Gut microbiome and inflammation in response to increasing intermittent hypoxia in the neonatal rat.

Background: Intermittent hypoxia (IH) and oxidative stress play key roles in gut dysbiosis and inflammation. We tested the hypothesis that increasing numbers of daily IH episodes cause microbiome dysbiosis and severe gut injury.

Methods: Neonatal rats were exposed to hyperoxia (Hx), growth restriction, and IH. For IH, pups were exposed to 2-12 daily episodes from birth (P0) to postnatal day 7 (7D) or P0-P14 (14D), with or without recovery in room air (RA) until P21. Animals raised in RA from P0 to P21 served as normoxia controls. Stool was expressed from the large intestines for microbiome analysis, and tissue samples were assessed for histopathology and biomarkers of inflammation.

Results: Hx and IH caused a significant reduction in the number and diversity of organisms. The severity of gut injury and levels of inflammatory cytokines and TLR4 increased, while total glutathione (tGSH) declined, with increasing daily IH episodes. The number of organisms correlated with the villi number (p < 0.05) and tGSH depletion (p < 0.001).

Conclusions: The critical number of daily IH episodes that the newborn gut may sustain is 6, beyond which irreversible damage occurs. The immature gut is highly susceptible to IH-induced injury, and IH may contribute to pathological outcomes in the immature gut.

Impact Statement: 1. The neonatal gut at birth is highly susceptible to intermittent hypoxia (IH) injury. 2. IH causes gut dysbiosis, inflammation, and glutathione depletion. 3. The severity of gut injury worsens as a function of increasing daily IH episodes. 4. The critical number of daily IH episodes that the newborn gut may sustain is 6, beyond which irreversible damage occurs.