Inflammatory bowel diseases (IBD) are associated with berrant mucosal immune responses to the enteric microflora. Innate immunity drives the active flares of disease while adaptive immune responses are thought to maintain the chronically inflamed state. While IBD has generally been associated with elevated immune responses to gut bacteria, the recent findings that IBD patients have impaired levels of innate immunity suggest that, in fact, at least some incidence of IBD may in fact result from an underlying innate immune deficiency. Thus, mechanistically dissecting how alterations in innate immunity can eventuate in chronic inflammation should help understand the pathophysiology of IBD. The bacterial protein flagellin, the monomeric subunit of flagella, is a dominant innate immune activator of intestinal epithelial cells. Thus, experimental study of the flagellin receptor, toll-like receptor 5 (TLR5), may provide mechanistic insights into how alterations in innate immunity can result in IBD. In accordance, we have recently observed that TLR5-KO mice develop spontaneous colitis. Such colitis is associated with alterations in gut microflora and appears to be dependent upon both innate and adaptive immunity. Thus, we hypothesize that TLR5 plays an essential role in """"""""managing"""""""" the commensal microflora and that loss of TLR5 renders mice unable to properly manage their commensal microflora, resulting in chronic activation of other innate immune signaling pathways and development of """"""""colitogenic"""""""" T-cells. Thus we propose to 1) Determine how loss of TLR5 affects immune cells and examine their role in TLR5KO colitis and 2) Define how loss of TLR5 affects the enteric microbiota and the role such changes play in driving colitis.

Public Health Relevance

Engineered deletion toll-like receptor 5 (TLR5), in mice, results in pontaneous colitis. This project seeks to define the pathophysiologic mechanisms that underlie such colitis. We expect this information will prove insightful toward understanding the pathogenesis of Crohn's disease and ulcerative colitis, collectively referred to as inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK083890-03
Application #
8208232
Study Section
Special Emphasis Panel (ZRG1-DKUS-G (08))
Program Officer
Grey, Michael J
Project Start
2010-04-15
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$267,705
Indirect Cost
$62,280
Name
Georgia State University
Department
Type
Other Domestic Higher Education
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Etienne-Mesmin, Lucie; Chassaing, Benoit; Adekunle, Oluwaseyi et al. (2017) Genome Sequence of a Toxin-Positive Clostridium difficile Strain Isolated from Murine Feces. Genome Announc 5:
Etienne-Mesmin, Lucie; Chassaing, Benoit; Gewirtz, Andrew T (2017) Tryptophan: A gut microbiota-derived metabolites regulating inflammation. World J Gastrointest Pharmacol Ther 8:7-9
Viennois, Emilie; Merlin, Didier; Gewirtz, Andrew T et al. (2017) Dietary Emulsifier-Induced Low-Grade Inflammation Promotes Colon Carcinogenesis. Cancer Res 77:27-40
Etienne-Mesmin, Lucie; Chassaing, Benoit; Adekunle, Oluwaseyi et al. (2017) Toxin-positive Clostridium difficile latently infect mouse colonies and protect against highly pathogenic C. difficile. Gut :
Chassaing, Benoit; Van de Wiele, Tom; De Bodt, Jana et al. (2017) Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut 66:1414-1427
Miles, Jennifer P; Zou, Jun; Kumar, Matam-Vijay et al. (2017) Supplementation of Low- and High-fat Diets with Fermentable Fiber Exacerbates Severity of DSS-induced Acute Colitis. Inflamm Bowel Dis 23:1133-1143
Zhang, Benyue; Oyewole-Said, Damilola; Zou, Jun et al. (2017) TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation. Blood Adv 1:1796-1806
Chassaing, Benoit; Raja, Shreya M; Lewis, James D et al. (2017) Colonic Microbiota Encroachment Correlates With Dysglycemia in Humans. Cell Mol Gastroenterol Hepatol 4:205-221
Etienne-Mesmin, Lucie; Vijay-Kumar, Matam; Gewirtz, Andrew T et al. (2016) Hepatocyte Toll-Like Receptor 5 Promotes Bacterial Clearance and Protects Mice Against High-Fat Diet-Induced Liver Disease. Cell Mol Gastroenterol Hepatol 2:584-604
Singh, Vishal; Yeoh, Beng San; Chassaing, Benoit et al. (2016) Microbiota-inducible Innate Immune, Siderophore Binding Protein Lipocalin 2 is Critical for Intestinal Homeostasis. Cell Mol Gastroenterol Hepatol 2:482-498.e6

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