Early life stress in mice promotes chronicity of experimental colitis

Abstract

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 leading to adverse health outcomes later in life. Our goal was to determine whether ELS in mice affects susceptibility to, and severity of, colitis – induced subsequent to stress exposure. We used an established mouse model of ELS, maternal separation with early weaning (MSEW), in which newborn mice are separated from their mothers for 4–8 hours daily from day of life (DOL) 2 until early weaning on DOL 17. Then, starting on DOL 28, colitis was induced in MSEW mice and their normally-reared (NR) counterparts by transient blockade of the interleukin-10 receptor (IL-10R). Prior to induction of colitis, MSEW mice showed systemic and colon-specific depletion of corticosterone relative to NR mice. In addition, MSEW mice with active colitis harbored significantly reduced numbers of colonic Foxp3+ T cells compared to colitic NR mice. Finally, whereas NR mice were mostly in remission by 15 days following cessation of IL-10R blockade, MSEW mice showed consistently elevated Tnf in the proximal colon and sustained epithelial damage. Our results suggest that ELS-mediated HPA-axis dysfunction causes hypo-corticosteronism, which may subsequently promote prolonged colonic inflammation in susceptible hosts.