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.
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.
|Chassaing, Benoit; Etienne-Mesmin, Lucie; Gewirtz, Andrew T (2014) Microbiota-liver axis in hepatic disease. Hepatology 59:328-39|
|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|
|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; Ley, Ruth E; Gewirtz, Andrew T (2014) Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice. Gastroenterology 147:1363-77.e17|
|Oh, Jason Z; Ravindran, Rajesh; Chassaing, Benoit et al. (2014) TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41:478-92|
|Johansson, Malin E V; Gustafsson, Jenny K; Holmen-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|
|Aitken, Jesse D; Gewirtz, Andrew T (2013) Gut microbiota in 2012: Toward understanding and manipulating the gut microbiota. Nat Rev Gastroenterol Hepatol 10:72-4|
|Carvalho, Frederic A; Nalbantoglu, Ilke; Ortega-Fernandez, Sophie et al. (2012) Interleukin-1? (IL-1?) promotes susceptibility of Toll-like receptor 5 (TLR5) deficient mice to colitis. Gut 61:373-84|
|Carvalho, F A; Nalbantoglu, I; Aitken, J D et al. (2012) Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges. Mucosal Immunol 5:288-98|
|Carvalho, F A; Aitken, J D; Gewirtz, A T et al. (2011) TLR5 activation induces secretory interleukin-1 receptor antagonist (sIL-1Ra) and reduces inflammasome-associated tissue damage. Mucosal Immunol 4:102-11|
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