All ETDs from UAB

Advisory Committee Chair

David A Randolph

Advisory Committee Members

Charles O Elson

Robinna G Lorenz

Chad Steele

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Neonatal late-onset sepsis is invasive infection occurring after the first 48 hours of life, and one of the leading causes of death among preterm infants in the United States and abroad. Infections with Gram-negative bacteria, such as Klebsiella pneumonia, occurring when bacteria translocate across premature gut epithelium into the bloodstream, can be particularly severe. Preterm infants in the neonatal intensive care unit undergo intense antibiotic regimens due to high risk of infection. Paradoxically, prolonged exposure of preterm infants to empiric antibiotic therapy early in the hospital stay is associated with increased risk of intestinal infection and death after adjustment for covariates. Bacterial translocation rates across mature gut epithelium are determined by complex interactions between the host's commensal microbiota and immune system, and pathogens. Commensal microbes are believed to confer protection from bacterial translocation by competing with pathogens for space and resources, and by inducing gut immune system development directly. This study explores the role of gut microbial colonization early in life in protecting neonates from invading pathogens and in inducing gut maturation. The execution of these studies relies heavily on a mouse model of late-onset sepsis we developed in which an engineered bioluminescent strain of Klebsiella pneumonia can be imaged in real-time within live animals. MiSeq high-throughput sequencing for bacterial 16S was used to elucidate the kinetics of colonization in pups from birth to weaning age. Sequencing revealed an important trend in colonization that early colony founders are hearty, ubiquitous species that may help prime the gut environment for colonization by microbes with stricter environmental or nutritional limitations, such as anaerobes. Importantly, our analyses demonstrate that although the maternal-derived colonization plays a critical role in early colonization of her pups, exposure to vaginal flora is not necessary for successful early colonization. Further, maternal antibiotics were found to drastically change the microbial landscape in young pups with downstream detrimental effects on resistance to Klebsiella challenge depending on the type of antibiotic administered. This novel mouse model affords us the opportunity to examine gut and colony maturation more closely. Data acquired from these studies provides new insights into the etiology of neonatal late-onset sepsis that may become important for treatment and prevention of the human disease.

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