343 - Increasing Intermittent Hypoxia Episodes Reduces Microbiome Diversity and Increases Inflammatory Biomarkers in the Large Intestine of Neonatal Rats

Friday, April 28, 2023

5:15 PM – 7:15 PM ET

Poster Number: 343
Publication Number: 343.134

Magdalena Latkowska, State University of New York Downstate Medical Center College of Medicine, Brooklyn, NY, United States; Charles Cai, State University of New York Downstate Medical University, Brooklyn, NY, United States; Marina Mitrou, State University of New York Downstate Medical Center College of Medicine, New York, NY, United States; Matthew Marcelino, State University of New York Downstate Medical Center College of Medicine, Brooklyn, NY, United States; Jacob (Jack) v\V. Aranda, State University of New York Downstate Medical Center College of Medicine, Brooklyn, NY, United States; Kay Beharry, SUNY Downstate Health Sciences University, Brooklyn, NY, United States

Presenting Author(s)

Magdalena Latkowska, MD, FAAP

Neonatal Fellow
State University of New York Downstate Medical Center College of Medicine
Brooklyn, New York, United States

Background: Preterm infants experience frequent intermittent hypoxia (IH) episodes during oxygen therapy, rendering them susceptible to necrotizing enterocolitis (NEC). NEC is the leading cause of gastrointestinal (GI)-related death in preterm infants and is highly associated with dysgenesis of gut microbiome.

Objective: We examined the hypothesis that exposure of the immature gut to increasing IH episodes causes significant injury with associated microbiome dysbiosis and elevations in biomarkers of NEC.

Design/Methods: Neonatal rats were exposed to hyperoxia (50% O₂) with 2, 4, 6, 8, 10, or 12 IH (12% O₂) episodes per day (EPD) from birth (P0) to postnatal day 7 (P7; 7D) or P0-P14 (14D). Pups were studied at P7 or P14, or allowed to recover in room air (RA) until P21. P7 animals remained in RA for 14 days (P21-7D), and P14 animals for 7 days (P21-14D). Animals exposed to 50% O₂ only from P0 to P21 served as hyperoxia controls, and animals raised in RA from P7 to P21 served as normoxia controls. The large intestines were assessed for histopathology, apoptosis, cytokines (IL-1β, IL-6, TNFα, TGFβ), and toll-like receptor (TLR-4). Stool samples were assessed for microbiome profile.

Results: IH resulted in significant injury including villous atrophy, denuded villi, mucosal and intestinal wall injury, apoptosis, and hemorrhage, consistent with NEC. These characteristics manifested with 2 IH EPD and were associated with a marked reduction in microbiota diversity particularly in the P21-7D group exposed to 10 IH EPD. The severity of intestinal damage increased with the number of IH episodes. Similarly, elevations in TLR-4 and inflammatory cytokines progressively increased to peak at 8-12 IH EPD, with no appreciable reduction during the recovery/reoxygenation period.

Conclusion(s): The immature gut is highly susceptible to IH-induced injury, with severity increasing as a function of daily IH episodes. In these experiments, 10-12 daily IH episodes were the critical numbers that initiated irreparable microbiome dysbiosis and cytokine induction. Close monitoring of IH episodes in preterm infants at risk for NEC is warranted.