Inflammatory bowel disease (IBD) is caused by the complex interaction of host genetics, environmental insults such as diet or infection, and the gut microbiota. While it is well accepted that commensal microbiota are involved in the etiology of IBD, it is not well understood how changes in the microbiota, termed dysbiosis, occur nor is it understood the impact that dysbiosis has on mucosal immunity. Our preliminary data demonstrate that a polymorphism in human TLR1, which abrogates signaling, is selected in pediatric IBD patients. Using a mouse model, we have found that TLR1-deficient mice infected with Yersinia have a failure to gain weight, demonstrate anti-commensal immune responses and have an altered microbiota ten weeks after infection. Specifically, we see an increase in sulfate-reducing bacteria, which has also been identified in patients with IBD, and a concomitant decrease in probiotic Lactobacillus. Herein, I propose an extension of research project (K01 DK8275) that will examine the cause of dysbiosis in the absence of TLR1-signaling after infection by the enteropathogen, Yersinia enterocolitica. The project will look to identify host factors, pathogenic strategies and the contribution of commensal bacteria that contribute to dysbiosis. Further, we will examine how an altered microbiota may impact inflammation and mucosal immunity. These data will provide important insights into how genetics can influence mucosal immunity as well as suggest a new set of strategies to tailor treatments to patients with particular genetic backgrounds.
I propose to examine the cause of dysbiosis that occurs in TLR1-deficient mice after infection. We will examine host, pathogen and commensal contribution to microbial diversity. In addition we will examine how the altered microbiota and the specific bloom in sulfate-reducing bacteria contribute to inflammation and IBD.
|Sugiura, Y; Kamdar, K; Khakpour, S et al. (2013) TLR1-induced chemokine production is critical for mucosal immunity against Yersinia enterocolitica. Mucosal Immunol 6:1101-9|
|Michail, Sonia; Bultron, Gilberto; Depaolo, R William (2013) Genetic variants associated with Crohn's disease. Appl Clin Genet 6:25-32|