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

  • Lin Chang
    Correspondence
    Reprint requests Address requests for reprints to: Lin Chang, MD, Center for Neurobiology of Stress, 10833 Le Conte Avenue, CHS 47-122, Los Angeles, California 90095-7378. fax: (310) 206-3343
    Affiliations
    Center for Neurobiology of Stress, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
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Published:January 21, 2011DOI:https://doi.org/10.1053/j.gastro.2011.01.032

      Abbreviations used in this paper:

      ANS (autonomic nervous system), CRF (corticotropin releasing factor), EALs (early adverse life events), GI (gastrointestinal), HPA (hypothalamic–pituitary–adrenal), IBS (irritable bowel syndrome), PI-IBS (postinfectious irritable bowel syndrome)
      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, physiologic reactivity, and other changes in the body that can lead to disease and health-damaging behaviors.
      • McEwen B.S.
      Protective and damaging effects of stress mediators: central role of the brain.
      Chronic overactivity or underactivity of allostatic (or adaptive) systems can occur.
      • McEwen B.S.
      Protective and damaging effects of stress mediators.
      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 demoralization
      • Appels A.
      Mental precursors of myocardial infarction.
      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.
      • Whitehead W.E.
      • Palsson O.
      • Jones K.R.
      Systemic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?.
      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 (Supplementary Figure 1).
      • Mayer E.A.
      • Naliboff B.D.
      • Chang L.
      • et al.
      Stress and the gastrointestinal tract: V. Stress and irritable bowel syndrome.
      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
      • Whitehead W.E.
      • Crowell M.D.
      • Robinson J.C.
      • et al.
      Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared with subjects without bowel dysfunction.
      • Bennett E.J.
      • Tennant C.C.
      • Piesse C.
      • et al.
      Level of chronic life stress predicts clinical outcome in irritable bowel syndrome.
      • Gwee K.A.
      • Leong Y.L.
      • Graham C.
      • et al.
      The role of psychological and biological factors in postinfective gut dysfunction.
      or traumatic
      • Drossman D.A.
      Abuse, trauma, and GI illness: is there a link?.
      life events, the frequently reported comorbidity with anxiety disorders,
      • Creed F.
      The relationship between psychosocial parameters and outcome in the irritable bowel syndrome.
      and peripheral factors such as gut inflammation, motility, and sensation. Understanding the biologic mechanisms of stress hyperresponsiveness in IBS patients may help to identify targets for drug development. Recognition of IBS patients with stress-related IBS symptoms can help to guide management approaches, including earlier and more effective treatment interventions, which can potentially result in a decrease in the disproportionately high health care costs and economic burden associated with IBS. The objectives of this review are to discuss the role of stress in the clinical presentation and course of IBS and the physiologic effects of chronic stress on gastrointestinal (GI) function and central stress response systems. Although this review focuses 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 and IBS

      Early adverse life events (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).
      • Anda R.F.
      • Felitti V.J.
      • Bremner J.D.
      • et al.
      The enduring effects of abuse and related adverse experiences in childhood A convergence of evidence from neurobiology and epidemiology.
      • Felitti V.J.
      • Anda R.F.
      • Nordenberg D.
      • et al.
      Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults The Adverse Childhood Experiences (ACE) Study.
      Medical conditions associated with EALs include autoimmune disorders, chronic obstructive lung disease, asthma, obesity, mood disorders, substance abuse, and prescription drug use.
      • Anda R.F.
      • Felitti V.J.
      • Bremner J.D.
      • et al.
      The enduring effects of abuse and related adverse experiences in childhood A convergence of evidence from neurobiology and epidemiology.
      • Anda R.F.
      • Brown D.W.
      • Dube S.R.
      • et al.
      Adverse childhood experiences and chronic obstructive pulmonary disease in adults.
      • Creed F.
      • Tomenson B.
      • Guthrie E.
      • et al.
      The relationship between somatisation and outcome in patients with severe irritable bowel syndrome.
      Figure thumbnail gr1
      Figure 1Physiologic 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, 2008.
      • Lightman S.L.
      The neuroendocrinology of stress: a never ending story.
      )
      Previous studies have demonstrated that IBS patients have experienced a greater prevalence of physical, verbal, and sexual abuse compared with healthy individuals and patients with organic GI conditions.
      • Chitkara D.K.
      • van Tilburg M.A.
      • Blois-Martin N.
      • et al.
      Early life risk factors that contribute to irritable bowel syndrome in adults: a systematic review.
      • Drossman D.A.
      • Leserman J.
      • Nachman G.
      • et al.
      Sexual and physical abuse in women with functional or organic gastrointestinal disorders.
      • Talley N.J.
      • Fett S.L.
      • Zinsmeister A.R.
      Self-reported abuse and gastrointestinal disease in outpatients: Association with irritable bowel-type symptoms.
      • Salmon P.
      • Skaife K.
      • Rhodes J.
      Abuse, dissociation, and somatization in irritable bowel syndrome: towards an explanatory model.
      • Ross C.A.
      Childhood sexual abuse and psychosomatic symptoms in irritable bowel syndrome.
      Although 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.
      • Chitkara D.K.
      • van Tilburg M.A.
      • Blois-Martin N.
      • et al.
      Early life risk factors that contribute to irritable bowel syndrome in adults: a systematic review.
      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.
      • Videlock E.J.
      • Mayer E.A.
      • Naliboff B.D.
      • et al.
      Childhood trauma and abuse is associated with an increased vulnerability for multiple somatic symptoms including irritable bowel syndrome (IBS).
      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 GI disorders, and that it impacts health-related quality of life.
      • Drossman D.A.
      Abuse, trauma, and GI illness: is there a link?.
      • Creed F.
      • Tomenson B.
      • Guthrie E.
      • et al.
      The relationship between somatisation and outcome in patients with severe irritable bowel syndrome.
      • Van Oudenhove L.
      • Vandenberghe J.
      • Vos R.
      • et al.
      Risk factors for impaired health-related quality of life in functional dyspepsia.
      There is evidence to support that stress affects the clinical outcome in IBS. In a prospective study, Bennett et al
      • Bennett E.J.
      • Tennant C.C.
      • Piesse C.
      • et al.
      Level of chronic life stress predicts clinical outcome in irritable bowel syndrome.
      showed that the presence of ≥1 chronic life stressor during the first 6 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
      • Drossman D.A.
      • Li Z.
      • Leserman J.
      • et al.
      Health status by gastrointestinal diagnosis and abuse history.
      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 Postinfectious IBS

      Studies implicate chronic stress as playing a significant role in increasing the vulnerability to develop IBS.
      • Mayer E.A.
      The neurobiology of stress and gastrointestinal disease.
      Gwee et al
      • Gwee K.A.
      • Leong Y.L.
      • Graham C.
      • et al.
      The role of psychological and biological factors in postinfective gut dysfunction.
      found that stressful life events in the 1 year preceding gastroenteritis and the hypochondriasis score independently predicted postinfectious (PI)-IBS even after controlling for age, gender, marital and employment status, and stool culture results. A subsequent study by Dunlop et al
      • Dunlop S.P.
      • Jenkins D.
      • Neal K.R.
      • et al.
      Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS.
      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 that 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, which is composed of parallel motor outputs from the brain regions involved in emotional function.
      • Mayer E.A.
      The neurobiology of stress and gastrointestinal disease.
      • Holstege G.
      The emotional motor system.
      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.
      • Mayer E.A.
      The neurobiology of stress and gastrointestinal disease.
      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 systems.
      • McEwen B.S.
      Protective and damaging effects of stress mediators: central role of the brain.
      In response to stress, CRF activates the HPA axis and the ANS, including activation of noradrenergic-containing sites, such as the locus coeruleus–noradrenergic system, and other neurotransmitters that are involved in maintaining homeostasis. Release of CRF from the paraventricular nucleus of the hypothalamus is under excitatory input from the central nuclei of the amygdala and inhibitory input from the hippocampus (Supplementary Figure 2).
      • Fish E.W.
      • Shahrokh D.
      • Bagot R.
      • et al.
      Epigenetic programming of stress responses through variations in maternal care.
      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.
      • Owens M.J.
      • Nemeroff C.B.
      Physiology and pharmacology of corticotropin-releasing factor.
      • Kiank C.
      • Tache Y.
      • Larauche M.
      Stress-related modulation of inflammation in experimental models of bowel disease and post-infectious irritable bowel syndrome: role of corticotropin-releasing factor receptors.
      • Martinez V.
      • Taché Y.
      CRF1 receptors as a therapeutic target for irritable bowel syndrome.

       Stress-Induced Alterations in GI Function in IBS

      Although the effects of stress on gut function are universal, patients with IBS seem 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).
      • Welgan P.
      • Meshkinpour H.
      • Beeler M.
      Effect of anger on colon motor and myoelectric activity in irritable bowel syndrome.
      • Dickhaus B.
      • Mayer E.A.
      • Firooz N.
      • et al.
      Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress.
      • Elsenbruch S.
      • Lovallo W.R.
      • Orr W.C.
      Psychological and physiological responses to postprandial mental stress in women with the irritable bowel syndrome.
      • Posserud I.
      • Agerforz P.
      • Ekman R.
      • et al.
      Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.
      Table 1Summary of Stress-Induced Physiologic Changes in IBS
      FunctionFindings in IBS vs controls
      GI motilitySuppressed antral and small bowel motor activity and enhanced colonic motor activity.
      Visceral perceptionDecreased nonpainful and pain rectal 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 secretionIncreased 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 with those with low stress.

      Chloride secretion was lower and albumin was higher in moderate stress vs low stress, but not a significant difference.
      Autonomic toneIncreases in blood pressure and heart rate after mental stress in IBS and controls, but no group differences.
      HPA axisIncreased basal levels of cortisol in IBS vs controls.

      Two studies show increased HPA axis response and 1 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 years ago, Welgan et al demonstrated that IBS patients had higher colonic motor activity at the resting state compared with healthy controls and showed greater increases with various psychological and physical stressors compared with baseline, and controls did not.
      • Welgan P.
      • Meshkinpour H.
      • Beeler M.
      Effect of anger on colon motor and myoelectric activity in irritable bowel syndrome.
      • Welgan P.
      • Meshkinpour H.
      • Hoehler F.
      The effect of stress on colon motor and electrical activity in irritable bowel syndrome.
      In 1 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.
      • Welgan P.
      • Meshkinpour H.
      • Beeler M.
      Effect of anger on colon motor and myoelectric activity in irritable bowel syndrome.
      Several other studies have demonstrated alterations in upper gut (antrum and proximal small bowel) to stress in IBS patients.
      • Welgan P.
      • Meshkinpour H.
      • Ma L.
      Role of anger in antral motor activity in irritable bowel syndrome.
      • Lind C.D.
      Motility disorders in the irritable bowel syndrome.
      • Kellow J.E.
      • Langeluddecke P.M.
      • Eckersley G.M.
      • et al.
      Effects of acute psychologic stress on small-intestinal motility in health and the irritable bowel syndrome.
      • Fukudo S.
      • Nomura T.
      • Hongo M.
      Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome.
      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 et al
      • Posserud I.
      • Agerforz P.
      • Ekman R.
      • et al.
      Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.
      demonstrated that although healthy controls had higher sensory thresholds (decreased perception) to nonpainful 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 with controls. Dickhaus et al
      • Dickhaus B.
      • Mayer E.A.
      • Firooz N.
      • et al.
      Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress.
      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 versus relaxation condition in IBS patients but not in controls. Murray et al
      • Murray C.D.
      • Flynn J.
      • Ratcliffe L.
      • et al.
      Effect of acute physical and psychological stress on gut autonomic innervation in irritable bowel syndrome.
      found that lower nonpainful 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. The lack of 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 with healthy controls.
      • Dunlop S.P.
      • Hebden J.
      • Campbell E.
      • et al.
      Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes.
      • Zhou Q.
      • Zhang B.
      • Verne G.N.
      Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome.
      Barbara et al demonstrated that colonic biopsies from IBS patients had increased paracellular permeability
      • Piche T.
      • Barbara G.
      • Aubert P.
      • et al.
      Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators.
      and release of mediators including tryptase, histamine, and prostaglandin E2,
      • Barbara G.
      • Wang B.
      • Stanghellini V.
      • et al.
      Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome.
      compared with 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.
      • Piche T.
      • Barbara G.
      • Aubert P.
      • et al.
      Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators.
      Animal studies suggest that stress-induced increases in paracellular and transcellular permeability in the ileum and colon are mediated via CRF1 receptors.
      • Larauche M.
      • Kiank C.
      • Tache Y.
      Corticotropin releasing factor signaling in colon and ileum: regulation by stress and pathophysiological implications.
      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.
      • Alonso C.
      • Guilarte M.
      • Vicario M.
      • et al.
      Maladaptive intestinal epithelial responses to life stress may predispose healthy women to gut mucosal inflammation.
      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

       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.
      • Mayer E.A.
      • Naliboff B.D.
      • Chang L.
      Evolving pathophysiological model of functional gastrointestinal disorders: Implications for treatment.
      • Crowell M.D.
      • Harris L.
      • Jones M.P.
      • et al.
      New insights into the pathophysiology of irritable bowel syndrome: implications for future treatments.
      Through its 3 divisions, the ANS modulates and coordinates GI motility, secretion, and immune function.
      • Elenkov I.J.
      • Wilder R.L.
      • Chrousos G.P.
      • et al.
      The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system.
      • Hansen M.B.
      The enteric nervous system I: organisation and classification.
      In addition to the alterations in gut motility and transit that have been reported in IBS,
      • Camilleri M.
      • McKinzie S.
      • Busciglio I.
      • et al.
      Prospective study of motor, sensory, psychologic, and autonomic functions in patients with irritable bowel syndrome.
      studies measuring cardioautonomic tone in IBS further support that dysregulations in ANS exist in IBS.
      • Cain K.C.
      • Jarrett M.E.
      • Burr R.L.
      • et al.
      Heart rate variability is related to pain severity and predominant bowel pattern in women with irritable bowel syndrome.
      • Heitkemper M.
      • Burr R.L.
      • Jarrett M.
      • et al.
      Evidence for autonomic nervous system imbalance in women with irritable bowel syndrome.
      • Tillisch K.
      • Mayer E.A.
      • Labus J.S.
      • et al.
      Sex-specific alterations in autonomic function among patients with irritable bowel syndrome.
      Increased sympathetic nervous system activity and decreased parasympathetic nervous system activity are the most frequently noted differences when IBS patients are compared with healthy controls.
      • Heitkemper M.
      • Jarrett M.
      • Cain K.C.
      • et al.
      Autonomic nervous system function in women with irritable bowel syndrome.
      • Aggarwal A.
      • Cutts T.F.
      • Abell T.L.
      • et al.
      Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities.
      • Thompson J.J.
      • Elsenbruch S.
      • Harnish M.J.
      • et al.
      Autonomic functioning during REM sleep differentiates IBS symptom subgroups.
      • Burr R.L.
      • Heitkemper M.
      • Jarrett M.
      • et al.
      Comparison of autonomic nervous system indices based on abdominal pain reports in women with irritable bowel syndrome.
      • Waring W.S.
      • Chui M.
      • Japp A.
      • et al.
      Autonomic cardiovascular responses are impaired in women with irritable bowel syndrome.
      Enhanced cardiosympathetic and decreased cardiovagal tone have been demonstrated in subgroups of IBS patients during 24-hour monitoring
      • Cain K.C.
      • Jarrett M.E.
      • Burr R.L.
      • et al.
      Heart rate variability is related to pain severity and predominant bowel pattern in women with irritable bowel syndrome.
      • Heitkemper M.
      • Burr R.L.
      • Jarrett M.
      • et al.
      Evidence for autonomic nervous system imbalance in women with irritable bowel syndrome.
      and during rectosigmoid distension.
      • Tillisch K.
      • Mayer E.A.
      • Labus J.S.
      • et al.
      Sex-specific alterations in autonomic function among patients with irritable bowel syndrome.
      Measurements of cardioautonomic responses to stress are very limited in IBS. Elsenbruch et al
      • Elsenbruch S.
      • Lovallo W.R.
      • Orr W.C.
      Psychological and physiological responses to postprandial mental stress in women with the irritable bowel syndrome.
      • Elsenbruch S.
      • Lucas A.
      • Holtmann G.
      • et al.
      Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome.
      compared autonomic responses with stressful mental tasks in female IBS patients and controls. A significant decrease in sympathetic activity followed by a rebound sympathetic activation was only seen in IBS and control subjects who perceived the mental task as at least moderately stressful.
      • Elsenbruch S.
      • Lovallo W.R.
      • Orr W.C.
      Psychological and physiological responses to postprandial mental stress in women with the irritable bowel syndrome.
      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.
      • Elsenbruch S.
      • Lucas A.
      • Holtmann G.
      • et al.
      Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome.
      Two studies found elevated basal plasma levels of norepinephrine in IBS patients versus controls, but no significant changes in response to a psychological stressor.
      • Dickhaus B.
      • Mayer E.A.
      • Firooz N.
      • et al.
      Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress.
      • Posserud I.
      • Agerforz P.
      • Ekman R.
      • et al.
      Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.
      Thus, these studies suggest that, although 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 paraventricular nucleus 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 (Supplementary Figure 2). CRF synthesis and release are subsequently inhibited through a glucocorticoid negative feedback system mediated by both glucocorticoid and mineralocorticoid receptors in the paraventricular nucleus, pituitary gland and hippocampus.
      • Fish E.W.
      • Shahrokh D.
      • Bagot R.
      • et al.
      Epigenetic programming of stress responses through variations in maternal care.
      Although dysregulations in HPA axis activity have also been reported in IBS,
      • Posserud I.
      • Agerforz P.
      • Ekman R.
      • et al.
      Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.
      • Tillisch K.
      • Mayer E.A.
      • Labus J.S.
      • et al.
      Sex-specific alterations in autonomic function among patients with irritable bowel syndrome.
      • Heitkemper M.
      • Jarrett M.
      • Cain K.C.
      • et al.
      Autonomic nervous system function in women with irritable bowel syndrome.
      • Chang L.
      • Sundaresh S.
      • Elliott J.
      • et al.
      Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.
      • Videlock E.J.
      • Adeyemo M.
      • Licudine A.
      • et al.
      Childhood trauma is associated with hypothalamic-pituitary-adrenal axis responsiveness in irritable bowel syndrome.
      • Dinan T.G.
      • Quigley E.M.
      • Ahmed S.M.
      • et al.
      Hypothalmic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential marker?.
      • Patacchioli F.R.
      • Angelucci L.
      • Dellerba G.
      • et al.
      Actual stress, psychopathology and salivary cortisol levels in the irritable bowel syndrome (IBS).
      • Bohmelt A.H.
      • Nater U.M.
      • Franke S.
      • et al.
      Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls.
      • Burr R.L.
      • Jarrett M.E.
      • Cain K.C.
      • et al.
      Catecholamine and cortisol levels during sleep in women with irritable bowel syndrome.
      • Elsenbruch S.
      • Orr W.C.
      Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses.
      • Zhou Q.
      • Fillingim R.B.
      • Riley 3rd, J.L.
      • et al.
      Central and peripheral hypersensitivity in the irritable bowel syndrome.
      • FitzGerald L.Z.
      • Kehoe P.
      • Sinha K.
      Hypothalamic–pituitary–adrenal axis dysregulation in women with irritable bowel syndrome in response to acute physical stress.
      there are conflicting reports with respect to both basal and stress or hormone stimulated responses (Supplementary Table 1). Studies have reported increased basal cortisol levels
      • Chang L.
      • Sundaresh S.
      • Elliott J.
      • et al.
      Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.
      • Patacchioli F.R.
      • Angelucci L.
      • Dellerba G.
      • et al.
      Actual stress, psychopathology and salivary cortisol levels in the irritable bowel syndrome (IBS).
      • Burr R.L.
      • Jarrett M.E.
      • Cain K.C.
      • et al.
      Catecholamine and cortisol levels during sleep in women with irritable bowel syndrome.
      and enhanced responses to physical
      • Videlock E.J.
      • Adeyemo M.
      • Licudine A.
      • et al.
      Childhood trauma is associated with hypothalamic-pituitary-adrenal axis responsiveness in irritable bowel syndrome.
      • Zhou Q.
      • Fillingim R.B.
      • Riley 3rd, J.L.
      • et al.
      Central and peripheral hypersensitivity in the irritable bowel syndrome.
      or psychological
      • Posserud I.
      • Agerforz P.
      • Ekman R.
      • et al.
      Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.
      • Elsenbruch S.
      • Orr W.C.
      Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses.
      stressors and hormone stimulation,
      • Fukudo S.
      • Nomura T.
      • Hongo M.
      Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome.
      • Dinan T.G.
      • Quigley E.M.
      • Ahmed S.M.
      • et al.
      Hypothalmic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential marker?.
      but also blunted HPA axis responses
      • Bohmelt A.H.
      • Nater U.M.
      • Franke S.
      • et al.
      Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls.
      • FitzGerald L.Z.
      • Kehoe P.
      • Sinha K.
      Hypothalamic–pituitary–adrenal axis dysregulation in women with irritable bowel syndrome in response to acute physical stress.
      or no difference between IBS and control groups.
      • Elsenbruch S.
      • Lovallo W.R.
      • Orr W.C.
      Psychological and physiological responses to postprandial mental stress in women with the irritable bowel syndrome.
      • Elsenbruch S.
      • Lucas A.
      • Holtmann G.
      • et al.
      Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome.
      • Elsenbruch S.
      • Holtmann G.
      • Oezcan D.
      • et al.
      Are there alterations of neuroendocrine and cellular immune responses to nutrients in women with irritable bowel syndrome?.
      These differences may be due to differences in study methodology and/or the patient populations (eg, psychological comorbidity) studied.
      • Videlock E.J.
      • Adeyemo M.
      • Licudine A.
      • et al.
      Childhood trauma is associated with hypothalamic-pituitary-adrenal axis responsiveness in irritable bowel syndrome.
      Blunted basal ACTH levels were found in the presence of elevated cortisol levels over 24 hours, which is likely a reflection of enhanced negative feedback of cortisol and/or down-regulation of CRF1 receptors at the pituitary gland level.
      • Chang L.
      • Sundaresh S.
      • Elliott J.
      • et al.
      Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.
      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 with 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,
      • Heim C.
      • Newport D.J.
      • Bonsall R.
      • et al.
      Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse.
      • Heim C.
      • Newport D.J.
      • Heit S.
      • et al.
      Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood.
      parental loss during childhood,
      • Tyrka A.R.
      • Wier L.
      • Price L.H.
      • et al.
      Childhood parental loss and adult hypothalamic-pituitary-adrenal function.
      and EALs and high levels of chronic stress.
      • Rao U.
      • Hammen C.
      • Ortiz L.R.
      • et al.
      Effects of early and recent adverse experiences on adrenal response to psychosocial stress in depressed adolescents.
      Videlock et al
      • Videlock E.J.
      • Adeyemo M.
      • Licudine A.
      • et al.
      Childhood trauma is associated with hypothalamic-pituitary-adrenal axis responsiveness in irritable bowel syndrome.
      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 health-related quality of life. 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 owing 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.
      • Coutinho S.V.
      • Plotsky P.M.
      • Sablad M.
      • et al.
      Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat.
      • Gareau M.G.
      • Jury J.
      • Perdue M.H.
      Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability.
      • Gareau M.G.
      • Jury J.
      • Yang P.C.
      • et al.
      Neonatal maternal separation causes colonic dysfunction in rat pups including impaired host resistance.
      • Ladd C.O.
      • Owens M.J.
      • Nemeroff C.B.
      Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation.
      These phenotypic features are similar to those seen in IBS patients, and thus maternal separation has served as an animal model of IBS.
      • Mayer E.A.
      • Naliboff B.D.
      • Chang L.
      • et al.
      Stress and the gastrointestinal tract: V. Stress and irritable bowel syndrome.
      Perinatal stress is associated with decreased hippocampal GR expression, increased hypothalamic CRF mRNA expression, and basal and stress-induced corticosterone levels.
      • Liu D.
      • Diorio J.
      • Tannenbaum B.
      • et al.
      Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress.
      • Meaney M.J.
      • Szyf M.
      • Seckl J.R.
      Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health.
      Szyf et al
      • Szyf M.
      • Weaver I.C.G.
      • Champagne F.A.
      • et al.
      Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat.
      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 with suicide victims without abuse and to controls without abuse who died of unrelated causes.
      • McGowan P.O.
      • Sasaki A.
      • D'Alessio A.C.
      • et al.
      Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.

      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 hyperresponsiveness, which may be mediated by epigenetic programming. Chronic stress has been also shown to affect the clinical course and health outcome in IBS patients. Although both central and peripheral mechanisms are likely to play important roles in the initiation and maintenance of IBS symptoms, it is the interactions between brain and gut that seem 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 whether genetic factors predispose an individual to be more susceptible to the damaging effects of stress and predisposition to IBS.

      Supplementary material

      Figure thumbnail gre1
      Supplementary Figure 1The role of stress in the development and modulation of IBS symptoms.
      • Mayer E.A.
      • Naliboff B.D.
      • Chang L.
      • et al.
      Stress and the gastrointestinal tract: V. Stress and irritable bowel syndrome.
      Different types of stressors may play a role in the permanent biasing of stress responsiveness, the transient activation of the stress response, the increased vulnerability of developing IBS, and the persistence of symptoms
      (From Mayer EA et al,
      • Mayer E.A.
      • Naliboff B.D.
      • Chang L.
      • et al.
      Stress and the gastrointestinal tract: V. Stress and irritable bowel syndrome.
      with permission).
      Figure thumbnail gre2
      Supplementary Figure 2The stress system. The HPA axis has been studied extensively in the stress response. Neurons in the medial parvocellular region of the PVN of the hypothalamus release corticotropin releasing hormone (CRH) and arginine vasopressin (AVP). This then triggers the secretion of adrenocorticotropin hormone (ACTH) from the pituitary gland, subsequently leading to the production of glucocorticoids by the adrenal cortex. The stress-induced responsiveness of the HPA axis is in part modulated by the ability of glucocorticoids to regulate ACTH and CRF release by binding to 2 corticosteroid receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which are part of the feedback loop. Under normal physiologic conditions, after the HPA axis is activated and the stressor is perceived to have subsided, these feedback loops are triggered at various levels of the system to shut down the HPA axis and return to a set homeostatic point. However, the amygdala has a feed-forward mechanism to activate the HPA axis during stress to deal with the challenge.
      Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Neuroscience 2009;10:434–445, copyright 2009.
      Supplementary Table 1Basal and Stimulated Levels of HPA Axis Hormones in IBS
      StudyDiagnosis (n)StimulusSourceTime of collectionACTH levels

      (IBS vs controls)
      Cortisol levels

      (IBS vs controls)
      Basal levels
       Heitkemper 1996
      • Heitkemper M.
      • Jarrett M.
      • Cain K.
      • et al.
      Increased urine catecholamines and cortisol in women with irritable bowel syndrome.
      IBS (24)

      IBS non-patients (24)

      Controls (25)
      NAUrineam and pmTrend for ↑
       Patacchioli 2001
      • Patacchioli F.R.
      • Angelucci L.
      • Dellerba G.
      • et al.
      Actual stress, psychopathology and salivary cortisol levels in the irritable bowel syndrome (IBS).
      IBS (55)

      Controls (28)
      NASalivaam and pm
       Bohmelt 2005
      • Bohmelt A.H.
      • Nater U.M.
      • Franke S.
      • et al.
      Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls.
      IBS/NUD (30)

      Controls (24)
      NASaliva8am, 11am, 3pm, 8pm
       Burr NGM 2009
      • Burr R.L.
      • Jarrett M.E.
      • Cain K.C.
      • et al.
      Catecholamine and cortisol levels during sleep in women with irritable bowel syndrome.
      IBS (30)

      Controls (31)
      NABloodq20min, 8pm to awake↑ in IBS-C
       Chang 2009
      • Chang L.
      • Sundaresh S.
      • Elliott J.
      • et al.
      Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.
      IBS (24)

      IBS+FM (16)

      Controls (25)
      NABloodq10min × 24 hrs
      Hormone challenge
       Bohmelt 2005
      • Bohmelt A.H.
      • Nater U.M.
      • Franke S.
      • et al.
      Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls.
      IBS/NUD (30)

      Controls (24)
      CRFBlood

      Saliva
      Baseline and 20, 30, 45, 60, 90, and 120 min after CRF
       Dinan 2006
      • Dinan T.G.
      • Quigley E.M.
      • Ahmed S.M.
      • et al.
      Hypothalmic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential marker?.
      IBS (21)

      Controls (21)
      CRFBloodBaseline and immediately and 15, 30, 45, 60, 90, and 120 minutes after CRF
       Fukudo 1998
      • Fukudo S.
      • Nomura T.
      • Hongo M.
      Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome.
      IBS (10)

      Controls (10)
      CRFBloodStandard collectionNo difference
      Meal and/or mental stressor
       Elsenbruch 2001
      • Elsenbruch S.
      • Orr W.C.
      Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses.
      IBS (24)

      Controls (20)
      Standard mealSalivaBaseline × 2, immediately and 30 and 60 min after meal↑ IBS-D/A post-meal vs baseline but no group difference
       Elsenbruch 2001
      • Elsenbruch S.
      • Lovallo W.R.
      • Orr W.C.
      Psychological and physiological responses to postprandial mental stress in women with the irritable bowel syndrome.
      IBS (24)

      Controls (20)
      Standard meal + Modified Stroop testSalivaBaseline × 2, immediately after meal, after stressor/rest period, after recovery periodNo difference
       Walter 2006
      • Walter S.A.
      • Aardal-Eriksson E.
      • Thorell L.H.
      • et al.
      Pre-experimental stress in patients with irritable bowel syndrome: high cortisol values already before symptom provocation with rectal distensions.
      IBS (27)

      Functional constipation (13)

      Controls (18)
      Liquid meal + rectal distensionsSaliva8am, 1pm, 3pm, 10pm on day without stressor and day of stressorNo difference
       Elsenbruch 2004
      • Elsenbruch S.
      • Holtmann G.
      • Oezcan D.
      • et al.
      Are there alterations of neuroendocrine and cellular immune responses to nutrients in women with irritable bowel syndrome?.
      IBS (15)

      Controls (15)
      Liquid nutrient loadBloodBaseline, immediately and 15, 45, 75, 105 min after mealNo difference
       Elsenbruch 2006
      • Elsenbruch S.
      • Lucas A.
      • Holtmann G.
      • et al.
      Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome.
      IBS (17)

      Controls (12)
      Public speakingBloodBaseline and immediately and 45 min after stressorNo differenceNo difference
       Posserud 2004
      • Posserud I.
      • Agerforz P.
      • Ekman R.
      • et al.
      Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.
      IBS (18)

      Controls (22)
      Mental stress + rectal distensionsBloodAfter distension only and after stress + distension↑ CRF and ACTH in IBS and not controls; no group differenceNo difference
      Physical stressor
       Videlock 2009
      • Videlock E.J.
      • Adeyemo M.
      • Licudine A.
      • et al.
      Childhood trauma is associated with hypothalamic-pituitary-adrenal axis responsiveness in irritable bowel syndrome.
      IBS (44)

      Controls (39)
      SigmoidoscopySalivaBaseline and immediately and 10, 20, 30, 45, and 60 min after stressorNo difference
       FitzGerald 2009
      • FitzGerald L.Z.
      • Kehoe P.
      • Sinha K.
      Hypothalamic–pituitary–adrenal axis dysregulation in women with irritable bowel syndrome in response to acute physical stress.
      IBS-D (F, 13)

      Controls (F, 13)
      Lumbar punctureBlood

      Saliva
      Every 15 min for 1 hour before and after the stressor
       Zhou 2010
      • Zhou Q.
      • Fillingim R.B.
      • Riley 3rd, J.L.
      • et al.
      Central and peripheral hypersensitivity in the irritable bowel syndrome.
      IBS-D (78)

      Controls (57)
      Ischemic arm testBloodBaseline, immediately after stressor, 60 min after stressor
       Zhou 2010
      • Zhou Q.
      • Fillingim R.B.
      • Riley 3rd, J.L.
      • et al.
      Central and peripheral hypersensitivity in the irritable bowel syndrome.
      IBS-D (78)

      Controls (57)
      Thermal, mechanical, and cold pressorBloodBaseline, immediately after stressor, 60 min after stressorNo differenceNo difference
      ACTH, adrenocorticotrophic hormone; FM, fibromyalgia; IBS-C, constipation-predominant IBS; IBS-D, diarrhea-predominant IBS; NUD, non–ulcer dyspepsia.

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