Early Life Stress Induced Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction Promotes Chronicity of Experimental Colitis in Mice

Academic Article

Abstract

  • Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract with peak onset during adolescence. The etiology of IBD remains poorly understood, but is believed to involve genetic susceptibility, improper immune regulation, and environmental factors. Psychological stress is one environmental trigger that has been associated with an increased risk of inflammatory diseases. Specifically, previous studies have linked early life stress (ELS) with hypothalamic-pituitary-adrenal (HPA) axis dysfunction that ultimately increases susceptibility for adverse health outcomes later in life. The aim of this study was to determine whether ELS in mice affects susceptibility to, and/or severity of colitis induced subsequent to stress exposure. We hypothesized that ELS would contribute to earlier onset disease and exacerbated colitis. We used an established mouse model of ELS, maternal separation with early weaning (MSEW), where newborn mice are separated from their mothers for 4-8 hours daily from postnatal day (PD) 2 until early weaning on PD 17. Beginning at PD 28, colitis was induced in MSEW mice and their normally-reared (NR) counterparts by transient blockade of the interleukin-10 receptor (IL-10R). Relative to their NR counterparts, MSEW mice exhibited systemic and colon-specific deficits of the HPA-axis endpoint molecule corticosterone, prior to induction of colitis. Following disease onset, NR mice were mostly in remission by 15 days after cessation of IL-10R blockade, whereas MSEW mice displayed sustained histological pathology with an emphasis on epithelial damage, in addition to consistently elevated colonic tumor necrosis factor (Tnf). Furthermore, pharmacologic induction of HPA-axis dysfunction via early life exposure (PD 1-14) to the synthetic glucocorticoid, dexamethasone, mirrors the results we observed in the MSEW model of ELS - both prior to and subsequent to colitis induction. Our results indicate that early life exposure to prolonged stress leads to HPA-axis dysfunction and colonic corticosterone deficits which may subsequently promote persistent colonic inflammation in susceptible hosts.
  • Published In

  • The FASEB Journal  Journal
  • Digital Object Identifier (doi)

    Author List

  • Muir R; Klocke B; Foote J; Jennings M; Molina P; Kellum C; Pollock J; Maynard C
  • Volume

  • 36