and colon of CRS rats. However, NLRP2 was only activated in the hippocampus. These results revealed CRS induced inflammatory responses along the brain-gut axis of rats might be controlled through the NLRP3/NLRP2 inflammasome signaling pathway, which may be the underlying regulator for CRS-induced TRP-KYN metabolic changes. This study provides a new experimental background for developing stress-related health products.
Motivational disposition towards psychological characteristics of israeli children with inflammatory bowel diseases: A case-control study
2022, Journal of Pediatric Nursing
Psychological stress is a general and non-specific factor associated with many health conditions, including Inflammatory Bowel Diseases (IBD). It is related not only to external stressors but also to internal characteristics which enhance patients' vulnerability to stress.
To identify specific psychological characteristics of pediatric IBD related to stress.
A case-control-cohort study that compared the psychological characteristics of 49 patients and 56 comparisons. The psychological characteristics were defined by four belief types – beliefs about self, general beliefs, beliefs about norms, and goals – which refer to a set of specific themes.
The belief types differentiated between the two groups, and the patients were characterized by six themes: like routines, strive to get others' love, caring about the body and the health, doing things only at their own pace, expressing negative emotion without regulations, and feeling over-identification with others. Patients' likelihood of being characterized by the themes is 2.18 to 2.90 times higher than the comparisons.
Children with IBD are characterized by a set of specific psychological characteristics. These characteristics were discussed mainly concerning generating chronic stress (e.g., over-identification with others) and interpersonal conflicts (e.g., doing things only at their own pace) among the patients.
It is suggested to healthcare workers to be aware of the specific psychological characteristics of children with IBD, and sensitive to these characteristics during interactions with them. Besides, the characteristics may pave the way for developing a targeted psychological intervention that corresponds specifically to the patients' needs.
Zanthoxylum alatum Roxb. seed extract ameliorates stress aggravated DSS-induced ulcerative colitis in mice: Plausible role on NF-κB signaling axis
2021, Journal of Ethnopharmacology
Zanthoxylum alatum (ZA) Roxb (family: Rutaceae) plant has been traditionally used for multiple indications by local healers among different communities of South Asian countries mainly in India and Bangladesh. The extracts of ZA have reported strong anti-inflammatory and anti-oxidant activities, but no scientific report is available on its efficacy in intestinal inflammatory disorders like ulcerative colitis.
The overall objective of our study was to evaluate the anti-inflammatory potency of hydro-ethanolic extract of Zanthoxylum alatum seed (ZAHA) using both in-vitro NF-κB-luciferase translocation assay and in-vivo stress aggravated dextran sodium sulfate (DSS)-induced ulcerative colitis model.
The in-vitro anti-inflammatory effect of ZAHA extract was evaluated by luciferase assay in HEK293 cells. Parameters such as body weights, behavioural, colonoscopy, colon lengths and spleen weights were measured and recorded in stress aggravated DSS-induced colitis model in C57BL/6 mice. Biochemical, histological and immunoblot analysis in the colon tissues were determined to prove its anti-inflammatory and anti-oxidant activities. Characterization of the extract was done by LC-MS/MS study.
Initial in vitro NF-κB-luciferase translocation assay showed that the hydroalcoholic extract of ZA (ZAHA) showed potent inhibitory activity for NF-κB translocation by TNF-α stimulation and hence this particular extract was further evaluated in stress aggravated DSS-induced ulcerative colitis model in C57BL/6 mice. Treatment of ZAHA for two weeks at a dose of 200 mg/kg significantly ameliorated the stress aggravated DSS-induced colitis in mice. Histological alterations, infiltration of inflammatory cells, and the levels of IL-1β, IL-6, TNF-α in colon tissue and serum samples were significantly decreased in ZAHA treatment groups compared to the stress aggravated DSS induced colitis animals. Moreover, the protein expressions of p-NF-κB, p-IκBα, p-STAT3, COX-2, and TNF-α were significantly reduced in colon tissues of ZAHA treated groups and also increased anti-oxidant markers like SOD-1, Nrf2 significantly when compared with disease control group. Characterization of the extract further by LC-MS/MS revealed the presence of several active compounds which could be responsible for its anti-inflammatory activity.
Thus from the above findings it can be concluded that ZAHA ameliorates stress aggravated DSS-induced ulcerative colitis due to its anti-inflammatory and anti-oxidant activity.
Endocrine Disruption and the Gut Microbiome
2021, Endocrine Disruption and Human Health
There is mounting evidence that the gut microbiome has a profound impact on human health and disease. In this chapter, we discuss interactions between endocrine disrupting chemicals (EDCs) and gut microbiota. We consider how the gut microbiota, through cross-talk with the gut–liver and gut–brain axes, can mediate the outcome of EDC exposure. In addition, evidence is provided for the sex-specific, transgenerational effects of early EDC exposure, primarily through disruption of the vertical transfer of maternal gut microbiota. Furthermore, the potential role of gut microbiota dysbiosis in inflammatory, autoimmune, and anxiety-related diseases caused by EDC exposure is presented. Finally, evidence is provided that gut microbiota could be considered a therapeutic target for mitigating some of the effects of EDC on human health and disease. More specifically, inherent individual differences in gut microbiota can be used as a tool in developing a personalized microbiome-modifying approach to treating EDC-induced disorders.
Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease
2021, Cellular and Molecular Gastroenterology and Hepatology
Inflammatory bowel disease (IBD) is a polygenic disorder characterized principally by dysregulated inflammation impacting the gastrointestinal tract. However, there also is increasing evidence for a clinical association with stress and depression. Given the role of the hypothalamus in stress responses and in the pathogenesis of depression, useful insights could be gleaned from understanding its genetic role in IBD.
We conducted genetic correlation analyses on publicly available genome-wide association study summary statistics for depression and IBD traits to identify genetic commonalities. We used partitioned linkage disequilibrium score regression, leveraging our ATAC sequencing and promoter-focused Capture C data, to measure enrichment of IBD single-nucleotide polymorphisms within promoter-interacting open chromatin regions of human embryonic stem cell-derived hypothalamic-like neurons (HNs). Using the same data sets, we performed variant-to-gene mapping to implicate putative IBD effector genes in HNs. To contrast these results, we similarly analyzed 3-dimensional genomic data generated in epithelium-derived colonoids from rectal biopsy specimens from donors without pathologic disease noted at the time of colonoscopy. Finally, we conducted enrichment pathway analyses on the implicated genes to identify putative IBD dysfunctional pathways.
We found significant genetic correlations (rg) of 0.122 with an adjusted P (P_adj) = 1.4 × 10^-4 for IBD: rg = 0.122; P_adj = 2.5 × 10^-3 for ulcerative colitis and genetic correlation (rg) = 0.094; P_adj = 2.5 × 10^-3 for Crohn’s disease, and significant approximately 4-fold (P = .005) and approximately 7-fold (P = .03) enrichment of IBD single-nucleotide polymorphisms in HNs and colonoids, respectively. We implicated 25 associated genes in HNs, among which CREM, CNTF, and RHOA encode key regulators of stress. Seven genes also additionally were implicated in the colonoids. We observed an overall enrichment for immune and hormonal signaling pathways, and a colonoid-specific enrichment for microbiota-relevant terms.
Our results suggest that the hypothalamus warrants further study in the context of IBD pathogenesis.

View all citing articles on Scopus

View full text

ReviewStress and animal models of inflammatory bowel disease—An update on the role of the hypothalamo–pituitary–adrenal axis

Summary

Section snippets

General introduction

IBD in humans

Risk factors for IBD

The stress concept

Evidence for chronic stress to be a risk factor for IBD in human and non-human primates

Rodent data supporting stress to be a risk factor for IBD

Summary (see Fig. 1)

Role of the funding source

Conflict of interest

Acknowledgements

Psychoneuroendocrinology

J. Neuroimmunol.

Horm. Behav.

Brain Behav. Immun.

J. Neuroimmunol.

Gastroenterology

Gastroenterology

Front. Neuroendocrinol.

Neuroscience

Am. J. Gastroenterol.

Curr. Opin. Immunol.

Peptides

Gastroenterology

Adv. Pharmacol.

Brain Behav. Immun.

Brain Behav. Immun.

Gastroenterology

Biol. Psychol.

Psychoneuroendocrinology

J. Neuroimmunol.

Gastroenterology

Gastroenterology

Baillieres Best Pract. Res. Clin. Gastroenterol.

Life Sci.

Biol. Psychiatry

Rheum. Dis. Clin. North Am.

Cell

Lancet

Am. J. Gastroenterol.

Gastroenterology

Gastroenterology

Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia

Mol. Psychiatry

Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus

Nat. Neurosci.

Bacterial translocation can increase plasma corticosterone and brain catecholamine and indoleamine metabolism

Am. J. Physiol. Regul. Integr. Comp. Physiol.

Etiology and pathophysiology of inflammatory bowel disease-environmental factors

Hepatogastroenterology

Expression of glucocorticoid resistance following social stress requires a second signal

J. Leukoc. Biol.

Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by citrobacter rodentium

Infect. Immun.

Repeated social defeat increases the bactericidal activity of splenic macrophages through a toll-like receptor dependent pathway

Am. J. Physiol. Regul. Integr. Comp. Physiol.

Prenatal stress alters bacterial colonization of the gut in infant monkeys

J. Pediatr. Gastroenterol. Nutr.

Level of chronic life stress predicts clinical outcome in irritable bowel syndrome

Gut

A prospective population-based study of triggers of symptomatic flares in IBD

Am. J. Gastroenterol.

Predicting relapse in Crohn's disease: a biopsychosocial model

Gut

Prospects for research in inflammatory bowel disease

JAMA

Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4

J. Exp. Med.

Inflammatory bowel disease: clinics and pathology. Do inflammatory bowel disease and periodontal disease have similar immunopathogeneses?

Acta Odontol. Scand.

Psychobiological aspects of atopic dermatitis: an overview

Psychother. Psychosom.

The relationship between personality, stress and disease activity in ulcerative colitis

Gastroenterology

Intimate partner violence and physical health consequences

Arch. Int. Med.

The Wisdom of the Body

Acute stress causes mucin release from rat colon: role of corticotropin releasing factor and mast cells

Review
Stress and animal models of inflammatory bowel disease—An update on the role of the hypothalamo–pituitary–adrenal axis