(37) Antibiotic Exposure Disrupts Small Intestine Goblet Cell Associated Antigen Passages in Neonatal Mice

Background: Antibiotics can be life saving for premature neonates, yet paradoxically early life antibiotic exposure is associated with an increased risk of late onset sepsis (LOS), a blood infection that can arise due to bacterial translocation from the intestinal lumen. Goblet cell associated antigen passages (GAPs) deliver antigens to the immune system for development of tolerogenic responses in the homeostatic state. However, inappropriately opened GAPs in neonates can facilitate the translocation of gut resident bacteria precipitating a blood stream infection resembling LOS in a mouse model.

Objectives: We hypothesized that early life antibiotic exposure in neonates induces inappropriate GAP opening and may contribute to antibiotic associated LOS risk.

Design/Methods: Wildtype C57BL/6 mice were exposed to ampicillin and neomycin (A/N) from day of life (DOL) 1-8. GAPs were labelled by endocytic uptake of luminal rhodamine dextran. We have conducted an ELISA with homogenized samples of small intestine. We conducted a commercialized legend plex with homogenized samples of small intestine for cytokine measurements.

Results: A/N exposed pups had more small intestinal GAPs compared to control. Epidermal growth factor (EGF) is the dominant regulator of GAPs in neonates. However, we found no significant difference in EGF levels in the small intestine of control and A/N treated mice. Goblet cell intrinsic microbial sensing via TLRs/Myd88 can inhibit GAPs in adults. Utilizing a mouse with inducible deletion of MyD88 in goblet cells revealed no difference in the frequency of GAPs between the mice with or without MyD88 in the goblet cells, suggesting that MyD88 signaling in goblet cells is not inhibiting GAPs at this time in life. Select cytokines have also been shown to inhibit GAPs, specifically IL-1, we have found that there is a decrease in antibiotic treated mice as compared to control.

Conclusion: In conclusion GAPs are inappropriately open in DOL 8 pups exposed to maternal antibiotic exposure. The antibiotic exposure induced GAP regulation is not due to decreased breast milk EGF. The cytokines IL-1, is a candidate for the dysregulation of GAPs in the antibiotic exposed mice.