Neuroendocrine and Neuroimmune Markers in IBS: Pathophysiological Role or Epiphenomenon?
2006; Elsevier BV; Volume: 130; Issue: 2 Linguagem: Inglês
10.1053/j.gastro.2005.12.047
ISSN1528-0012
Autores Tópico(s)Child Nutrition and Feeding Issues
ResumoA growing body of evidence suggests that chronic stressors may be important in the onset and maintenance of irritable bowel syndrome (IBS). Sustained, threatening life events (psychosocial stressors) predict symptom exacerbation in patients with IBS1Whitehead W.E. Crowell M.D. Robinson J.C. Heller B.R. Schuster M.M. Effects of stressful life events on bowel symptoms subjects with irritable bowel syndrome compared with subjects without bowel dysfunction.Gut. 1992; 33: 825-830Crossref PubMed Scopus (369) Google Scholar, 2Bennett E.J. Tennant C.C. Piesse C. Badcock C.A. Kellow J.E. Level of chronic life stress predicts clinical outcome in irritable bowel syndrome.Gut. 1998; 43: 256-261Crossref PubMed Scopus (343) Google Scholar and the development of IBS symptoms in asymptomatic individuals following a gastroenteric infection ("post-infectious IBS").3Gwee K.A. Leong Y.L. Graham C. McKendrick M.W. Collins S.M. Walters S.J. Underwood J.E. Read N.W. The role of psychological and biological factors in postinfective gut dysfunction.Gut. 1999; 44: 400-406Crossref PubMed Scopus (708) Google Scholar, 4Dunlop S.P. Jenkins D. Neal K.R. Spiller R.C. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS.Gastroenterology. 2003; 125: 1651-1659Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar Compared with patients with organic disease and healthy controls, a significantly greater proportion of patients with IBS have reported histories of childhood physical assault and adult physical and sexual abuse.5Drossman D.A. Leserman J. Nachman G. Li Z.M. Gluck H. Toomey T.C. Mitchell C.M. Sexual and physical abuse in women with functional or organic gastrointestinal disorders.Ann Intern Med. 1990; 113: 828-833Crossref PubMed Scopus (783) Google Scholar, 6Drossman D.A. Li Z. Leserman J. Toomey T.C. Hu Y.J. Health status by gastrointestinal diagnosis and abuse history.Gastroenterology. 1996; 110: 999-1007Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Evolving clinical, epidemiological, and experimental evidence supports a neurobiological model of IBS that includes a prominent role for altered central stress system circuits, referred to as the emotional motor system.7Mayer E.A. Emerging disease model for functional gastrointestinal disorders.Am J Med. 1999; 107: 12S-19SAbstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar This system is associated with an inadequate antinociceptive response to visceral stimuli,8Mertz H. Naliboff B. Munakata J. Niazi N. Mayer E.A. Altered rectal perception is a biological marker of patients with irritable bowel syndrome.Gastroenterology. 1995; 109: 40-52Abstract Full Text PDF PubMed Scopus (913) Google Scholar, 9Munakata J. Naliboff B. Harraf F. Kodner A. Lembo T. Chang L. Silverman D.H. Mayer E.A. 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Abrahamsson H. Simren M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.Gut. 2004; 53: 1102-1108Crossref PubMed Scopus (247) Google Scholar altered autonomic nervous system activity,12Dickhaus B. Mayer E.A. Firooz N. Stains J. Conde F. Olivas T.I. Fass R. Chang L. Mayer M. Naliboff B.D. Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress.Am J Gastroenterol. 2003; 98: 135-143Crossref PubMed Scopus (179) Google Scholar, 14Tillisch K. Mayer E.A. Labus J.S. Stains J. Chang L. Naliboff B.D. Sex-specific alterations in autonomic function among patients with irritable bowel syndrome.Gut. 2005; 54: 1396-1401Crossref PubMed Scopus (123) Google Scholar, 15Heitkemper M. Jarrett M. Cain K.C. Burr R. Levy R.L. Feld A. Hertig V. Autonomic nervous system function in women with irritable bowel syndrome.Dig Dis Sci. 2001; 46: 1276-1284Crossref PubMed Scopus (104) Google Scholar, 16Elsenbruch S. Lovallo W.R. Orr W.C. Psychological and physiological responses to postprandial mental stress in women with the irritable bowel syndrome.Psychosom Med. 2001; 63: 805-810Crossref PubMed Scopus (49) Google Scholar, 17Elsenbruch S. Orr W.C. Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses.Am J Gastroenterol. 2001; 96: 460-466Crossref PubMed Google Scholar and altered hypothalamic-pituitary-adrenal (HPA) axis responses.18Fukudo 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.Gut. 1999; 42: 845-849Crossref Scopus (318) Google Scholar Traditionally, the HPA axis and the sympathetic nervous system have been considered the 2 main branches of the central stress response.19Elenkov I.J. Wilder R.L. Chrousos G.P. Vizi E.S. The sympathetic nerve– an integrative interface between two supersystems the brain and the immune system.Pharmacol Rev. 2000; 52: 585-638Google Scholar Neurons in the paraventricular nucleus of the hypothalamus secrete corticotropin-releasing factor (CRF) which, in turn, stimulates secretion of adrenocorticotropin hormone (ACTH) from the pituitary gland. ACTH then acts on the adrenal medulla resulting in the release of cortisol. Release of CRF from the paraventricular nucleus is under excitatory input from the amygdala and inhibitory input from the hippocampus. In addition to its key role in regulating the endocrine response to stress, CRF is crucially involved in mediating stress-related autonomic, immune, behavioral, and visceral responses.20Dunn A.J. Berridge C.W. Physiological and behavioral response to corticotropin-releasing factor administration is CRF a mediator of anxiety or stress responses?.Brain Res Brain Res Rev. 1990; 15: 71-100Crossref PubMed Scopus (1272) Google Scholar, 21Owens M.J. Nemeroff C.B. Physiology and pharmacology of corticotropin-releasing factor.Pharmacol Rev. 1991; 43: 425-473PubMed Google Scholar, 22Turnbull A.V. Rivier C. Corticotropin-releasing factor (CRF) and endocrine responses to stress CRF receptors, binding protein, and related peptides.Proc Soc Exp Biol Med. 1997; 215: 1-10Crossref PubMed Scopus (237) Google Scholar, 23Taché Y. Million M. Nelson A.G. Lamy C. Wang L. Role of corticotropin-releasing factor pathways in stress-related alterations of colonic motor function and viscerosensibility in female rodents.Gend Med. 2005; 2: 145-154Abstract Full Text PDF Scopus (59) Google Scholar Although there are many studies in IBS patients evaluating alterations in perceptual and autonomic responses, there are relatively few examining HPA axis activity. As levels of CRF released from the hypothalamus cannot be accurately measured in peripheral blood samples, HPA axis activity is usually assessed by ACTH and cortisol measurements. With the development of therapeutic agents for IBS that are targeted on receptor sites along the HPA axis (eg, CRF antagonist),24Sagami Y. Shimada Y. Tayama J. Nomura T. Satake M. Endo Y. Shoji T. Karahashi K. Hongo M. Fukudo S. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome.Gut. 2004; 53: 958-964Crossref PubMed Scopus (245) Google Scholar current understanding of the role of the HPA axis in IBS is particularly relevant. The HPA axis is a highly dynamic system that has an intrinsic diurnal and pulsatile rhythm that can be stimulated under certain conditions (eg, infection, sleep deprivation, psychological stress). There is limited data evaluating HPA axis responses at baseline and to hormone challenge and experimental stress in IBS patients, and the results are often conflicting. Basal cortisol levels have been measured in a small number of studies. Heitkemper et al reported generally increased urine cortisol levels in a subset of patients with IBS compared with healthy individuals.25Heitkemper M. Jarrett M. Cain K. Shaver J. Bond E. Woods N.F. Walker E. Increased urine catecholamines and cortisol in women with irritable bowel syndrome.Am J Gastroenterol. 1996; 91: 906-913PubMed Google Scholar In contrast, Bohmelt et al found blunted mean salivary cortisol levels after awakening in patients with functional gastrointestinal disorders.26Bohmelt A.H. Nater U.M. Franke S. Hellhammer D.H. Ehlert U. Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls.Psychosom Med. 2005; 67: 288-294Crossref PubMed Scopus (107) Google Scholar The patient group in this study was comprised of those with IBS only (n = 10), functional dyspepsia only (n = 5), and both IBS and functional dyspepsia (n = 15). There was a high prevalence of psychiatric co-morbidity in the patient group.27Ehlert U. Nater U.M. Bohmelt A. High and low unstimulated salivary cortisol levels correspond to different symptoms of functional gastrointestinal disorders.J Psychosom Res. 2005; 59: 7-10Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar The studies by Heitkemper and Bohmelt both collected samples for cortisol at only a few selected time points. A more recent study using serial plasma samples (every 10 minutes) that compared diurnal rhythm and pulsatility over 24 hours in IBS patients without psychiatric comorbidity and healthy controls found blunted basal ACTH levels associated with mildly elevated cortisol levels in IBS patients suggestive of a dysregulated HPA axis in IBS, specifically that of an enhanced HPA axis with greater negative feedback control of cortisol.28Chang L. Sundaresh S. Baldi P. Licudine A. Mayer M. Vuong T. Hirano M. Olivas T.I. Liu C. Naliboff B.D. Mayer E.A. Dysregulation of basal circadian and pulsatile secretion of hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome and fibromyalgia.Gastroenterology. 2005; 128: A620-A621Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar Similar to the conflicting reports on baseline HPA axis measures in IBS, those on stimulated cortisol responses in IBS have also shown inconsistent findings. With regard to postprandial cortisol responses in IBS, one study demonstrated increases in salivary cortisol levels in IBS-D, but not IBS-C, compared with healthy controls.17Elsenbruch S. Orr W.C. Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses.Am J Gastroenterol. 2001; 96: 460-466Crossref PubMed Google Scholar However, a second study by the same authors failed to show changes in postprandial plasma cortisol levels.17Elsenbruch S. Orr W.C. Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses.Am J Gastroenterol. 2001; 96: 460-466Crossref PubMed Google Scholar There are 2 studies that measured HPA axis responses to hormone challenge18Fukudo 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.Gut. 1999; 42: 845-849Crossref Scopus (318) Google Scholar, 26Bohmelt A.H. Nater U.M. Franke S. Hellhammer D.H. Ehlert U. Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls.Psychosom Med. 2005; 67: 288-294Crossref PubMed Scopus (107) Google Scholar and two other studies which evaluated responses to mental stress.12Dickhaus B. Mayer E.A. Firooz N. Stains J. Conde F. Olivas T.I. Fass R. Chang L. Mayer M. Naliboff B.D. Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress.Am J Gastroenterol. 2003; 98: 135-143Crossref PubMed Scopus (179) Google Scholar, 13Posserud I. Agerforz P. Ekman R. Bjornsson E.S. Abrahamsson H. Simren M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.Gut. 2004; 53: 1102-1108Crossref PubMed Scopus (247) Google Scholar Fukudo et al found increased plasma ACTH, but normal cortisol levels, in response to ovine CRF injection,18Fukudo 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.Gut. 1999; 42: 845-849Crossref Scopus (318) Google Scholar whereas Bohmelt et al demonstrated both blunted plasma ACTH responses and plasma and salivary cortisol levels to the same stimulus.26Bohmelt A.H. Nater U.M. Franke S. Hellhammer D.H. Ehlert U. Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls.Psychosom Med. 2005; 67: 288-294Crossref PubMed Scopus (107) Google Scholar In response to simultaneous mental stress and rectal distension, one study found increased plasma ACTH, but not cortisol levels, compared with controls,13Posserud I. Agerforz P. Ekman R. Bjornsson E.S. Abrahamsson H. Simren M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.Gut. 2004; 53: 1102-1108Crossref PubMed Scopus (247) Google Scholar while the other found no differences in ACTH and cortisol levels compared with controls.12Dickhaus B. Mayer E.A. Firooz N. Stains J. Conde F. Olivas T.I. Fass R. Chang L. Mayer M. Naliboff B.D. Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress.Am J Gastroenterol. 2003; 98: 135-143Crossref PubMed Scopus (179) Google Scholar One may speculate that the reported differences in the results of these studies may be related to a variety of factors, including methodology and small sample sizes. Most importantly, the heterogeneity of patients studied (in terms of symptom severity, presence of symptom flare at the time of study, etiology, trauma history, psychiatric co-morbidity, responsiveness of adrenal glands to ACTH, etc) may introduce a considerable variability in the observed results. Despite the limitations, published studies to date are consistent with the concept that the HPA axis may be dysregulated in some IBS patients. The majority of studies support an enhanced HPA axis responsiveness, manifesting both during basal and stimulated conditions in IBS without psychiatric co-morbidity. During basal conditions, cortisol appears to exert a negative feedback effect on the pituitary gland, resulting in blunted ACTH secretion and HPA axis activity. In contrast, the reactivity of the HPA axis to a stressor may be variable and dependent on the significance of the stressor to the respective individual. In IBS patients with psychiatric co-morbidity (eg, depression or post-traumatic stress disorder [PTSD]), which has been associated with greater chronic symptom severity,29Drossman D.A. Camilleri M. Mayer E.A. Whitehead W.E. AGA technical review on irritable bowel syndrome.Gastroenterology. 2002; 123: 2108-2131Abstract Full Text Full Text PDF PubMed Scopus (1211) Google Scholar the stimulated HPA axis responses are blunted. HPA axis studies in depression support that these findings are due to a hyperactivity of central CRF systems and down-regulation of CRF1 receptors on the pituitary gland.30Heim C. Plotsky P.M. Nemeroff C.B. Importance of studying the contributions of early adverse experience to neurobiological findings in depression.Neuropsychopharmacology. 2004; 29: 641-648Crossref PubMed Scopus (430) Google Scholar The associated blunted cortisol responses suggest a relative adrenocortical insufficiency that may increase the risk for the development of immune-related or pain disorders. A compromised negative feedback may additionally drive central CRF release and symptoms of stress, depression, and anxiety because of the behavioral effects of CRF on extrahypothalamic sites.31Heim C. Newport D.J. Bonsall R. Miller A.H. Nemeroff C.B. Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse.Am J Psychiatry. 2001; 158: 575-581Crossref PubMed Scopus (595) Google Scholar In view of the recent increase in publications postulating altered immune activation as a mechanism in the pathophysiology of IBS, it is important to understand the relationships between stress, HPA axis responsiveness, and gut immune function. For example, a number of studies have demonstrated increased mast cell numbers in the colonic mucosa,32O'Sullivan M. Clayton N. Breslin N.P. Harman I. Bountra C. McLaren A. O'Morain C.A. Increased mast cells in the irritable bowel syndrome.Neurogastroenterol Motil. 2000; 12: 449-457Crossref PubMed Scopus (435) Google Scholar, 33Barbara G. Stanghellini V. De Giorgio R. Cremon C. Cottrell G.S. Santini D. Pasquinelli G. Morselli-Labate A.M. Grady E.F. Bunnett N.W. Collins S.M. Corinaldesi R. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.Gastroenterology. 2004; 126: 693-702Abstract Full Text Full Text PDF PubMed Scopus (1183) Google Scholar and increased cellularity of the colonic mucosa and lamina propria in selected4Dunlop S.P. Jenkins D. Neal K.R. Spiller R.C. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS.Gastroenterology. 2003; 125: 1651-1659Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar, 34Gwee K.A. Collins S.M. Marshall J.S. Underwood J.E. Moochala S.M. Read N.W. Evidence of inflammatory pathogenesis in post-infectious irritable bowel syndrome.Gastroenterology. 1998; 114: 758Google Scholar and unselected IBS patients.35Chadwick V.S. Chen W. Shu D. Paulus B. Bethwaite P. Tie A. Wilson I. Activation of the mucosal immune system in irritable bowel syndrome.Gastroenterology. 2002; 122: 1778-1783Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar As stress can influence both innate and specific immune responses via the HPA axis and the sympathetic nervous system,36Chrousos G.P. Stress, chronic inflammation, and emotional and physical well-being concurrent effects and chronic sequelae.J Allergy Clin Immunol. 2000; 106: S275-S291Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar it is conceivable that alterations in the stress response systems may be associated with an altered GI mucosal inflammatory response in some IBS patients. However, this relationship is not simplistic and, in fact, the regulation of inflammation and immune function occurs through complex bi-directional brain-periphery interactions involving the afferent and efferent vagal, sympathetic, and HPA axis pathways.37Pavlov V.A. Tracey K.J. The cholinergic anti-inflammatory pathway.Brain Behav Immun. 2005; 19: 493-499Crossref PubMed Scopus (420) Google Scholar In this issue, Dinan et al38Dinan T.G. Quigley E.M.M. Ahmed S.M.M. Scully P. O'Brien S. O'Mahony L. O'Mahony S. Shanahan F. Keeling P.W.N. Hypothalmic-pituitary-gut axis dysregulation in irritable bowel syndrome plasma cytokines as a potential biomarker?.Gastroenterology. 2006; 130: 304-311Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar aimed to evaluate the relationship between HPA axis responses and peripheral cytokine levels in IBS compared with healthy controls. The number of subjects recruited for the study was relatively larger than other similar studies with 49 IBS patients and 48 healthy controls. None of the subjects had a significant psychiatric illness by a mental examination. While all subjects had plasma cytokine levels (ie, interleukin [IL]-6, IL-8, IL-10, sIL-6R, and tumor necrosis factor [TNF]-α) measured, only a subset from each group had HPA axis levels measured by either the CRF stimulation test (n = 21 from each group) or the dexamethasone suppression test (n = 27 from each group). Although plasma levels of IL-6, sIL-6R, and IL-8 were significantly elevated in IBS patients as a group compared with controls, levels of IL-10 and TNF-α were not different between groups. CRF-stimulated plasma ACTH and cortisol levels were significantly higher in IBS patients compared with controls. Similar to the findings by Bohmelt et al, plasma cortisol levels in response to dexamethasone administration were similarly suppressed in both patients and controls. The dexamethasone suppression test assesses the ability of glucocorticoids to suppress the release of CRF and ACTH, ie, the intactness of the negative feedback regulation of the HPA axis. Although the lack of difference in cortisol levels to dexamethasone suppression suggests that a lack of negative feedback of cortisol on the HPA axis is not likely to explain the increased cortisol levels in IBS, the combined dexamethasone/CRF test may provide more accurate information on the responsiveness of the pituitary gland to both feed-forward stimulation from CRF and feedback inhibition from glucocorticoids.39Rinne T. de Kloet E.R. Wouters L. Goekoop J.G. DeRijk R.H. van den Brink W. Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.Biol Psychiatry. 2002; 52: 1102-1112Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar This study also demonstrated a significant positive correlation between the stimulated ACTH response and IL-6 levels. The authors summarize these findings to suggest that IBS patients show an exaggerated stress response manifested by increased stimulated HPA axis hormones and peripheral cytokines. The proinflammatory cytokine IL-6, as well as TNF-α and IL-1, independently, but synergistically, stimulate the HPA axis, as well as the sympathetic nervous system.36Chrousos G.P. Stress, chronic inflammation, and emotional and physical well-being concurrent effects and chronic sequelae.J Allergy Clin Immunol. 2000; 106: S275-S291Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar However, in this study, levels of the proinflammatory cytokine TNF-α were not elevated and levels of the anti-inflammatory IL-10 levels were not decreased in IBS patients compared with controls. In another study, the authors found that symptomatic response to the probiotic Bifidobacterium infantis was associated with normalization of plasma anti-inflammatory:pro-inflammatory cytokine ratio in IBS patients.40O'Mahony L. McCarthy J. Kelly P. Hurley G. Luo F. Chen K. O'Sullivan G.C. Kiely B. Collins J.K. Shanahan F. Quigley E.M. Lactobacillus and bifidobacterium in irritable bowel syndrome symptom responses and relationship to cytokine profiles.Gastroenterology. 2005; 128: 541-551Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar However, the current study failed to show any correlation between symptom severity and either HPA axis hormone or cytokine levels. It is counter-intuitive that there should be a positive correlation of increases in ACTH levels with pro-inflammatory cytokine levels. It would have been expected that activation of the HPA axis would suppress cytokine release and immune activation, particularly because the cytokine levels were only mildly increased. Reasons for the discrepancy include factors that affect immune regulation other than HPA axis hormones such as vagal and sympathetic control and a decreased responsiveness of glucocorticoid receptors. The authors also suggest that cytokine alterations are a potential biomarker of IBS. Based on the current findings, it is plausible that cytokines could be a marker of some form in IBS, but with the lack of correlation with symptom ratings and significant overlap of cytokine values between IBS patients and controls, it is not likely to be considered a diagnostic biomarker. Because chronic stressors and colonic mucosal immune markers were not measured in this study, the relationship between HPA axis hormones and cytokines with these central and peripheral measures could not be evaluated. Despite these limitations, this is a novel study noting that IBS patients without significant psychiatric co-morbidity show increased neuroendocrine and immune reactivity. Further studies are needed to determine the clinical relevance of these findings, ie, are they truly pathophysiologic mechanisms related to gut function and IBS symptoms? Or are they one more epiphenomenon in the growing list of abnormalities that have been reported over the years in IBS patients? Given these findings and our evolving knowledge in this area, it is particularly important to consider 4 points when interpreting studies of HPA axis reactivity in IBS and other medical conditions: (1) the HPA axis is a highly dynamic system that is subject to complex modulatory influences of feedback and feed-forward mechanisms at numerous levels within the HPA axis.41Newport D.J. Heim C. Owens M.J. Ritchie J.C. Ramsey C.H. Bonsall R. Miller A.H. Nemeroff C.B. Cerebrospinal fluid corticotropin-releasing factor (CRF) and vasopressin concentrations predict pituitary response in the CRF stimulation test a multiple regression analysis.Neuropsychopharmacology. 2003; 28: 569-576Crossref PubMed Scopus (42) Google Scholar This can include responses to psychological and physical stress, and influence from the central noradrenergic system, opioids and other hormones and neurotransmitters; (2) HPA axis responses may also be affected by psychiatric and medical co-morbidities. For example, depression,31Heim C. Newport D.J. Bonsall R. Miller A.H. Nemeroff C.B. Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse.Am J Psychiatry. 2001; 158: 575-581Crossref PubMed Scopus (595) Google Scholar PTSD,42Yehuda R. Current status of cortisol findings in post-traumatic stress disorder.Psychiatr Clin North Am. 2002; 25: 341-368Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar and chronic fatigue syndrome43Demitrack M.A. Dale J.K. Straus S.E. Laue L. Listwak S.J. Kruesi M.J. Chrousos G.P. Gold P.W. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome.J Clin Endocrinol Metab. 1991; 73: 1224-1234Crossref PubMed Scopus (654) Google Scholar, 44Scott L.V. Dinan T.G. The neuroendocrinology of chronic fatigue syndrome focus on the hypothalamic-pituitary-adrenal axis.Functional Neurology. 1999; 14: 3-11PubMed Google Scholar are associated with blunted responses to stimulation, a history of early life stress without depression is associated with increased stimulated ACTH but blunted cortisol levels,30Heim C. Plotsky P.M. Nemeroff C.B. Importance of studying the contributions of early adverse experience to neurobiological findings in depression.Neuropsychopharmacology. 2004; 29: 641-648Crossref PubMed Scopus (430) Google Scholar and fibromyalgia is associated for the most part with an enhanced HPA axis.45Crofford L.J. Young E.A. Engleberg N.C. Korszun A. Brucksch C.B. McClure L.A. Brown M.B. Demitrack M.A. Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome.Brain Behav Immun. 2004; 18: 314-325Crossref PubMed Scopus (185) Google Scholar; (3) regulation of "tonic" (basal) secretion of HPA axis hormones may differ from that of "phasic" secretion, eg, patients with major depression show basal hypercortisolemia during serial measurements of diurnal rhythm and pulsatility,46Young E.A. Altemus M. Parkison V. Shastry S. Effects of estrogen antagonists and agonists on the ACTH response to restraint stress in female rats.Neuropsychopharmacology. 2001; 25: 881-891Crossref PubMed Scopus (147) Google Scholar but blunted responses are seen to hormone challenge or stress.31Heim C. Newport D.J. Bonsall R. Miller A.H. Nemeroff C.B. Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse.Am J Psychiatry. 2001; 158: 575-581Crossref PubMed Scopus (595) Google Scholar; and (4) a dissociation of CRF reactivity and adrenal dysfunction may be present in disease states (eg, trauma), but not in others (eg, depression without trauma).41Newport D.J. Heim C. Owens M.J. Ritchie J.C. Ramsey C.H. Bonsall R. Miller A.H. Nemeroff C.B. Cerebrospinal fluid corticotropin-releasing factor (CRF) and vasopressin concentrations predict pituitary response in the CRF stimulation test a multiple regression analysis.Neuropsychopharmacology. 2003; 28: 569-576Crossref PubMed Scopus (42) Google Scholar In summary, stress-sensitive disorders such as IBS are associated with alterations in the activity and responsiveness of endogenous pain modulatory pathways, of the autonomic nervous system and of the HPA axis. The latter two mechanisms interact in modulating the immune system, including the mucosal immune system. Recognizing that there is heterogeneity in physiologic responses and symptom severity within the IBS population, IBS patients without psychiatric co-morbidity appear to have a generally greater sensitivity of the HPA axis to stress. In the more severe IBS patients with co-morbid depression, PTSD, or chronic fatigue syndrome, and possibly chronic sustained stress, CRF reactivity is likely enhanced with down-regulation of pituitary and adrenocortical receptors downstream, resulting in blunted ACTH and cortisol responses. It is possible that IBS patients with sustained disease flares develop blunted ACTH and cortisol levels associated with increased mucosal immune activation, whereas those with mild and stable symptoms have normal levels of mucosal immune markers, ACTH, and cortisol but demonstrate HPA axis activation in response to stress. However, the relationship between HPA axis hormones and inflammatory or immune responses and their influence on gut function and, particularly, IBS symptoms remain unclear and require further study. Future studies in IBS should explore the following: (1) the association of HPA axis response and extrahypothalamic CRF activity; (2) whether HPA axis response to hormone challenge can predict the symptomatic response to a CRF1 antagonist; (3) if relationships exist between HPA axis hormone levels and colonic mucosal immune response, visceral perception, and gut-related and extraintestinal symptoms; and (4) if HPA axis reactivity represents a risk factor for stress-related conditions such as IBS. Hypothalamic-Pituitary-Gut Axis Dysregulation in Irritable Bowel Syndrome: Plasma Cytokines as a Potential Biomarker?GastroenterologyVol. 130Issue 2PreviewBackground & Aims: Irritable bowel syndrome (IBS) is a functional disorder with an etiology that has been linked to both psychological stress and infection. The primary aim of this study was to examine the hypothalamic-pituitary-adrenal axis in patients with IBS and to relate such response to plasma cytokine profiles. Methods: A total of 151 subjects, 76 patients and 75 controls, were recruited. The patients with IBS were diagnosed according to Rome II criteria. Forty-nine patients and 48 matched controls had cytokine levels measured, and a subset of 21 patients and 21 controls also underwent a corticotropin-releasing hormone (CRH) stimulation test with plasma levels of adrenocorticotropic hormone (ACTH) and cortisol measured. Full-Text PDF
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