Thrasher Research Fund - Medical research grants to improve the lives of children

Project Details

Early Career

Status: Funded - Closed

Antibiotics disrupt the gut microbiome and immune response, and increase vulnerability to bacteremia

Drew Schwartz, MD, PhD


BACKGROUND: Preterm neonates receive numerous antibiotic courses which decrease microbial diversity, distort the immune system, and increase the likelihood of developing late onset sepsis and bacteremia. In a subset of neonates, the same strain of bacteria can be cultured from the stool prior to bacteremia. Term neonates in the first month of life have an equally immature gut microbiome with some susceptible to serious bacterial infections. GAP: All neonates under 30 days of life with fever or clinical instability are treated with antibiotics while cultures are pending. Can we use the gut microbiome to predict those that will have a serious bacterial infection? HYPOTHESIS: An immature gut microbiome contains the pathogen that causes serious bacterial infection in preterm and term neonates. METHODS: We conducted shotgun metagenomic sequencing of fecal samples from preterm infants with bloodstream infection, term infants with urinary tract infection and/or bloodstream infection, and preterm and term infants without serious bacterial infection. We performed whole genome sequencing of the blood or urinary isolate and used inStrain to determine the presence of the invasive strain within the metagenome at single nucleotide precision. We used generalized linear mixed effect models with MaAsLin2 to identify clinical variables associated with microbiome composition. RESULTS: Relative to controls, gut microbiomes of cases had increased relative abundance of the BSI-causing species and clustered into enterotypes and by Bray-Curtis dissimilarity according to BSI pathogen. We demonstrated that 11/19 (58%) of preterm infant gut microbiomes before bacteremia harbored the BSI isolate with fewer than 20 genomic substitutions establishing identity. Similarly, 25/40 (62.5%) of term infants harbored an isogenic strain with >99.99% average nucleotide identity in their gut at the time of serious bacterial infection. The most significant feature in the gut microbiome of cases relative to controls was the abundance of the causative species at the time of or before serious bacterial infection. IMPACT: Identifying neonates prior to or at the time of serious bacterial infection by sequencing the gut microbiome, identifying potential antibiotic resistant pathogens, and informing antibiotic decision-making would greatly reduce the frequency and morbidity due to serious bacterial infection.

Supervising Institution:
Washington University in St. Louis

Gautam Dantas

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