Abstract
Background: Irritable bowel syndrome (IBS) is characterized by visceral pain and abnormal bowel habits that are worsened during stress. Evidence also suggests altered intestinal barrier function in IBS. Previously, we demonstrated that stereotaxic application of the stress hormone corticosterone (CORT) onto the central nucleus of the amygdala (CeA) induces colonic hyperalgesia and anxiety-like behavior in a rat model, however the effect on intestinal permeability and mucosal function remain to be evaluated.Methods: Male Fischer 344 rats underwent bilateral stereotaxic implantation of CORT or inert cholesterol (CHOL)-containing micropellets (30 μg) onto the dorsal margin of the CeA. Seven days later, colonic tissue was isolated to assess tissue permeability in modified Ussing chambers via transepithelial electrical resistance (TEER) and macromolecular flux of horseradish peroxidase (HRP). Secretory responses to electrical field stimulation (EFS) of submucosal enteric nerves as well as activation with forskolin were used to assess movements of ions across the isolated colonic tissues. In a separate cohort, colonic histology, and mast cell infiltration was assessed.Key Results: Compared to CHOL-implanted controls, we determined that exposing the CeA to elevated levels of CORT significantly increased macromolecular flux across the colonic epithelial layer without changing TEER. Nerve-mediated but not cAMP-mediated active transport was inhibited in response to elevated amygdala CORT. There were no histological changes or increases in mast cell infiltration within colonic tissue from CORT treated animals.Conclusion and Inferences: These observations support a novel role for the CeA as a modulator of nerve-mediated colonic epithelial function.
Highlights
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder associated with chronic abdominal pain accompanied by a change in stool frequency or consistency, and a 2:1 female predominance (Chang, 2004; Drossman and Dumitrascu, 2006; Foxx-Orenstein, 2006; Defrees and Bailey, 2017)
Evidence in IBS patients has shown that following an Abbreviations: ACh, acetylcholine; ANOVA, analysis of variance; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; CHOL, cholesterol; CORT, corticosterone; diH2O, deionized, distilled water; EFS, electrical field stimulation; F-344, Fischer 344 rat; FBDSI, functional bowel disorder severity index; GI, gastrointestinal; HPA, hypothalamic-pituitary-adrenal axis; HRP, horseradish peroxidase; IBS, irritable bowel syndrome; in short-circuit current (Isc), shortcircuit current; PD, potential difference; SEM, standard error of the mean; TEER, transepithelial electrical resistance; TJ, tight junction; TMB, 3,3′,5,5′tetramethylbenzidine; ZO, zonula occludens
In the same experimental preparation, we measured TEER and found that there was no significant change in TEER (Mann–Whitney U = 88.5, p = 0.339) across the colonic epithelium from CORT implanted rats compared to tissue from CHOL implanted controls (Figure 1C)
Summary
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder associated with chronic abdominal pain accompanied by a change in stool frequency or consistency, and a 2:1 female predominance (Chang, 2004; Drossman and Dumitrascu, 2006; Foxx-Orenstein, 2006; Defrees and Bailey, 2017). Central factors include stress and anxiety while peripheral factors such as an acute episode of infective gastroenteritis and changes in the gut microbiota may contribute to pain perception by amplification of sensory signaling in IBS (Greenwood-Van Meerveld et al, 2015; Greenwood-Van Meerveld and Johnson, 2017). From both human studies and animal models, evidence points toward interplay between visceral hypersensitivity in IBS, low levels of inflammation and increased intestinal permeability (Piche et al, 2009; Barbara et al, 2011; Camilleri et al, 2012; Martinez et al, 2012). We demonstrated that stereotaxic application of the stress hormone corticosterone (CORT) onto the central nucleus of the amygdala (CeA) induces colonic hyperalgesia and anxiety-like behavior in a rat model, the effect on intestinal permeability and mucosal function remain to be evaluated
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