Abstract
Glucocorticoids (GC) contribute to human intestine ontogeny and accelerate gut barrier development in preparation to birth. Rat gut is immature at birth, and high intestinal GC sensitivity during the first two weeks of life resembles that of premature infants. This makes suckling rats a model to investigate postpartum impact of maternal separation (MS)-associated GC release in preterm babies, and whether GC sensitivity may shape MS effects in immature gut. A 4 hours-MS applied once at postnatal day (PND)10 enhanced plasma corticosterone in male and female pups, increased by two times the total in vivo intestinal permeability (IP) to oral FITC-Dextran 4 kDa (FD4) immediately after the end of MS, and induced bacterial translocation (BT) to liver and spleen. Ussing chamber experiments demonstrated a 2-fold increase of permeability to FD4 in the colon immediately after the end of MS, but not in the ileum. Colonic permeability was not only increased for FD4 but also to intact horseradish peroxidase 44 kDa in MS pups. In vivo, the glucocorticoid receptor (GR) antagonist RU486 or ML7 blockade of myosin light chain kinase controlling epithelial cytoskeleton contraction prevented MS-induced IP increase to oral FD4 and BT. In addition, the GR agonist dexamethasone dose-dependently mimicked MS-increase of IP to oral FD4. In contrast, MS effects on IP to oral FD4 and BT were absent at PND20, a model for full-term infant, characterized by a marked drop of IP to FD4 in response to dexamethasone, and decreased GR expression in the colon only compared to PND10 pups. These results show that high intestinal GC responsiveness in a rat model of prematurity defines a vulnerable window for a post-delivery MS, evoking immediate disruption of epithelial integrity in the large intestine, and increasing susceptibility to macromolecule passage and bacteremia.
Highlights
The intestinal epithelium and associated immune system have important barrier functions through life, with immunological signaling pathways acting both as a defense against luminal pathogens, or favoring tolerance to food antigens and commensal microorganisms [1]
From PND40 to PND50, a sharp decrease of intestinal permeability (IP) to fluoro isothiocyanate (FITC)-Dextran 4 kDa (FD4) occurred in both sexes, with plasma FD4 concentration at PND50 of 1.360.3 mg/ml in females (276% vs. PND40; p,0.001) and 0.760.2 mg/ml in males (287% vs. PND40; p,0.0001), approximately 10% of PND10 levels
Our study shows a vulnerable window in rats during early postnatal life (i.e. 10-days-old) through which a single episode of mother-infant separation evoked an immediate increase of gut permeability to macromolecules in the large intestine, enhancing the passage of viable bacteria to systemic organs
Summary
The intestinal epithelium and associated immune system have important barrier functions through life, with immunological signaling pathways acting both as a defense against luminal pathogens, or favoring tolerance to food antigens and commensal microorganisms [1]. Bacterial colonization together with endocrine and nutritional factors drive mucosal immune system development, and stimulate growth and renewal of gut epithelium [3,4,5] Among these factors, glucocorticoids (GC) play important roles for the maturation of digestive and absorptive functions, and stimulate morphogenesis in the small intestine and the colon in human [6,7,8] as well as in rodents [9,10,11]. Glucocorticoids (GC) play important roles for the maturation of digestive and absorptive functions, and stimulate morphogenesis in the small intestine and the colon in human [6,7,8] as well as in rodents [9,10,11] In rodents, these beneficial activities occur during the first two weeks of life, a period characterized by high responsiveness to GC in various organs including the gut, with low levels of circulating corticosterone (CORT) [12,13]. There is no study with stress-based animal models aimed at investigating the consequences of a single MS on the developing gut taking into account the period of postnatal development and endogenous GC sensitivity
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