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Changes in intestinal glucocorticoid sensitivity in early life shape the risk of epithelial barrier defect in
Nabila Moussaoui1, Viorica Braniste2, Afifa Ait-Belgnaoui3
1Intestinal Development, Xenobiotics & Immunotoxicology, Institut National de la Recherche Agronomique (INRA), Research Centre in Food Toxicology (Toxalim), Toulouse, France ; Integrative Toxicology & Metabolism, INRA, Toxalim, Toulouse, France.
Insights
Maternal separation in immature rats increases gut permeability and bacterial translocation, mimicking preterm infant vulnerability. Glucocorticoid receptor sensitivity in the gut influences these effects.
Area of Science:
- Physiology
- Developmental Biology
- Gastroenterology
Background:
- Glucocorticoids (GC) are crucial for intestinal development and gut barrier maturation.
- Immature rat gut exhibits high GC sensitivity, similar to premature infants, making it a model for studying early-life stress.
- Postpartum maternal separation (MS) can lead to GC release, potentially impacting the developing gut.
Purpose of the Study:
- To investigate the impact of maternal separation (MS)-associated glucocorticoid (GC) release on the immature rat gut.
- To determine if GC sensitivity influences the effects of MS on gut integrity in preterm models.
- To explore the role of the glucocorticoid receptor (GR) in mediating MS-induced gut changes.
Main Methods:
- Utilized a rat model at postnatal day (PND) 10 (preterm) and PND20 (full-term).
- Administered a 4-hour maternal separation (MS) and assessed plasma corticosterone, in vivo intestinal permeability (IP) to FITC-Dextran 4 kDa (FD4), and bacterial translocation (BT).
- Employed Ussing chamber experiments, GR antagonist (RU486), GR agonist (dexamethasone), and myosin light chain kinase inhibitor (ML7).
Main Results:
- MS at PND10 increased plasma corticosterone, doubled in vivo intestinal permeability (IP) to FD4, and induced bacterial translocation (BT).
- Colonic permeability to FD4 and horseradish peroxidase increased post-MS, while ileal permeability remained unchanged.
- GR antagonism or ML7 blockade prevented MS-induced IP and BT; dexamethasone mimicked MS effects, while at PND20, MS effects were absent and GR expression decreased.
Conclusions:
- High intestinal GC responsiveness in preterm-like rats creates a vulnerable window for MS, causing immediate disruption of large intestine epithelial integrity.
- MS increases susceptibility to macromolecule passage and bacteremia in immature gut due to heightened GC sensitivity.
- GC signaling pathways are critical in mediating the adverse effects of early-life stress on gut barrier function in preterm neonates.
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.
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