Neonatal maternal separation causes colonic dysfunction in rat pups including impaired host resistance

Previous studies have shown that early life stress in the form of intermittent maternal separation (MS) predisposes adult rats to develop stress-induced intestinal mucosal dysfunction and visceral hypersensitivity. However, the mechanism involved in the functional abnormalities is unclear. Our aim was to study immature animals during or shortly after exposure to MS to determine whether there are early pathophysiological changes in the gut. Sprague-Dawley rat pups were individually separated from the dam for 3 h/d from 4 to 21 d of age; nonseparated (NS) control pups remained in the home cage with the dam. On d 19-20, d 24-25, and d 29-30, blood was collected for corticosterone measurement, and colonic tissues were removed for functional and morphologic assessment. Corticosteroid levels were elevated in MS pups compared with NS, indicating that MS was indeed stressful. The distal colon demonstrated significantly enhanced ion secretion and macromolecular permeability at d 19-20 and d 24-25, returning to normal by d 29-30. Electron microscopy and bacterial culture studies indicated bacteria adhering to and penetrating into the colonic epithelium of the MS pups at all time points, while such events were rare in NS pups. The pathophysiological changes were inhibited by injecting pups sc with a corticotropin-releasing hormone (CRH) receptor antagonist daily during MS. Our studies indicate that early psychological trauma predisposes neonatal rats to develop persistent mucosal barrier dysfunction, including impaired host defense to luminal bacteria, by a mechanism involving peripheral CRH receptors.