Investigating the impact of ESBL E. coli colonization on infant microbiome

ABSTRACT
The rapid rise of extended spectrum beta-lactamase-producing (ESBL) Enterobacteriaceae is severely
threatening the way we treat common infectious diseases. Enterobacteriaceae such as Escherichia coli (E.
coli) are a major cause of infections such as bacteremia, meningitis, and urinary tract infections in neonates.
Gut colonization with ESBL E. coli is a risk factor for these invasive infections. Additionally, infants who are
asymptomatically colonized with ESBL E. coli also contribute to the community reservoir of these strains.
Several recent studies have shown that acquisition and persistence of gut colonization with ESBL E. coli can
occur even in the absence of antibiotic exposure, traditionally considered a key risk factor. At birth the neonatal
gut is only sparsely populated with microbes, and therefore provides a unique environment for acquisition of
ESBL E. coli due to the limited competition from other microbes. A significant proportion of infants who acquire
ESBL E. coli early in life remain persistently colonized with them. However, the impact of early life acquisition
on the rapidly developing infant gut microbiome is not well studied, especially in the setting of varying age of
acquisition and nutritional intake.
Previous work in the Arshad laboratory using a murine model of early life E. coli acquisition has shown that
several ESBL E. coli persistently colonize the mouse gut through adulthood with a significantly higher burden
of colonization compared to commensal non-ESBL E. coli. In vitro studies show that some of the strains adept
in gut colonization are also able to out compete non-ESBL E. coli in a limited nutrient growth media as well as
in vivo in the animal model. Perinatal transmission of at least one ESBL E. coli in our murine model results in
an overabundance of E. coli in the infant gut microbiome and a displacement of usual commensal microbes.
This proposal aims to utilize clinically relevant ESBL E. coli, genomic sequencing, and animal models to 1)
determine the gut microbiome characteristics associated with ESBL E. coli colonization during the early life
period, and 2) assess gut colonization with ESBL E. coli and impact on microbiome according to age and
nutritional status. These objectives will be achieved by building on existing collaborations between the Arshad
lab (expertise in bacterial pathogenesis and animal models) and DePlaen lab (expertise in mouse gut nutrition)
at Lurie Children’s Hospital, and Hartmann lab at Northwestern University (expertise in bacterial genomics,
next-generation sequencing), and Grobe lab at University of Wisconsin (expertise in caloric assessment of
stool).
We anticipate that the results from the proposed experiments will provide in vivo evidence of the long-term
impact of gut colonization with ESBL E. coli on the infant gut microbiome. Further, the results of the proposed
study will aid in developing nutritional interventions and/or identification of commensal microbes that may be
used as probiotics, to prevent long-term colonization with ESBL E. coli.

Grant Number: 5R21AI178334-02
NIH Institute/Center: NIH
Principal Investigator: Mehreen Arshad