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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Alexander, William A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Medicine
United States
Zip Code
Kudelka, Matthew R; Hinrichs, Benjamin H; Darby, Trevor et al. (2016) Cosmc is an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk. Proc Natl Acad Sci U S A 113:14787-14792
Alam, Ashfaqul; Leoni, Giovanna; Quiros, Miguel et al. (2016) The microenvironment of injured murine gut elicits a local pro-restitutive microbiota. Nat Microbiol 1:15021
Leoni, Giovanna; Neumann, Philipp-Alexander; Kamaly, Nazila et al. (2015) Annexin A1-containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair. J Clin Invest 125:1215-27
Jones, Rheinallt M; Desai, Chirayu; Darby, Trevor M et al. (2015) Lactobacilli Modulate Epithelial Cytoprotection through the Nrf2 Pathway. Cell Rep 12:1217-25
Lambeth, J David; Neish, Andrew S (2014) Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited. Annu Rev Pathol 9:119-45
Ardita, Courtney S; Mercante, Jeffrey W; Kwon, Young Man et al. (2014) Epithelial adhesion mediated by pilin SpaC is required for Lactobacillus rhamnosus GG-induced cellular responses. Appl Environ Microbiol 80:5068-77
Neish, Andrew S; Jones, Rheinallt M (2014) Redox signaling mediates symbiosis between the gut microbiota and the intestine. Gut Microbes 5:250-3
Alam, A; Leoni, G; Wentworth, C C et al. (2014) Redox signaling regulates commensal-mediated mucosal homeostasis and restitution and requires formyl peptide receptor 1. Mucosal Immunol 7:645-55
Leoni, Giovanna; Alam, Ashfaqul; Neumann, Philipp-Alexander et al. (2013) Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair. J Clin Invest 123:443-54
Jones, Rheinallt M; Luo, Liping; Ardita, Courtney S et al. (2013) Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox-mediated generation of reactive oxygen species. EMBO J 32:3017-28

Showing the most recent 10 out of 21 publications