Population Genomic Analysis of Gut Microbial Colonization in Premature Infants

Abstract
A large body of literature now indicates that antenatal and neonatal antibiotic exposure is associated with adverse
childhood outcomes due to disruption of the developing microbiome. In premature infants, the standard of care
for many decades has included the administration of broad-spectrum antibiotics in the first hours of life as
treatment for a presumptive diagnosis of early onset sepsis. However, nearly all preterm infants receiving these
antibiotics do not actually have sepsis. This grant renewal application proposes an ancillary microbiome study
linked to the NANO (NICU Antibiotics and Outcomes) Trial, a recently launched clinical trial that will challenge
this longstanding practice of immediately prescribing antibiotics to newborn preterm infants. NANO will test the
hypothesis that antibiotics at birth worsens outcomes in preterm infants that are clinically stable. This multicenter
trial, which is led by members of our research team, will randomize 802 premature infants to receive intravenous
ampicillin and gentamicin or a saline placebo control. The study will measure the impact of variables including
mode of delivery, gestational age, sex, and receipt of maternal milk, and administration of maternal antepartum
antibiotics.
Infant fecal samples in the first month of life as well as maternal fecal and vaginal swabs will be collected in
NANO for basic microbiome profiling in the antibiotics and placebo groups using 16S rRNA gene sequencing.
Here, we propose to augment microbiome analyses of NANO study subjects using novel strain-level
metagenomic strategies and by analyzing samples beyond the first month of life. With this strategy, we propose
to Aim 1. Test the hypothesis that empiric antibiotics (EA) disrupts mother-infant strain sharing in preterm infants.
Aim 2. Test the hypothesis that EA increases the abundance of gut bacterial antimicrobial resistance genes in
preterm infants. Aim 3. Test the hypothesis that EA delays the transition from a gut ecosystem dominated by
facultative anaerobes to one dominated by obligate anaerobes. Because NANO is a first-of-its-kind clinical trial
evaluating antibiotic therapy during the first days of life, this ancillary study will provide a rare opportunity to ask
and answer a unique set of questions about the biology of early gut bacterial colonization.

Grant Number: 5R01AI092531-15
NIH Institute/Center: NIH
Principal Investigator: Jillian Banfield