The Role of Stress on Physiological Responses and Clinical Symptoms in Irritable Bowel Syndrome

Abstract

Studies support the concept that irritable bowel syndrome (IBS) is a biopsychosocial disorder that can be explained by a neurobiological model which postulates stress-induced alterations in central stress and arousal circuits and activation of parallel motor outputs from brain regions that can affect bodily function and behavior. Sustained stress can result in chronic overactivity or underactivity of allostatic (or adaptive) systems, including the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system, metabolic, and immune systems, can occur. Animal and human studies have demonstrated that chronic or sustained stress is associated with the onset and exacerbation of symptoms of IBS. Chronic stress is also an independent predictor of developing post-infectious IBS. IBS patients specifically show stress-induced alterations in gastrointestinal motility, rectal perception, autonomic tone and HPA axis responses, although these findings are not entirely consistent among studies. This can be in part due to differences in study methodology or to various factors that can affect these physiologic responses. A greater recognition and understanding of the effects of stress in IBS may help identify targets for future drug development and also help guide more effective management of IBS symptoms.

Introduction

Stressors can be acute or chronic and range from daily hassles to life-threatening situations, such as natural disasters and violence that trigger the “fight or flight” response. Over time, chronic or recurrent stress results in an increase demand on physiologic systems. The wear and tear on the body, termed “allostatic load,” set in motion long-term behavioral patterns, physiological reactivity, and other changes in the body that can lead to disease and health-damaging behaviors.¹ Chronic overactivity or underactivity of allostatic (or adaptive) systems can occur.² Allostatic systems include the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system (ANS), and cardiovascular, metabolic, and immune systems. Allostatic load clinically manifests as undue fatigue, irritability, and feelings of demoralization³ among other visceral and somatic symptoms that are often reported in patients with irritable bowel syndrome (IBS) and other functional pain syndromes that commonly overlap with IBS.⁴

Increasing evidence supports a prominent role of stress in the pathophysiology and clinical presentation of IBS. It has been postulated that in the predisposed individual, sustained stress can result in persistent increased responsiveness of central stress circuits and vulnerability to develop functional and affective disorders (Figure A, supporting document).⁵ The role of stress may be particularly important in altering brain-gut interactions, resulting in the development and/or exacerbation of IBS symptoms. A conceptual pathophysiologic model for IBS can take into account the reported relationship of IBS symptoms with central factors such as stressful^6–8 or traumatic⁹ life events, the frequently reported co-morbidity with anxiety disorders,¹⁰ and peripheral factors such as gut inflammation, motility, and sensation. Understanding the biologic mechanisms of stress hyperresponsiveness in IBS patients may help identify targets for drug development. Recognition of IBS patients with stress-related IBS symptoms can help guide management approaches, including earlier and more effective treatment interventions which can potentially result in a decrease in the disproportionately high healthcare costs and economic burden associated with IBS. The objectives of this review are to: 1) discuss the role of stress in the clinical presentation and course of IBS and 2) the physiologic effects of chronic stress on gastrointestinal (GI) function and central stress response systems. While this review will focus on human studies conducted in IBS, relevant preclinical and translational studies are also discussed.

Effect of chronic stressors on the development of IBS and health outcomes

The association of early adverse life events (EALs) and IBS

EALs refer to traumatic experiences during childhood including, but not limited to, maladjusted relationships with a parent or primary caregiver, severe illness or death of a parent, and physical, sexual or emotional abuse. Converging neurobiology and epidemiology studies suggest that EALs, such as abuse and other traumatic events, cause sustained brain dysfunction resulting in alterations in stress-responsive neurobiological systems, which in turn, increase the vulnerability of developing long-term health, behavioral and social problems (Figure 1).^{11, 12} Medical conditions associated with EALs include autoimmune disorders, chronic obstructive lung disease, asthma, obesity, mood disorders, substance abuse, and prescription drug use.^{11, 13, 14}

Figure 1. Physiologic and pathologic responses to stress.

An adult’s resilience or vulnerability to stress can be determined by genetic inherence and early life experiences. Activation of the central stress response sets in motion the HPA axis, ANS and other adaptive systems. Stress-induced changes in GI function occur and these can in turn result in perceived symptoms of IBS. (Adapted from Lightman, 2008⁸⁴)

Previous studies demonstrated that IBS patients have experienced a greater prevalence of physical, verbal, and sexual abuse compared to healthy individuals and patients with organic GI conditions.^{15, 16, 17, 18, 19} While other types of EALs have not been well studied in IBS, studies suggest that perturbations during the pre- and perinatal period might contribute to the development of IBS in adults.¹⁵

A recent preliminary study conducted in 233 IBS patients and 353 healthy controls showed that IBS was associated with a higher total early life trauma score, including general trauma, and physical, emotional and sexual abuse events under the age of 18, even after controlling for anxiety and depression.²⁰ However, somatization was the strongest predictor of IBS and mediated the association of early life trauma score and IBS, suggesting that factors associated with the presence of widespread non-GI symptoms mediate the relationship between childhood trauma or abuse and development of IBS. Previous studies have demonstrated that somatization is associated with a history of sexual and/or physical abuse in patients with functional gastrointestinal disorders, and that it impacts health related quality of life (HRQOL).^{9, 14, 21}

There is evidence to support that stress affects the clinical outcome in IBS. In a prospective study, Bennett et al.⁷ showed that the presence of at least one chronic life stressor during the first six months of the observational period was highly predictive of symptom intensity at 16 months, explaining 97% of the variance. All patients who experienced symptom improvement did not report a current chronic life stressor. Drossman et al.²² found that an abuse history was associated with greater pain, bed disability days, psychological distress and daily function in GI clinic patients independent of their diagnosis.

Chronic stress and psychological symptoms independently predict PI - IBS

Studies implicate chronic stress as playing a significant role in increasing the vulnerability to develop IBS.²³ Gwee and colleagues⁸ found that stressful life events in the one year preceding gastroenteritis and the hypochondriasis score independently predicted PI-IBS even after controlling for age, sex, marital and employment status, and stool culture results. A subsequent study by Dunlop et al.²⁴ found that rectal mucosal enterochromaffin cell count and depression score were independently associated with PI-IBS. These studies suggest that both biological and psychological factors are important in the development of PI-IBS.

Bidirectional brain -gut interactions and central stress response

Studies support the concept that IBS is a biopsychosocial disorder which can be explained by a neurobiological model which postulates stress-induced alterations in central stress and arousal circuits, referred to as the emotional motor system (EMS), which is comprised of parallel motor outputs from the brain regions involved in emotional function.^{23, 25} These outputs include the sympathetic and parasympathetic nervous systems, HPA axis, endogenous pain modulation systems, and ascending aminergic pathways. A variety of stressors can activate these output systems and affect bodily functions and behavior.²³

Stress results in increased corticotropin releasing factor (CRF) and noradrenergic release and activation of behavioral and autonomic responses. The principal branches of the general stress response are the HPA axis and the locus coeruleus-noradrenergic (LC-NE) systems.¹ In response to stress, CRF activates the HPA axis and the autonomic nervous system (ANS), including activation of noradrenergic-containing sites, e.g., LC-NE system, and other neurotransmitters that are involved in maintaining homeostasis. Release of CRF from the paraventricular nucleus (PVN) of the hypothalamus is under excitatory input from the central nuclei of the amygdala and inhibitory input from the hippocampus (Figure B, supporting documents).²⁶ In addition to its major role in regulating the endocrine response to stress, CRF is crucially involved in mediating stress-related autonomic, immune, behavioral, and visceral responses.^27–29

Stress-induced alterations in GI function in IBS

Although the effects of stress on gut function are universal, patients with IBS appear to have greater reactivity to stress compared with healthy individuals in terms of gut motility, visceral perception, emotional ratings and HPA axis hormone levels (Table 1).^30–33

Table 1.

Summary of stress -induced physiologic changes in IBS

Function	Findings in IBS vs. controls
GI motility	Suppressed antral and small bowel motor activity and enhanced colonic motor activity
Visceral perception	Decreased rectal non-painful and pain thresholds to distension and electrostimulation during psychological stress in IBS but not in controls Higher stress, anxiety and anger ratings higher in IBS vs. controls
Intestinal permeability and secretion	Increased small intestinal and colonic permeability demonstrated in IBS but not measured in response to stress Net water flux was significantly lower in healthy women with moderate stress compared to those with low stress. Chloride secretion was lower and albumin was higher in moderate stress vs. low stress but not statistically significant
Autonomic tone	Increases in blood pressure and heart rate and shift to lower cardiosympathetic/vagal balance after mental stress in IBS and controls but no group differences
HPA axis	Increased basal levels of cortisol in IBS vs. controls Two studies show increased HPA axis response and one shows blunted response to hormone stimulation in IBS vs. controls Most studies report lack of a response to a meal and/or mental stressor in IBS HPA axis response varies depending on the type of physical stressor

GI motility

Experimental stress can provoke alterations in GI motility. Over 20 year ago, Welgan and colleagues demonstrated that IBS patients had higher colonic motor activity at the resting state compared to healthy controls and showed greater increases with various psychological and physical stressors compared to baseline, while controls did not.^{30, 34} In one of Welgan’s studies, IBS patients exhibited both greater increases in colonic motor and spike potential activity and anger ratings during anger stressors than controls.³⁰ Several other studies have demonstrated alterations in upper gut (antrum and proximal small bowel) to stress in IBS patients.^35–38 These studies support the impact of stress on alterations in upper and lower gut motility in IBS patients.

Visceral perception

In experimental studies, stress has been associated with an increase in visceral perception. Posserud and colleagues³³ demonstrated that while healthy controls had higher sensory thresholds (decreased perception) to non-painful rectal distensions during mental stress, IBS patients showed no change. Furthermore, sensory thresholds significantly decreased (increased perception) in IBS patients but not controls during subsequent distensions whether or not mental stress was given. In addition, IBS patients reported significantly higher ratings of stress during the rectal distensions compared to controls. Dickhaus et al.³¹ reported significantly higher intensity and unpleasantness sensory ratings to phasic 45 mmHg rectal distensions in IBS patients during dichotomous listening auditory stress but not during the control condition of relaxing sounds. Emotional ratings of stress, anger, and anxiety were significantly higher during the stressful vs. relaxation condition in IBS patients but not in controls. Murray and colleagues³⁹ found that lower non-painful and painful thresholds to rectal electrostimulation during a physical (cold water hand immersion) or psychological stressor (dichotomous listening) in IBS patients but not in controls.

Although these studies support a greater visceral perceptual and emotional responsiveness to stress in IBS patients, the significant findings were detected by within-group comparisons rather than between-group comparisons with controls. Group differences may be due to smaller than required sample sizes to detect significant stress-induced perceptual differences between IBS patients and controls.

Intestinal secretion and permeability

There is evidence that stress and IBS are associated with changes in intestinal secretion and permeability, but there are no definitive data that stress induces alterations in epithelial secretion and permeability in IBS patients. Two studies reported increased small intestinal permeability in some patients with IBS-D compared to healthy controls.^{40, 41} Barbara and colleagues demonstrated that colonic biopsies from IBS patients had increased paracellular permeability⁴² and release of mediators including tryptase, histamine and prostaglandin E₂⁴³ compared to that from healthy controls. Furthermore, the supernatant from colonic biopsy cultures from IBS patients reduced transepithelial resistance and ZO-1 mRNA expression and increased permeability of human intestinal epithelial Caco-2 cells.⁴² Animal studies suggest that stress-induced increases in paracellular and transcellular permeability in the ileum and colon are mediated via CRF1 receptors.⁴⁴

A recent study conducted in healthy young women showed that the physical stressor of cold water hand immersion was associated with changes in net water flux and chloride and albumin outputs from the jejunum.⁴⁵ This study suggests that acute stress can alter small intestinal epithelial secretion in healthy women particularly in the presence of underlying chronic stress, but further studies are needed, particularly in patients with IBS.

Alterations in the central stress response in IBS

Autonomic nervous system (ANS) tone

The sympathetic and parasympathetic branches of the ANS mediate brain-gut communication largely through modulation of the third ANS branch, the enteric nervous system, and alterations in ANS output and interactions may play a role in IBS. ^{46, 47} Through its three divisions, the ANS modulates and coordinates GI motility, secretion, and immune function.^{48, 49}

In addition to the alterations in gut motility and transit that have been reported in IBS,⁵⁰ studies measuring cardioautonomic tone in IBS further support that dyregulations in ANS exist in IBS.^51–53 Increased SNS activity and decreased PNS activity are the most frequently noted differences when IBS patients are compared to healthy controls. ^54–58 Enhanced cardiosympathetic and decreased cardiovagal tone have been demonstrated in subgroups of IBS patients during 24-hour monitoring^{51, 52} and during rectosigmoid distension.⁵³

Measurements of cardioautonomic responses to stress are very limited in IBS. Elsenbruch et al.^{32, 59} compared evaluated autonomic responses to stressful mental tasks in female IBS patients and controls. A significant shift to a lower cardiosympathetic/vagal balance was only seen in IBS and control subjects who perceived the mental task as at least moderately stressful. They also noted increases in systolic and diastolic blood pressure and heart rate to a public speaking task in IBS and control subjects, but there were again no group differences.⁵⁹ Two studies found elevated basal plasma levels of norepinephrine in IBS patients vs. controls but no significant changes in response to a psychological stressor.^{31, 33} Thus, these studies suggest that while cardioautonomic tone and catecholamines may be altered in some patients with IBS, a significantly different ANS response to experimental psychological stressors may be challenging to provoke in IBS patients.

HPA axis function

In response to stress, CRF is released from the PVN of the hypothalamus and results in the secretion of adrenocorticotropin hormone (ACTH) from the pituitary gland via CRF1 receptors, which in turn, stimulates the adrenal cortex causing it to release cortisol (Figure B, supporting documents). CRF synthesis and release are subsequently inhibited through a glucocorticoid negative feedback system mediated by both glucocorticoid and mineralocorticoid receptors in the PVN, pituitary gland and hippocampus.²⁶

Although dysregulations in HPA axis activity have also been reported in IBS,^{33, 53, 54, 60–68} there are conflicting reports with respect to both basal and stress or hormone stimulated responses (Table A, supporting documents). Studies have reported increased basal cortisol levels,^{60, 63, 65} and enhanced responses to physical^{61, 67} or psychological^{33, 66} stressors and hormone stimulation,^{38, 62} but also blunted HPA axis responses^{64, 68} or no difference between IBS and control groups.^{32, 59, 69} These differences may be due to differences in study methodology and/or the patient populations (e.g., psychological co-morbidity) studied.⁶¹ Blunted basal ACTH levels were found in the presence of elevated cortisol levels over 24 hours, which is more likely a reflection of enhanced negative feedback of cortisol and/or downregulation of CRF₁ receptors at the pituitary gland level.⁶⁰ Overall, the current literature suggests that there is enhanced basal activity of the HPA axis and to hormone challenge, a lack of a significant response to a meal and/or mental stressor, and varying HPA axis response depending on the type of physical stressor in IBS patients compared to controls.

One confounding factor that can affect HPA axis function and may be more prevalent in the IBS patient population is the presence EALs. Increased HPA axis response to hormone challenge or mental stress has been reported in individuals with history of childhood sexual abuse,^{70, 71} parental loss during childhood,⁷² and EALs and high levels of chronic stress.⁷³ Videlock and colleagues⁶¹ demonstrated that IBS patients and controls with EALs had a greater cortisol response to a visceral stressor than individuals without EALs. There was also a faster rise and a slower return of stimulated cortisol to basal levels in IBS, which was associated with increased IBS symptom intensity and lower HRQOL. These findings support a role for EALs in the development and life-long functioning of the HPA axis.

In the setting of EALs, increased stress responsiveness due to a decrease in negative feedback at the level of the glucorticoid receptor (GR) in the hippocampus has been demonstrated in both animal and human studies. Exposure to perinatal stress (i.e. maternal separation) predisposes adult rats to develop stress-induced visceral hypersensitivity, enhanced defecation, intestinal mucosal dysfunction, increased HPA axis responses and anxiety-like behavior.^{74–76 77} These phenotypic features are similar to those seen in IBS patients, and thus maternal separation has served as an animal model of IBS.⁵ Perinatal stress is associated with decreased hippocampal GR expression, increased hypothalamic CRF mRNA expression and basal and stress-induced corticosterone levels.^{78, 79} Szyf and colleagues⁸⁰ found a link between maternal licking and grooming in early life and epigenetic alterations at the GR gene locus in the adult offspring, namely increased methylation of the GR exon 1₇ promotor. These findings provide a possible mechanism linking early life psychosocial exposure and long-lasting programming of gene expression elicited by maternal care in rats. Their group also recently reported strong evidence to support a similar mechanism in humans by demonstrating decreased hippocampal GR expression and increased methylation of the GR NR3C1 promoter in suicide victims with a history of childhood abuse compared to suicide victims without abuse and to controls without abuse who died of unrelated causes.⁸¹

Summary and Future Directions

There is strong evidence to support that IBS is a stress-sensitive disorder. In a predisposed individual, sustained stress can result in enhanced responsiveness of central stress circuits, dysregulation of adaptive systems, and an increased vulnerability to develop functional disorders including IBS. EALs have been shown to be associated with multiple medical illnesses and negative health behaviors. Animal models and, more recently, human studies support the impact of early life stress on the subsequent development of IBS symptoms and on persistent stress hyperresponsive which may be mediated by epigenetic programming. Chronic stress has been also shown to affect the clinical course and health outcome in IBS patients. While both central and peripheral mechanisms are likely to play important roles in the initiation of maintenance of IBS symptoms, it is the interactions between brain and gut that appear to play a key role in the stress-induced changes of GI function, autonomic and neuroendocrine responses, and pain modulation. Earlier recognition of stress-related symptoms may help to institute more effective treatment of IBS, such as comprehensive stress management and cognitive behavioral therapy and improve global outcome. Future studies are needed to determine if genetic factors predispose an individual to be more susceptible to the damaging effects of stress and predisposition to IBS.

Abbreviations

IBS

irritable bowel syndrome

CRF

corticotropin releasing factor

PI-IBS

post-infectious irritable bowel syndrome