grade inflammatory processes that set in motion the pathologic changes that lead to cardiovascular disease (Black and Garbutt 2002; Black et al. 2006). That hypothesis draws from evidence that during the acute stress response, cortisol, catecholamines, angiotensin, and other stress hormones induce the liver and abdominal fat tissue to release proinflammatory cytokines and other inflammatory mediators. Inflammatory molecules, when increased for a long time, lead to a chronic state of inflammation, especially in abdominal fat and vasculature, which contribute to insulin resistance. Inflammation in the vasculature is manifested by recruitment and adherence of white blood cells to the vascular lining and their migration to the inner portions of the lining, binding of receptors to LDL particles, and growth of fibrous tissue. Those processes set the stage for plaque development (Libby 2002). A key marker of the inflammatory process in the circulatory system is C-reactive protein, an independent predictor of cardiovascular risk (Kardys et al. 2006; Libby 2002). In a prospective study, older adults who were current or former caregivers for Alzheimer’s disease patients and harbored chronic hostility or pain had more inflammation, as measured by C-reactive protein, when other risk factors were accounted for, than did noncaregiver controls (Graham et al. 2006).

Gastrointestinal System and Brain-Gut Axis

Research is advancing our understanding of the interaction between stress and emotional trauma and the effects on the brain-gut axis, particularly with respect to irritable bowel syndrome (IBS) and other functional gastrointestinal disorders, such as functional dyspepsia (Dilley et al. 2005; Drossman 2005; Longstreth et al. 2006). IBS is the most common gastrointestinal condition seen in primary-care or gastroenterology practice; it is clinically manifested by symptoms of abdominal pain and altered bowel habit (for example, diarrhea, constipation, or both). Those symptoms are produced and amplified by gut-related stressors (such as eating, physical activity, and hormonal changes) or by other stressors, such as abuse, a history of trauma, or psychosocial comorbidities. The stressors appear to disrupt the brain-gut neurophysiologic regulatory pathways that alter intestinal motility and visceral sensation thresholds either centrally or peripherally.

Figure 4-4 shows the relative prevalence of IBS according to severity and shows the relative contributions of peripheral and psychosocial factors to severity. In effect, more severe psychosocial disturbance, including abuse and war trauma, leads to greater symptom reporting, poorer health status, greater psychologic comorbidity, and poorer quality of life.

Several lines of evidence support the concept of dysregulation of stress circuitry in IBS that is linked to and affects gut function (and vice versa). The evidence includes altered CRH and corticotropin reactivity to stress and an increased gut response (motility and pain) to CRH (Dinan et al. 2006; Fukudo et al. 1998; Sagami et al. 2004; Tache et al. 2005) which can be blocked by CRH antagonists (Sagami et al. 2004); increased mucosal inflammatory activity (Chadwick et al. 2002); stress-caused loss of the integrity of the intestinal mucosal barrier to bacterial pathogens and other toxins, which in turn causes entry or release of toxic substances that lead to inflammation and nerve sensitivity (Barbara et al. 2006, 2007; Soderholm et al. 2002; Yang et al. 2006); and altered brain regulation of incoming visceral pain signals leading to an increased pain experience that is enhanced by stress (Chang et al. 2003; Drossman et al. 2003; Naliboff et al. 2001; Ringel et al. 2003a,b). There is also evidence that the mediating mechanisms of reduction in pain can be evaluated with brain imaging (Drossman et al. 2003).

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