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 #
5R01DK083890-05
Application #
8597418
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
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$267,156
Indirect Cost
$82,273
Name
Georgia State University
Department
Type
Other Domestic Higher Education
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
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
Uchiyama, Robin; Chassaing, Benoit; Zhang, Benyue et al. (2015) MyD88-mediated TLR signaling protects against acute rotavirus infection while inflammasome cytokines direct Ab response. Innate Immun 21:416-28
Chassaing, Benoit; Koren, Omry; Goodrich, Julia K et al. (2015) Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519:92-6
Singh, Vishal; Chassaing, Benoit; Zhang, Limin et al. (2015) Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice. Cell Metab 22:983-96
Chassaing, Benoit; Miles-Brown, Jennifer; Pellizzon, Michael et al. (2015) Lack of soluble fiber drives diet-induced adiposity in mice. Am J Physiol Gastrointest Liver Physiol 309:G528-41
Singh, Vishal; Yeoh, Beng San; Carvalho, Frederic et al. (2015) Proneness of TLR5 deficient mice to develop colitis is microbiota dependent. Gut Microbes 6:279-83
Uchiyama, Robin; Chassaing, Benoit; Zhang, Benyue et al. (2014) Antibiotic treatment suppresses rotavirus infection and enhances specific humoral immunity. J Infect Dis 210:171-82
Chassaing, Benoit; Koren, Omry; Carvalho, Frederic A et al. (2014) AIEC pathobiont instigates chronic colitis in susceptible hosts by altering microbiota composition. Gut 63:1069-80
Chassaing, Benoit; Etienne-Mesmin, Lucie; Gewirtz, Andrew T (2014) Microbiota-liver axis in hepatic disease. Hepatology 59:328-39
Johansson, Malin E V; Gustafsson, Jenny K; Holmén-Larsson, Jessica et al. (2014) Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63:281-91

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