Guest Speaker Seminar - Dr. Alexandra-Chlo茅 Villani
Dr. Alexandra-Chlo茅 Villani
Post-Doctoral Associate
Broad Institute of MIT and Harvard
Boston, USA
"Genetic investigation of inflammatory bowel disease and
post-infectious irritable bowel syndrome:
the contribution of innate immunity candidate risk variants"
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Abstract
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The gastrointestinal (GI) tract represents the largest surface of the body that is continuously exposed to microorganisms. In this environment, host survival requires that the intestinal microbial flora be properly contained without excessive immune-reactivity to commensal bacteria while retaining the ability to respond to episodic pathogens. This discriminative recognition between beneficial commensal bacteria and potentially harmful pathogens demands an accurate interpretation of the GI mucosal immune system. Any defects in the processes of innate immune recognition and killing may lead to the development and perpetuation of chronic intestinal inflammation, namely inflammatory bowel disease (i.e. Crohn's disease (CD) and ulcerative colitis (UC)) and post-infectious irritable bowel syndrome (PI-IBS). Investigation of the contribution of genes involved in the homeostasis and regulation of the intestinal innate immune response to the susceptibility of CD, UC, and PI-IBS led to the discovery of NLRP3 as a novel CD susceptibility gene and TLR9, CDH1, and IL6 as the first genetic risk factors for PI-IBS susceptibility ever reported. This link between NLRP3 and CD, and follow-up functional studies, brought further emphasis to the importance of intra-cellular bacterial sensors (particularly the NALP3 inflammasome) in surveying the intestinal microbial flora and in contributing to CD pathogenesis, and supported the recent shift in CD immunopathogenesis paradigm. The unfortunate Walkerton contaminated-water tragedy provided a unique opportunity to study for the first time genetic determinants of PI-IBS in a large, well-defined study cohort with simultaneous and well-characterized exposure. The PI-IBS association results are consistent with current conceptual models of IBS pathogenesis, and emphasize the important roles of gut flora, intestinal epithelial barrier function, and inflammatory pathways in the onset of this disease. Overall, these results have deepened our comprehension of the complex interrelationship between enteric infection, intestinal microbial flora, genetic susceptibility, and disease pathogenesis by providing novel insights about potential mechanisms and pathways involved in the development of these diseases.
