The gastrointestinal mucosa functions as an interface between the luminal contents and the underlying tissue compartments, and is thus vital in maintaining mucosal and systemic 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. These events are mediated in part by the ability of the intestinal epithelia to respond to specific members of the microbiota by the production of reactive oxygen species (ROS), that serve to activate multiple cellular pathways involved in the maintenance of gut homeostasis. This proposal will employ in vivo systems including extensive use of germ-free mice, or mice gnotobiotically colonized with known ROS inducing bacteria. Additionally, taxonomic analysis of microbiota in neonatal mice will be used to identify other bacteria with functional effects on the gut mucosa. The proposal will study microbial influences on known and novel signaling pathway, and characterize the regulatory effects on gut survival, differentiation and proliferation. Our overall objectives are to define the participants, events, and processes involved in host microbial contact and how this interaction influences intestinal homeostasis, development and restitution. ROS and redox-stimulated pathways likely represent a conserved mechanism by which the host interacts with its commensal microbiota, and thus presents an attractive target for therapeutic manipulation.

Public Health Relevance

The mammalian gut microbiota is a complex and vast microbial community that influences a wide range of normal physiological functions in the intestine and in the body as a whole, and when quantitatively or qualitatively disturbed, can contribute to a wide and increasingly recognized range of inflammatory, immune, infectious and metabolic diseases. This proposal will use state of the art bioexclusion technology to maintain mice with highly specific and controlled microbiota and evaluate roles of specific bacteria on normal and pathological processes. This work aims to identify novel beneficial bacteria and mechanistically define how these bacteria can contribute to health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064462-12
Application #
9599430
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Ranallo, Ryan
Project Start
2006-07-01
Project End
2022-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
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
Neish, Andrew S; Jones, Rheinallt M (2014) Redox signaling mediates symbiosis between the gut microbiota and the intestine. Gut Microbes 5:250-3
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

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