Ellen Schill, Washington University in St. Louis School of Medicine, St.Louis, MO, United States; Shreya Gaddipati, Washington University in St. Louis School of Medicine, St.Louis, MO, United States; Keely G. Mc.Donald, Washington University in St. Louis School of Medicine, St. Louis, MO, United States; Elisabeth Joyce, Washington University in St. Louis, United States; Alexandria Floyd, Washington University in St. Louis, United States; Rodney Newberry, Washington University in Saint Louis School of Medicine, MO, United States
Clinical Fellow Washington University in St. Louis School of Medicine Washington University in St Louis School of Medicine St.Louis, MO, United States
Background: Antepartum antibiotic prophylaxis is the standard of care for women colonized with Group B Streptococcus (GBS) or those with other risk factors for infection. While these guidelines have decreased the rate of early onset sepsis , maternal antibiotic treatment (MAT) disrupts the development of the neonatal microbiome, intestinal immune development, and increases susceptibility to late onset sepsis in mouse models. Understanding the mechanisms by which MAT disrupts neonatal intestinal immune function will facilitate the development of novel strategies to reduce neonatal sepsis risk. Intestinal goblet cell-associated antigen passages (GAPs) are portals for physiologic exposure of the immune system to commensal gut bacteria. GAPs are inhibited by epidermal growth factor receptor (EGFR) signaling, induced by luminal EGFR ligands, or transactivated by sensing of the adult gut microbiota. Colonic GAPs are closed prior to postnatal day (P) 10 in mice when luminal EGF levels from breast milk are high, but then open after P10 when breast milk EGF levels decline. At weaning, goblet cells sense mature gut microbiota which then inhibits GAP activation. Small intestinal GAPs open late in the preweaning period and remain open throughout adult life. However, when colonic GAPs are opened inappropriately due to low levels of EGF prior to P10 or dysbiosis of the gut microbiota after weaning, they can facilitate pathological bacterial translocation causing sepsis.
Objectives: Determine how MAT impacts GAP regulation in neonatal mice.
Design/Methods: Dams were treated with ampicillin and neomycin (both 1g/L) in their drinking water from pup P1-8. On P8, pups were sacrificed. Small intestine was isolated. the lumen was injected with rhodamine dextran, and allowed to incubate on ice for 20 minutes to allow uptake by GAPs. Intestine was then fixed and processed for microscopy.
Results: MAT pups significantly more open GAPs in the small intestine compared controls (Controls 0.45 +/- 0.09 GAPs/Villus; Amp/Neo MAT pups 2.0 +/- 0.27 GAPs/Villus; Mean +/- Standard Error of the Mean, p=0.03). These data suggest that MAT creates a permissive environment for small intestinal GAPs in the neonatal period which could allow pathologic bacterial translocation. MAT pups weighed significantly less and were significantly hypoglycemic compared to pups from control dams, however after weaning MAT pups recover to a normal weight.
Conclusion: MAT induces GAP dysregulation in neonatal mice and may represent a novel mechanism by which early life antibiotic exposure contributes to increased risk of late onset sepsis.
