Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders. Chronic stress is associated with the onset and exacerbation of symptoms in IBS and female sex is a risk factor for this detrimental stress effect. Perturbations during the pre- and perinatal period or childhood may contribute to the development of IBS in adults. Early life stress is associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. IBS patients report an increased prevalence of early life stress and demonstrate increased HPA axis activity. Our preliminary data shows increased methylation of the glucocorticoid receptor (GR) NR3C1 promoter in IBS patients but none in controls. This finding may be associated with decreased negative feedback of glucocorticoids and HPA axis hyperreactivity in IBS. Rodents exposed to perinatal stress (i.e., maternal separation, [MS]) are predisposed as adult rats to develop stress-induced visceral hypersensitivity, enhanced defecation, intestinal mucosal dysfunction, increased HPA axis responses and anxiety-like behavior and these responses are mediated by activation of corticotropin releasing factor receptor 1 (CRF-R1) signaling pathways. These phenotypic features are homologous to those seen in IBS patients and thus, the MS animal model is a relevant model of IBS. Project 1 focuses on the identification of a biological marker for IBS and associated alterations in the stress response systems, and on a translational approach in rodents to identify alterations in CRF-R1 signaling and GR promoter methylation in specific brain regions and circuitries following early life stress.
Aim A's objective is to conduct a comprehensive genetic, molecular and functional phenotyping of HPA axis in male and female patients with IBS, IC/PBS and controls.
Aim B proposes to establish that perinatal stress (MS) alters the pattern of regional brain CRF and CRF-R1 expression, and DNA methylation of GR promoter region in male and female rats.
Aim C intends to delineate the increased engagement of central stress responsiveness/arousal mechanisms in the rat MS model with an emphasis on identifying homologies of rodent brain imaging with human findings from Project 3.

Public Health Relevance

IBS is a common, female-predominant gastrointestinal disorder that is charaterized by abdominal pain and altered bowel habits. It is associated with a significant health care and economic burden due to a lack of a diagnostic test and effective treatments. Chronic stress is associated with the development of IBS and disease flares. The proposal aims to identify biomarkers for increased stress responsiveness in IBS, which may help predict treatment response and guide the development of more effective therapeutic interventions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Specialized Center (P50)
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Special Emphasis Panel (ZRG1-EMNR-Q)
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University of California Los Angeles
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Mulak, Agata; Larauche, Muriel; Biraud, Mandy et al. (2015) Selective agonists of somatostatin receptor subtype 1 or 2 injected peripherally induce antihyperalgesic effect in two models of visceral hypersensitivity in mice. Peptides 63:71-80
Kilpatrick, Lisa A; Coveleskie, Kristen; Connolly, Lynn et al. (2014) Influence of sucrose ingestion on brainstem and hypothalamic intrinsic oscillations in lean and obese women. Gastroenterology 146:1212-21
Chang, Megan C; Shapiro, David; Joshi, Aditi et al. (2014) Stress reactivity in traditional Chinese medicine-based subgroups of patients with irritable bowel syndrome. J Altern Complement Med 20:276-83
Su, A M; Shih, W; Presson, A P et al. (2014) Characterization of symptoms in irritable bowel syndrome with mixed bowel habit pattern. Neurogastroenterol Motil 26:36-45
Hanna-Mitchell, Ann T; Wolf-Johnston, Amanda; Roppolo, James R et al. (2014) Corticotropin-releasing factor family peptide signaling in feline bladder urothelial cells. J Endocrinol 222:113-21
Mulak, Agata; Taché, Yvette; Larauche, Muriel (2014) Sex hormones in the modulation of irritable bowel syndrome. World J Gastroenterol 20:2433-48
Hong, Jui-Yang; Labus, Jennifer S; Jiang, Zhiguo et al. (2014) Regional neuroplastic brain changes in patients with chronic inflammatory and non-inflammatory visceral pain. PLoS One 9:e84564
Cohen, Erica; Bolus, Roger; Khanna, Dinesh et al. (2014) GERD symptoms in the general population: prevalence and severity versus care-seeking patients. Dig Dis Sci 59:2488-96
Labus, Jennifer S; Dinov, Ivo D; Jiang, Zhiguo et al. (2014) Irritable bowel syndrome in female patients is associated with alterations in structural brain networks. Pain 155:137-49
Gupta, Arpana; Kilpatrick, Lisa; Labus, Jennifer et al. (2014) Early adverse life events and resting state neural networks in patients with chronic abdominal pain: evidence for sex differences. Psychosom Med 76:404-12

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