Neonatal intermittent hypoxia, fish oil, and/or antioxidant supplementation on gut microbiota in neonatal rats.

BACKGROUND: Preterm infants frequently experience intermittent hypoxia (IH) episodes, rendering them susceptible to oxidative stress and gut dysbiosis. We tested the hypothesis that early supplementation with antioxidants and/or fish oil promotes gut biodiversity and mitigates IH-induced gut injury. METHODS: Newborn rats were exposed to neonatal IH from birth (P0) to P14 during which they received daily oral supplementation with: (1) coenzyme Q10 (CoQ10) in olive oil, (2) fish oil, (3) glutathione nanoparticles (nGSH), (4) CoQ10 + fish oil, or (5) olive oil (placebo control). Pups were placed in room air (RA) from P14 to P21 with no further treatment. RA controls were similarly treated. Stool samples were assessed for microbiota and terminal ileum for histopathology and morphometry, total antioxidant capacity, lipid peroxidation, and biomarkers of gut injury. RESULTS: Neonatal IH induced histopathologic changes consistent with necrotizing enterocolitis, which were associated with increased lipid peroxidation, toll-like receptor, transforming growth factor, and nuclear factor kappa B. Combination of CoQ10 + fish oil and nGSH were most effective for preserving gut integrity, reducing biomarkers of gut injury, and increasing commensal organisms. CONCLUSIONS: Combination of antioxidants and fish oil may confer synergistic benefits to mitigate IH-induced injury in the terminal ileum. IMPACT: Antioxidant and fish oil (PUFA) co-treatment was most beneficial for reducing neonatal IH-induced gut injury. The synergistic effects of antioxidant and fish oil is likely due to prevention of IH-induced ROS attack on lipids, thus preserving and augmenting its therapeutic benefits. Combination treatment was also effective for increasing the abundance of the non-pathogenic Firmicutes phylum, which is associated with a healthy gastrointestinal system of the newborn. Extremely low gestational age neonates who are at high risk for frequent, repetitive neonatal IH and oxidative stress-induced diseases may benefit from this combination therapy.

Effects of omega 3 polyunsaturated fatty acids, antioxidants, and/or non-steroidal inflammatory drugs in the brain of neonatal rats exposed to intermittent hypoxia.

Preterm infants experience frequent arterial oxygen desaturations during oxygen therapy, or intermittent hypoxia (IH). Neonatal IH increases oxidative distress which contributes to neuroinflammation and brain injury. We tested the hypotheses that exposure to neonatal IH is detrimental to the immature brain and that early supplementation with antioxidants and/or omega 3 polyunsaturated fatty acids (n-3 PUFAs) combined with non-steroidal anti-inflammatory drugs (NSAIDs) is protective. Newborn rats were exposed to brief hypoxia (12% O2 ) during hyperoxia (50% O2 ) from the first day of life (P0) until P14 during which they received daily oral supplementation with antioxidants, namely coenzyme Q10 (CoQ10) or glutathione nanoparticles (nGSH), n-3 PUFAs and/or topical ocular ketorolac. Placebo controls received daily oral olive oil and topical ocular saline. Room air (RA) littermates remained in 21% O2 from birth to P21 with all treatments identical. At P14 animals were allowed to recover in RA until P21 with no further treatment. Whole brains were harvested for histopathology and morphometric analyses, and assessed for biomarkers of oxidative stress and inflammation, as well as myelin injury. Neonatal IH resulted in higher brain/body weight ratios, an effect that was reversed with n-3 PUFAs and n-3 PUFAs+CoQ10 with or without ketorolac. Neonatal IH was also associated with hemorrhage, oxidative stress, and elevations in inflammatory prostanoids. Supplementation with n-3 PUFAs and nGSH with and without ketorolac were most beneficial for myelin growth and integrity when administered in RA. However, the benefit of n-3 PUFAs was significantly curtailed in neonatal IH. Neonatal IH during a critical time of brain development causes inflammation and oxidative injury. Loss of therapeutic benefits of n-3 PUFAs suggest its susceptibility to oxidation in neonatal IH and therefore indicate that co-administration with antioxidants may be necessary to sustain its efficacy.