The majority of patients with irritable bowel syndrome (IBS) associate stressful life events with the initiation or exacerbation of their symptoms. Emerging evidence suggests that this association may be due to an alteration in the way the brain communicates with the gut during periods of prolonged or severe life stresses. While stress and stress related symptoms have long been regarded as a domain of psychology, tremendous progress has been made in our understanding of the biological processes that mediate the body's response to stress. The brain network which plays a central role in the stress response is the hypothalamic-pituitary-adrenal cortex (HPA) axis which produces the hormone cortisol. The HPA axis interacts with other brain areas which are concerned with the responses to pain and in the autonomic (nervous system) function of the bowel during stress. There is a growing body of evidence that suggests that altered HPA responses in IBS and other chronic pain syndromes, such as fibromyalgia, play a role in the body's increased sensitivity to painful and non-painful stimuli resulting in chronic pain and other symptoms of discomfort and distress.

Activation of the HPA axis in response to stress leads normally to a coordinated series of adaptive physiologic and behavioral changes which attempt to maintain and restore our body's homeostasis (in a state of equilibrium). In the setting of stress, adaptive behaviors such as increased arousal, vigilance, focused attention, and alertness occur. Altered function of the HPA axis in response to stress may play a primary role in behavioral abnormalities such as fatigue, lack of motivation, abnormal sleep and appetite, which are commonly seen in patients with functional bowel disease, such as IBS. In our patient database of functional bowel disease, 71% reported frequent tiredness and fatigue and the two-thirds reported sleep disturbances. These symptoms in turn play an important role in the impact of IBS on quality of life.

Stress responses involving the HPA axis are mediated by the release of corticotropin releasing hormone (CRH) from a brain region called the hypothalamus. Stressful events activate the HPA axis which result in the eventual release of CRH which then results in release of adrenocorticotropin hormone (ACTH) from the pituitary gland. ACTH then acts on the adrenal cortex causing it to release cortisol into the bloodstream. Cortisol and ACTH are secreted in a specific rhythm over the course of 24 hours each day, and both reach their highest levels in the early morning and their lowest in the late afternoon and evening. The cortisol peaks correlate with the state of greatest alertness and energy in the majority of healthy people. Cortisol can be measured in the blood and urine. Regulation of the HPA axis has not been studied well in IBS. We have preliminary evidence which suggests that IBS patients have blunted or decreased levels of cortisol in response to a stressor such as balloon distension of the lower colon and rectum. There is also evidence that IBS and fibromyalgia patients have lower baseline levels of 24-hour urine cortisol.

In order to learn more about how stress may play a role in chronic pain disorders, the UCLA Neuroenteric Disease Program has several ongoing studies in IBS, fibromyalgia and gastroesophageal reflux disease (GERD). There is a study measuring ACTH and cortisol levels in the blood over a 24-hour period in patients with IBS and/or fibromyalgia, and healthy individuals. In addition, we are studying how stress may affect the perception of signals originating from the intestine. We are completing another study which has examined the relation of stressful life events and increase in heartburn symptoms in patients with GERD.

In summary, alterations in the HPA axis in patients with chronic pain syndromes such as IBS or fibromyalgia may play a role both in the inadequate activation of the body's own pain inhibition systems (including the "endorophin system"), resulting in bowel and/or muscle hypersensitivity. A better understanding of the way the body responds to stress via the HPA axis will therefore help in the development of novel therapies for these common conditions.