Systemic or interoceptive stressors, 28 in the context of the four chronic gastrointestinal disorders listed above, can occur in the form of mucosal inflammation (IBD, PUD) or tissue irritation by excessive acid exposure (GORD). Inflammatory cytokines, including tumour necrosis factor α (TNF-α), interleukin (IL)-1, and IL-6 cause acute stimulation of the hypothalamic-pituitary-adrenal (HPA) axis alone or in synergy. 33 34 The cytokine mediated stimulation is mediated through stimulation of corticotropin releasing hormone (CRH; or corticotropin factor, CRF) and arginine vasopressin release from hypothalamic neurones, and by direct eVects at the pituitary and adrenocortical levels. DiVerent mechanisms, including cytokine stimulation of vagal aVerents, have been proposed by which the cytokine signal crosses the blood-brain barrier. 28 The ultimate output of peripheral cytokine stimulated HPA axis activation, plasma cortisol, is the principal negative feedback mediator to shut oV both the inflammatory response as well as HPA axis activation. In contrast with the eVects of acute inflammation, several animal experimental34 35 and human studies in patients with certain chronic inflammatory disorders, such as rheumatoid arthritis, have provided evidence for a blunting of the HPA axis response. 34 36–38 This blunting appears to be secondary to downregulation of CRH gene expression and CRH secretion by mediators associated with chronic inflammation.

Psychological or exteroceptive stressors fall into diVerent categories, depending on the individual’s age during stress exposure, severity and chronicity of the stressor, and the subjectively perceived threat. For example, several diVerent types of psychological stressor can have permanent consequences on the responsiveness of the individual to stress and chronic disease later in life:(1) Early life stress in the form of altered mother-infant interaction during a species specific “window” of development has been shown to result in permanent hypersecretion of CRF and overactivity of the locus coeruleus. 31 (2) Chronic abuse (physical or sexual) and neglect throughout life have been found to be associated with alterations in the HPA axis response to stress. 39–41 (3) Exposure to a one time stressor which is perceived by the individual as life threatening (rape, combat situation, natural disaster) resulting in post-traumatic stress syndrome42 with alterations in sympathetic and HPA axis responses to stress and to exaggerated memory recall of the traumatic event. 43 Chronic stressors in adult life (such as losses, financial threats, etc), in particular when sustained and perceived as threatening, may result in transient reversible alterations in allostatic systems, which in the case of IBS have been shown to result in exacerbation of IBS symptoms. 3 It is primarily these latter types of pathological stressors that have been addressed in the epidemiological studies mentioned earlier.