Postnatal Exposure to Hyperoxia Causes Maladaptation of the Premature Intestine

Key Words: Prematurity, Intestine, Oxygen, Necrotizing enterocolitis, Stem cells

Premature infants frequently develop intestinal problems, ranging from milder problems like not tolerating their feedings from time to time, to developing a severe and often deadly disease called necrotizing enterocolitis (NEC). About 2500 infants get NEC every year in the U.S. alone. It is a leading cause of death in premature infants. Despite this, we still don’t understand why NEC happens. In this study, we hypothesize that exposure to high levels of oxygen may cause changes to the developing intestine that may then leave the intestine unable to tolerate a secondary insult, thereby contributing to NEC.

Premature infants are exposed to higher levels of oxygen than they would be in utero. The blood oxygen saturation in the fetal gut it around 45-50%, while it is about 75% in a premature infant at the same gestational age. This relative hyperoxia is already known to cause disease of the lung and eye in premature born infants. The impacts of hyperoxia on the intestine are not well studied, however. Our group has previously contributed to a study showing that hyperoxia causes changes to the intestine which drive premature lung disease due to hyperoxia. We now want to understand exactly how hyperoxia changes the developing intestine. Preliminary data show that hyperoxia causes significant changes to the types of cells present in the intestine, causing fewer stem cells and driving cells into a maturation process called differentiation. Increased differentiation and decreased stem cells could leave the intestine unable to recover if an injury occurred. In this proposal, we aim to further characterize what the effects of hyperoxia are on the developing intestine. We also aim to find out whether changes caused by hyperoxia affect the intestine’s ability to withstand subsequent stress. We will use mini-intestines, or organoids, from mice and premature babies as well as mouse models to examine these questions. We think that understanding the impacts of hyperoxia on the intestine may lead to new therapies to prevent intestinal disease in premature infants.