Early life stress in mice leads to impaired colonic corticosterone production and prolonged inflammation following induction of colitis

Early life stress (ELS) is an environmental trigger linked to increased risk of inflammatory bowel disease (IBD). Our goal was to identify mechanisms whereby ELS in mice affects susceptibility to, and/or severity of, intestinal inflammation. We hypothesized that ELS alters the delicate balance of typical homeostatic mediators in the intestinal microenvironment, predisposing ELS-exposed individuals to IBD onset or worsened disease upon a pro-inflammatory triggering event within the gut. We utilized 2 published animal models of ELS. In the first model, newborn mice were separated from the dam daily for 4-8 hours beginning on postnatal day 2, then weaned early on postnatal day 17. Normally reared (NR) control mice were left undisturbed with the dams until standard weaning on postnatal day 21. In the second model, dams were fed the synthetic glucocorticoid – dexamethasone, or vehicle ad libitum in drinking water (3 μg/mL) on post-partum days 1-14. Colitis was induced in 4-week-old mice via intraperitoneal injection of IL-10 receptor blocking antibody (100 μg) every 5 days for 15 days. Five or 15 days later, histological colitis scores and colonic transcripts for Tnf, glucocorticoid receptors, and steroidogenic enzymes were measured. ELS-exposed mice displayed altered mucosa-associated immune cell balances, with an initial deficit in anti-inflammatory IL-10-producing CD4 T cells at 4-wks of age (n≥11, p<0.05), followed by an increase in IFNγ-producing CD4 T cells at 8-wks of age (n≥7, p<0.05). ELS-exposed mice also displayed reduced levels of the glucocorticoid, corticosterone in the plasma (n≥10, p<0.01) as well as locally within the colon (n≥7, p<0.05). Upon colitis induction, NR control animals showed improvements in indices of inflammation following cessation of IL-10 receptor blockade, whereas ELS-exposed animals maintained high levels of intestinal Tnf (n≥7, p<0.01) and histological signs of colitis (n≥7, p<0.05). In colitic animals, prior exposure to ELS was associated with significantly lower expression of genes associated with corticosterone synthesis ( Cyp11a1; n≥5, p<0.05) and responsiveness ( Nr3c1, Nr5a2; n≥5, p<0.01). Finally, ex-vivo TNF stimulation of colonic crypt cells from ELS mice led to increased inhibition of corticosterone synthesis, relative to NR control mice (n≥4, p<0.05). Our study identifies impaired local colonic glucocorticoid production and responsiveness as a potential mechanism whereby ELS predisposes to chronic colitis in susceptible hosts. Crohn's and Colitis Foundation Research Initiatives Award This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.