Stress and the GIT

Does stress cause or exacerbate Crohn’s disease?

Marianne Martinello

Crohn’s disease (CD)

Inflammatory bowel disease Characterised by transmural inflammation

and ‘skip lesions’ (as compared with ulcerative colitis).

From a surgical perspective, transmural inflammation may lead to fibrosis, with resultant obstructive clinical presentations, or micro-perforations and fistulae.

May involve entire GIT (mouth to anus).

IBD: Role of environmental factors

IBD: Role of environmental factors

Epidemiological, clinical and experimental evidence supports an association between IBD and a large number of environmental factors, including…– Smoking– Diet– Drugs (esp. NSAIDS, OCPs)– Geographical and social status– Microbial agents– Intestinal permeability– Appendectomy– Stress

Stress and IBD

Popular belief that stress may trigger IBD among sufferers of UC and CD.

70% of IBD patients (in one gastroenterology unit) felt that flares of disease related to stressful life events.

However, evidence appears to point to stress modulating the disease course, as opposed to causing disease de novo.

Stress and the GIT Environmental signals, ie stress, are perceived

initially by the CNS (particularly hypothalamus). CNS is able to modulate degree of inflammation of

the bowel via neural and neuroendocrine pathways…– Spinal cord, dorsal root nuclei and intestinal neurons– HPA axis– Release of CRF and its effects on adrenal-corticoid

secretion.– Sympathetic-adrenal medullary (SAM) axis

• Modulates gut secretory, absorptive and defensive factors.

– ANS with stimulation or suppression of immune functions.

Stress and the GIT

Homeostasis between aggressive luminal factors and defensive mucosal agents is influenced and modulated by factors, which include environmental stress.

IBD and the Brain-Gut Axis Stress may modulate inflammatory processes in the

gut.– Human and animal studies have demonstrated that sustained,

chronic stress can alter responsiveness of feedback systems by down regulating receptors, and if severe, by structural brain alterations.

– Corticosteroid release through activation of the HPA by stress are anti-inflammatory; thus attenuated HPA responses may predispose to inflammation.

– Immune and inflammatory cells recognize and respond to neuropeptides.

– Stress may render an organism susceptible to an inflammatory stimulus by altering intestinal physiology, including epithelial permeability.

IBD and the Brain-Gut Axis In rats, environmental stress can reactivate the

disease or instigate inflammation. Rats given dinitrobenzene sulfonic acid, (DNBS)

at specific dosage and length of time, will develop colitis.

If allowed to recover and then re-challenged with a suboptimal dose of DNBS, colitis will develop only if they are subjected to environmental stress.

Addition of stress in rats can convert quiescent colitis to active disease.

IBD and the Brain-Gut Axis

Study of stable IBD patients, followed for >5yrs, explored influence of stress on exacerbating disease– Patients with high prolonged stressful life

events had 90% recurrence rate of their colitis, as compared to only 40% recurrence in low stress patients.

IBD and the Brain-Gut Axis

In summary, brain-gut interactions via neural, hormonal and cytokine signals can diminish mucosal protective factors and increase permeability of luminal antigens into intestinal epithelial and immune cells.

From a physiological standpoint, stress appears to play a key role in exacerbating and accentuating intestinal inflammation in IBD through brain-gut interactions.

Stress and CD

The association between psychological stress and IBD has not been well studied (though large numbers of trials have been conducted), nor have the findings been consistent, partly due to methodological limitations, including small sample size, lack of control groups, inappropriate assessment of psychological status and recall bias.

Stress and CD Emerging research trends suggest that daily

hassles are associated with exacerbation of IBD. Reports of positive associations between

perceived stress and risk of relapse. However, must consider confounding factors,

including effects of stress on symptom report. (BDI validated for medical illness). While some studies showed positive association

between life events and IBD, most of the available literature suggests that such is not the case.

Crohn’s disease: A 2-year Prospective Study of the Association Between Psychological Distress and Disease Activity

Mardini, H., Kip, K., Wilson, J. Digestive Dis and Sci. 2004. 49(3): 492-497.

18 patients with CD, followed prospectively for 2 yrs (8-12 wk intervals).

Aim to explore link between psychological distress and subsequent CD activity.

Disease activity assessed by CDAI Psychological distress assessed by BDI, BAI, BHS, Holmes RLC. Mean CDAI during follow-up: 138 (Median: 121). BDI scores were independently associated with CDAI score

simultaneously and 8-12 weeks later (p = 0.004). Higher levels of anxiety, hopelessness and recent life changes were

suggestive of higher CDAI score – though effects of lesser magnitude, and not independent of depressive symptoms.

Level of depressive symptoms positively associated with future changes in CDAI.

Psychological Stress and IBD: A Follow-Up Study in Parents Who Lost a Child in Denmark Li J, Norgard B, Precht D, Olsen J. Am J Gastroenterol. 2004; 1129-1133.

Aimed to determine whether the distress caused by death of a child is related to development and exacerbation of IBD in bereaved patients. Retrospective.

21 062 parents who lost a child between 1980-1996, as compared with 293 745 matched controls.

Primary outcome was incidence of IBD defined as parents’ 1st hospitalisation due to IBD in their life.

301 incident cases of CD (20 in exposed, 281 controls) 766 incident cases of UC (51 exposed, 715 unexposed) RRs 1st hospitalisation for CD 0.97 and UC 1.01. No association between 1st hospital dx of IBD and death of a child. No difference in frequency or duration of hospitalization in exposed or

control patients. Findings do not support a strong association between severe stress

and risk of IBD in young to middle-aged adults.

Life Events and IBD Relapse: A Prospective Study of Patients Enrolled in Remission

Vidal A, Gomez-Gil E, Sans M et al. Am J Gastroenterol. 2006; 101: 775-781.

Prospective study of 163 patients with inactive IBD (hx of relapse within last 2 yrs).

Social Readjustment Rating Scale (measuring life events) and CDAI/Truelove-Witts Index completed monthly till end of study (max 11 months). Interviewed by gastroenterologist and psychologist.

51 patients relapsed (32.9%), 104 remained in remission, 8 dropped out.

Number of life events was not associated with rate of relapse (p = 0.33), after adjusting for biological RFs for relapse.

Results suggested that stressful life events do not trigger exacerbations in patients suffering from IBD.

Stress and CD

Overall, observations from studies of IBD (particularly pertaining to CD) suggest that hassles or perceived stress may be more important than major life events in the prediction of health status.

Prospective studies support a role for depressive symptoms in the course of CD.