Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants. Despite advances in neonatal practice, its pathophysiology is poorly understood, treatments are mainly supportive, and no predictive test is available. In experimental NEC, we found that bile acids (BAs) are a crucial component of disease pathogenesis. In infants, preliminary data suggest that day-to-day fluctuations of total, fecal BAs are a better predictor of NEC than overall levels.
In Specific Aim 1, using prospectively collected fecal specimens from multiple NICUs, we will define the characteristics of BA levels and composition in premature infants that develop NEC, and in an independent cohort with blinded analyses, test the predictive ability of BAs in NEC. Preliminary studies suggest infants that develop NEC are have extreme variability in fecal BA levels and pulsa- tile exposure to hydrophobic BAs is more damaging to intestinal epithelium than continuous exposure. In Spe- cific Aim 2, we will test the hypothesis that in neonatal intestinal epithelium, pulsatile exposure to BAs is more cytotoxic than continuous exposure. Although bacteria have been suspected of playing a critical role in NEC, none have been definitively linked to disease development. However, gut bacteria play an important role in converting 1o BAs to their more hydrophobic?and cytotoxic?2o forms through their ability to dehydroxylate or deconjugate BAs. Preliminary data suggest bacteria capable of these transformations are more abundant in feces taken from infants that develop NEC compared to those that did not develop disease.
In Specific Aim 3, we will test the hypothesis that premature infants that develop NEC have increased bacteria capable of dehy- droxylating and deconjugating primary BAs resulting in increased BA hydrophobicity. In addition, germ-free, neonatal mice will be populated with bacteria that can dehydroxylate or deconjugate BAs to test the hypothesis that bacterial conversion of BAs to more cytotoxic forms is an initiator of NEC. Completion of these aims will elucidate the mechanisms of action of BAs in NEC, and could lead to future development of the first predictive test for this devastating disease.
Necrotizing Enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants with significant morbidity and mortality. Currently, there are no specific treatments or predictive tests for this devastating ailment. This project will define the characteristics of bile acid (BA) levels and composition in infants that develop NEC, define mechanisms by which pulsatile exposure to BAs leads to NEC, and determine how the microbiome and BAs interact in NEC pathogenesis.