Could stress play a role in IBD?
Article first published online: 24 SEP 2008
Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Supplement: A Clinician's Guide to Common Questions in IBD
Volume 14, Issue Supplement 2, pages S206–S207, October 2008
How to Cite
Levenstein, S. (2008), Could stress play a role in IBD?. Inflamm Bowel Dis, 14: S206–S207. doi: 10.1002/ibd.20663
- Issue published online: 24 SEP 2008
- Article first published online: 24 SEP 2008
Since inflammatory bowel disease (IBD) was first described, many physicians and patients have been convinced that stress contributes to its etiology or to its clinical evolution. The older literature supporting this concept, anecdotal or at best retrospective, is hampered by methodological limitations that from an informed contemporary perspective can only add new questions: Are the researchers being fooled by recall bias arising from the patients' desire to explain their illness? To what extent do apparent associations arise from confounding by the stressful effects of the disease itself? Might the effects of stress be limited to functional components of IBD patients' symptomatology? Are there plausible pathophysiological mechanisms? In short, is the biopsychosocial model of IBD a scientific advance, or is it a holdover from 19th century folk notions of disease causality? Only recently has methodologically adequate research allowed us to begin to sort out these issues.
Regarding the onset of IBD, early reports have not been confirmed: the first symptoms of the disease are not likely to be precipitated by life stress, nor is the probability of developing disease increased by severely distressing life experiences, such as the death of a child.1
However, prospective studies that largely eliminate confounding by recall bias and disease effects do support a role for psychological factors in the subsequent course of disease. Part of the effect of stress on IBD may be via factors that influence the patient's experience more than the disease itself: intensification of the “irritable bowel syndrome”-like symptoms that are common in these patients, or the hypervigilance to somatic phenomena that is typical of anxiety and depression. There also seems to be a potentiating effect on the inflammatory process itself. Ulcerative colitis (UC) patients in clinical remission are more likely to show endoscopic signs of activity if they have high perceived life stress,2 and patients under stress are more likely to experience an exacerbation over the next several years3, 4; long-term or cumulative stress seems to be more important than acute stressful events.3, 5 In Crohn's disease (CD), a condition where mind–body interactions are more difficult to study because of the often unremitting and distressing course of the disorder, recent prospective studies have reported that depression, and to a lesser degree anxiety and stressful life events, can lead to earlier and more frequent exacerbations.6, 7
Exposing laboratory animals to psychological stressors can by itself induce bowel inflammation.8 Stress can have a strong potentiating effect on experimental colitis induced by chemical agents such as trinitrobenzene sulfonic acid, dinitrobenzenesulfonic acid (DNBS), or dextran sulfate sodium. One important study in rats demonstrated that previously healed DNBS colitis recurred if the animals were exposed to a subthreshold dose of DNBS coupled with mild stress.9 In this and other animal studies, an increase in gut permeability to intestinal antigens and bacteria10—a defect believed to be central also to the pathogenesis of clinical IBD—seems to be a key mechanism by which stress affects colitis. The immune system also plays a crucial role: stress caused recurrent inflammation in these rats only if the luminal contents that leaked through the mucosa encountered and activated previously sensitized CD4 cells.9
Another possible stress mediator that emerges from animal studies is modification of the intestinal flora, a source of antigens believed to stimulate IBD activity. Social stress in the form of separation from the mother has been shown not only to modify the gut bacteria of infant monkeys, but also to increase their virulence.11
The demonstration of corticotrophin-releasing factor in the colonic tissues12 of IBD patients indirectly supports the biological plausibility of a stress effect, reflecting animal models.13 Among other possible mechanisms, a role can reasonably be postulated not only for the effects of stress on gut permeability, but for the possible modification of the release of intestinal and systemic immune mediators such as TNF-α. While the best-known effects of stress on immune function are suppressive, stress is paradoxically capable of enhancing aspects of immune reactivity under certain circumstances.14 Acute psychological stress in the laboratory has in fact been shown to induce intensified systemic and mucosal proinflammatory responses in UC patients.15, 16 There are also data to suggest that links between stress and inflammation may differ in biological subgroups of patients.17 Behavioral changes could also be important stress mediators; patients under stress are likely to smoke more cigarettes, consume more nonsteroidal antiinflammatory drugs, and neglect their regimen of prophylactic medication, all factors with well-known potential to trigger IBD. Dietary changes and neglect of personal hygiene could possibly come into play as well.
The acid test of an influence of psychosocial factors on any disease is the ability of psychosocial manipulations to influence disease course. For IBD this definitive criterion has not yet been met. Although several groups have achieved encouraging temporary effects of various psychologically oriented interventions on subjective distress18–20 on patients' ability to cope with their disease,18 and even on rectal inflammation,21 concrete benefits in terms of exacerbations, hospitalizations, surgery, or other “hard” outcomes have not been obtained.20, 22 Shortcomings in previous studies leave the question open. Some interventions have been relatively unsuccessful even in improving the patients' psychological state,23 making it unlikely they could influence disease activity for the better. In virtually all studies the researchers have included among their IBD subjects patients with low psychological distress levels and/or long-quiescent disease, groupings where a benefit of psychologically oriented interventions is unlikely to be detected.
So, could stress play a role in inflammatory bowel disease? Current evidence indicates that the answer is “yes.” Psychological factors are unlikely to play a role in the etiology of UC or CD, but stress and distress do seem to affect the ups and downs in inflammatory activity, at least in some patients. The mechanisms that have been postulated are biologically plausible, although much of the evidence in their favor comes from animal studies.
- 1Psychological stress and inflammatory bowel disease: a follow-up study in parents who lost a child in Denmark. Am J Gastroenterol. 2004; 99: 1129–1133., , , et al.Direct Link:
- 3Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am J Gastroenterol. 2000; 95: 1213–1220., , , et al.Direct Link:
- 4Psychosocial determinants of relapse in ulcerative colitis: a longitudinal study. Am J Gastroenterol. 2003; 98: 2203–2208., , , et al.Direct Link:
- 14Bidirectional effects of stress and glucocorticoid hormones on immune function: possible explanations for paradoxical observations. In: AderR, FeltenDL, CohenN, eds. Psychoneuroimmunology. 3rd ed. San Diego: Academic Press; 2001., .
- 16Heightened responses to stressors in patients with inflammatory bowel disease. Am J Gastroenterol. 2005; 100: 1796–1804., , , et al.Direct Link:
- 17Psychobiological subtypes of ulcerative colitis: pANCA status moderates the relationship between disease activity and psychological distress. Am J Gastroenterol. 2006; 101: 2546–2551., , , et al.Direct Link:
- 21The effect of hypnosis on systemic and rectal mucosal measures of inflammation in ulcerative colitis. Am J Gastroenterol. 2008 Jun; 103(6): 1460–1469., , , , .Direct Link:
- 22Effect of psychotherapy on the course of Crohn's disease. Results of the German prospective multicenter psychotherapy treatment study on Crohn's disease. German Study Group on Psychosocial Intervention in Crohn's Disease. Scand J Gastroenterol. 1998; 33: 1289–1296., , , et al.