The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression

Background & Aims: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in irritable bowel syndrome (IBS). Enhanced HPA axis responses have been associated with reduced glucocorticoid receptor (GR) mediated negative feedback inhibition. We aimed to study the effects of IBS status, sex, or presence of early adverse life events (EAL) on the cortisol response to corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and on GR mRNA expression in peripheral blood mononuclear cells (PBMCs). Methods: Rome III+ IBS patients and healthy controls underwent CRF (1μg/kg ovine) and ACTH (250μg) stimulation tests with serial plasma ACTH and cortisol levels measured (n=116). GR mRNA levels were measured using quantitative PCR (n=143). Area under the curve (AUC) and linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups. Results: There were divergent effects of IBS on the cortisol response to ACTH by sex. In men, IBS was associated with an increased AUC (p= 0.009), but in women AUC was blunted in IBS(p=0.006). Men also had reduced GR mRNA expression (p=0.007). Cumulative exposure to EALs was associated with an increased HPA response. Lower GR mRNA was associated with increased pituitary HPA response and increased severity of overall symptoms and abdominal pain in IBS. Conclusion: This study highlights the importance of considering sex in studies of IBS and the stress response in general. Our findings also provide support for PBMC GR mRNA expression as a peripheral marker of central HPA response

Molecular Mechanisms in Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain associated with alteration in stool form and/or frequency. The pathophysiology of IBS is poorly understood. Although structural or histological changes in the gastrointestinal tract are absent in IBS, changes in intestinal function (e.g. increased intestinal permeability, increased neuronal sensitivity) and changes at the molecular level (e.g. gene methylation, gene/protein expression) have been described.This dissertation describes a translational research project which began with data from gastrointestinal biopsies and concluded with studies in cell culture models. We performed a microarray gene expression profiling analysis of colonic mucosal biopsies in patients with IBS and healthy controls. I analyzed the differential gene and described the pathways involved in the regulation of IBS. These studies have direct clinical impact to patient care. Since data in the literature suggests a role for epigenetic changes (changes affecting gene expression) in IBS, I next focused on the role of differentially expressed long non-coding RNAs in IBS. The long non-coding RNA afadin-divergent transcript (AFDN-DT), which was up-regulated in IBS, was selected for further in vitro studies. I generated intestinal epithelial cell lines capable of inducible expression of AFDN-DT and tested the hypothesis that overexpression of AFDN-DT resulted in altered epithelial permeability