Intestinal mucosal surfaces harbor a vast complex microbial ecosystem, the microbiome, which is intimately involved in host development and protection. Our work has demonstrated a complex feedback loop between the microbiome and the innate and acquired immune system that mediates intestinal homeostasis. Perturbation of any aspect of this system may result in loss of homeostasis and host damage. One member of this ecosystem is Enterococcus faecalis (EF), a "pathobiont" that normally lives symbiotically with its host, but also can invade the host and cause systemic disease when intestinal homeostasis is disrupted. It is therefore an ideal model organism that can be use in a complex ecosystem to probe bacterial-bacterial and bacterial- host interactions that contribute to ecosystem dynamics at the intestinal mucosal interface. We hypothesize that EF is able to usurp the host-biome feedback loop to establish persistent colonization in the GI tract. It does this by altering the composition of the gut biome and triggering changes in host acquired and innate immune response, ultimately altering intestinal epithelial antimicrobial peptide (AMP) expression. Using a novel model for intestinal EF colonization that allows the study of both EF:commensal and commensal:host interaction, we will examine mechanisms by which EF alters the intestinal biome to establish a niche in the GI tract (Aim 1) and then investigate the importance of EF manipulation of host epithelial AMP expression on EF colonization (Aim 2). Finally we will investigate the importance of luminal and extra-luminal pathways for the regulation of epithelial AMP expression in EF niche formation. We will characterize both bacterial and host mechanisms that determine the balance between bacterial colonization and invasion by components of the normal microbiome. Ultimately, these findings will lead to a greater understanding of the complex bacterial- host interactions that lead to bacterial niche formation in the GI tract.

Public Health Relevance

The gastrointestinal tract is colonized by trillions of bacteria that have an important role in health and disease. The goal of these studies is to understand how bacteria that are normally found in the intestinal tract interact with other colonizing bacteri and the host immune system to persist in the gut. Ultimately, by understanding the mechanisms involved in the dynamic relationship between individuals and their colonizing bacteria, we will develop new approaches for manipulating this interaction to benefit individual health and prevent disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM099526-01
Application #
8211770
Study Section
Special Emphasis Panel (ZGM1-GDB-2 (MC))
Program Officer
Sledjeski, Darren D
Project Start
2012-02-13
Project End
2016-01-31
Budget Start
2012-02-13
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$344,250
Indirect Cost
$119,250
Name
Medical College of Wisconsin
Department
Pediatrics
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226