Antibiotic disruption of the gut microbiome and immune response in neonatal late-onset sepsis

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to describe a five-year training and mentorship plan to prepare Drew Schwartz, MD, PhD to become an independent physician-scientist investigator studying the effects of antibiotics on the preterm neonatal microbiome and host response. Dr. Schwartz obtained combined MD and PhD degrees in the Medical Scientist Training Program at Washington University School of Medicine in St. Louis where he studied how uropathogenic E. coli invade bladder cells to cause severe urinary tract infections. After clinical training in Pediatrics and Infectious Diseases at Washington University School of Medicine and St. Louis Children’s Hospital, he joined the lab of Dr. Gautam Dantas, PhD, a renowned expert on the microbiome and antibiotic resistance. Using fecal samples from an established repository of over 70,000 stools from hospitalized neonates, Dr. Schwartz developed a novel gnotobiotic mouse model of infant microbiome development and disruption. He colonizes germ-free dams with neonatal stool and treats microbiota-humanized pups with clinically relevant doses of antibiotics. He has identified that specific microbiome-antibiotic combinations result in mouse death concomitant with microbiome disruption and immune dysregulation. The central hypothesis is that antibiotic treatment predisposes infants with certain microbiome and resistome compositions to either bacteremic or culture-negative late-onset sepsis. The specific aims of the proposal are to: 1) Define the effects of early-life antibiotics on human infant microbiome maturation, gut mucosal immune response, and vulnerability to bacteremia, and 2) Determine microbial and immune mechanisms of bacteremic and culture-negative late-onset sepsis in a neonatal microbiome-humanized mouse model. The proposed studies will utilize microbiome sequencing, flow cytometry, host immune profiling, and computational modeling to identify modifiable risk factors to refine antibiotic prescribing in the neonatal intensive care unit with the overall goal of reducing incidence and mortality from late-onset sepsis. The mentor, Dr. Dantas, will primarily oversee the project providing training on microbiome analysis, resistome sequencing, and bioinformatic modeling. Dr. Schwartz has assembled an advisory committee with expertise on neonatal infections, antibiotic treatment, gut microbiome development and disruption, and mucosal and peripheral immune response to commensal and pathogenic bacteria. The training plan incorporates achievement of technical expertise, grant writing skills, responsible conduct of research, and mentorship through one-on-one learning, University-sponsored workshops, and presentation and workshops at international conferences. Washington University School of Medicine is the ideal training environment given its extensive track record, outstanding resources, commitment to physician scientists, and necessary expertise to complete the proposed research. This K08 award will provide the necessary skills and resources that Dr. Schwartz requires to become a successful physician scientist whose lab studies the infant microbiome host interface.