The gastrointestinal mucosa functions as an interface between luminal contents and underlying tissue compartments, and is thus vital in maintaining mucosal homeostasis. The gut lumen houses a numerically vast and taxonomically diverse prokaryotic microbiota. In health, the mucosa and microbiota thrive in a mutually beneficial symbiotic arrangement. Both host and microbe have evolved a complex system of mutual perception, response and reaction. This is mediated in part by the presence of microbiota derived macromolecules (MAMPs), and host pattern recognition receptors (PRRs) to respond to them. PRRs activate well studied intra cellular signaling pathways that allow the host cell to monitor commensals and react to pathogens. In this proposal we will study a highly conserved signaling pathway, Nrf2/ARE, well known for its role in monitoring exogenous xenobiotic threats, as a novel and distinct system for the perception and response to the microbiota. We will employ in vivo methods including genetically modified mice and Drosophila to study microbial activation of this pathway, evaluate the genes induced, and characterize the functional effects on gut survival, differentiation and proliferation. Our overall objectives are to define the pathobiologic function of microbially stimulated Nrf2 and its role regulating intestinal homeostasis. The Nrf2 pathway likely represents a conserved mechanism by which the host manages its commensal microbiota, and it presents an attractive target for therapeutic manipulation.

Public Health Relevance

The relationship of the human intestine and the normal bacterial microbiota within is important in normal physiology and in the development of numerous inflammatory and immune related diseases. This proposal will use novel animal systems to study the interaction of the host with commensal bacteria to determine how this cross talk influences health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064462-07
Application #
8435354
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Alexander, William A
Project Start
2005-04-01
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
7
Fiscal Year
2013
Total Cost
$364,250
Indirect Cost
$129,250
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Bienenstock, John; Gibson, Glenn; Klaenhammer, Todd R et al. (2013) New insights into probiotic mechanisms: a harvest from functional and metagenomic studies. Gut Microbes 4:94-100

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