Stress and Gene Expression of Individuals With Chronic Abdominal Pain

The term stress refers to the alterations, both positive and negative, in an organism’s environment, which elicit a response from that organism. The function of the stress response is to maintain homeostasis. As a normal function or response, the stress response is vital in supporting the body as it encounters negative changes in the environment. For the purposes of this article, we use the term stress to refer to both the perceived negative changes in a person’s environment and the psychological, physiologic, and behavioral changes that typically result (Mawdsley & Rampton, 2005). Research has revealed numerous negative health effects associated with stress. For example, stress causes an increased activation of inflammatory cytokines in arthritis (Edwards et al., 2009; Hirano, Nagashima, Ogawa, & Yoshino, 2001; Motivala, Khanna, FitzGerald, & Irwin, 2008) and delays in oral mucosal wound healing in healthy college students (Marucha, Kiecolt-Glaser, & Favagehi, 1998) and in skin barrier function recovery in healthy women (Altemus, Rao, Dhabhar, Ding, & Granstein, 2001). Focusing on its effects on the gastrointestinal (GI) tract, investigators have associated stress with alterations in tight junctions and barrier function (Mazzon, Sturniolo, Puzzolo, Frisina, & Fries, 2002; Rhodes & Karnovsky, 1971) and worsening of symptoms in irritable bowel syndrome (IBS; Drossman et al., 2000) and inflammatory bowel disease (IBD; Duffy et al., 1991). Brain–gut interactions play a vital role in maintaining GI health, and disruption of these interactions is associated with symptoms in a number of disorders and syndromes, including IBS and IBD (Mayer & Tillisch, 2011). Stress negatively impacts the brain–gut axis, thus contributing to GI dysfunction (Konturek, Brzozowski, & Konturek, 2011). The specific mechanisms by which stress induces such disruption are unknown, but the effects of stress include visceral hypersensitivity; changes in motility, gut microbiota, and release of hormones and neurotransmitters; and increased expression of proinflammatory cytokines. Inflammation is the process by which pathogens in the body are deactivated, destroyed, and or rendered incapable of infecting or affecting the body. A pathogen or physical injury damages tissue, and macrophages, after activation, release pro-inflammatory cytokines like interleukin-1 alpha (IL-1α) that then recruit leukocytes and neutrophils to the damaged or injured area. IL-1α, specifically, is produced by activated macrophages, neutrophils, and epithelial cells and functions primarily to increase the systemic inflammatory response by increasing systemic neutrophil counts. IL-1α is present locally at mucosal surfaces, like skin and the GI tract, and has the potential to transform a local mucosal insult into systemic inflammation (Hauser, Saurat, Schmitt, Jaunin, & Dayer, 1986). This cytokine functions in many inflammatory pathologies such as arthritis, renal disease, graft-versus-host disease, osteoporosis, and diabetes (Arend, 2002). As suggested above, although inflammation is a normal immune response, alterations to its mechanisms may have negative physiologic consequences. The literature, in fact, suggests an inflammatory component to stress. In the GI tract, specifically, stress is associated with disruption of the intestinal barrier to macromolecular substances and may involve stressrelated cholinergic mechanisms (Kiliaan et al., 1998) related to altered motility. Corticotropin-releasing hormone (CRH), a highly studied endogenous substance related to stress and the resulting effects on the GI tract, has been associated with stress-related increases in distal colonic secretion and permeability (Santos et al., 1999). CRH is also responsible for stress-related changes in rat and human GI secretion, motility, and function (Lenz, 1990; Tache & Perdue, 2004). Additionally, cortisol and the adrenocorticotropic hormone (ACTH)-to-cortisol ratio are commonly used physiological measures of stress (Deechakawan, Cain, Jarrett, Burr, & Heitkemper, 2011; Kuroki et al., 2010; Voss et al., 2011; Vythilingam et al., 2009). A subclinical inflammatory component mediated by stress may be part of the molecular mechanisms in chronic abdominal pain (CAP; Barbara, 2006; R. Spiller & Garsed, 2009), a widely acknowledged symptom that affects an estimated 15–20% of people worldwide (Creed et al., 2001; Russo, Gaynes, & Drossman, 1999). CAP is one of the main symptoms associated with functional GI disorders (Drossman et al., 2006) such as IBS, which cost the United States more than $30 billion annually in direct medical care costs and time lost from work (Ashburn & Gupta, 2006; Spinelli, 2007; Thompson et al., 1999). Investigators have found low-grade inflammation and mast cells in mucosal biopsies of IBS and CAP patients (Barbara, 2006; Barbara, De Giorgio, Stanghellini, Cremon, & Corinaldesi, 2002; De Giorgio & Barbara, 2008; Mertz, 2003; O’Sullivan, Mahmud, Kelleher, Lovett, & O’Morain, 2000; R. C. Spiller, 2004; Taylor, Youssef, Shankar, Kleiner, & Henderson, 2010), supporting the hypothesis of an inflammatory component in this pathology. Females report symptoms consistent with IBS more frequently than males (2:1) in the United States. This variation in reporting could reflect an increased prevalence in females or an underreporting in males, but literature does reveal that females request care for GI symptom distress more often than males (Frissora & Koch, 2005). Gender effects on CAP and IBS are considered a multifactorial phenomenon that includes inherent biological sex differences in hormones, stress and inflammatory reactions as well as sociocultural variations in pain responses and/or changes in bowel patterns (Cain et al., 2009; Frissora & Koch, 2005; M. Heitkemper & M. Jarrett, 2008; M. M. Heitkemper & M. E. Jarrett, 2008). The purpose of this study was to examine the expression of genes involved in stress and toxicity in men and women with high and low levels of perceived stress, with and without CAP.