Giardiasis as a model to study microbial-microbial interactions in the gut

点击翻译按钮获取中文摘要

The overarching goal of my now 19-year-old NSERC program is to use the model of giardiasis to understand fundamental mechanisms of host-microbial as well as microbial-microbial interactions that regulate healthy state function in the gut. Infection with Giardia duodenalis, is a cosmopolitan cause of waterborne diarrhea in a broad range of animals, including livestock, making this parasite a significant cause of economic loss to the food-producing industry. In addition to its direct effects on gut function, recent evidence illustrates that giardiasis leads to post-infectious disruptions, in the gut as well as extra-intestinally, via mechanisms that remain unclear (dog/horses urticaria, lameness, impaired weight gain). Our recent findings also demonstrate that Giardia sp. may protect against gut bacterial infection via direct anti-inflammatory properties. Gut commensal microbial communities live as highly structured consortia within spatial organizations called biofilms. The interplay between gut microbiota and host is increasingly recognized as a key to host immunity, development, and physiology; yet little is known of the homeostatic significance of their biofilm phenotype, and how this contributes to homeostasis. Hypothesis : Microbiota biofilm structure and function are key to intestinal homeostasis, and Giardia-induced disruptions of this state may demonstrate its physiological significance. This research therefore will enable us to uncover new aspects of fundamental intestinal physiology. Long-term goal: To improve our understanding of how microbial-microbial interactions and host factors modulate gastrointestinal biology. Using complimentary models of microbiota from porcine or human gut samples, in conjunction with porcine and human intestinal cells, the nematode C. elegans, or in mice, the overall objective of the present application is to identify new mechanisms of how disruptions to commensal gut microbiota biofilms and mucus caused by an enteropathogen (Giardia) may be responsible for post-infectious intestinal disruption, and to evaluate the stabilizing effects of a prototype H2S-releasing compound on these abnormalities in animal models systems. Specific aims will characterize: 1) the effects of G. duodenalis on porcine and human mucosal microbiota biofilms, and mucus. 2) the effects of G. duodenalis on commensal and enteropathogenic bacteria, and gut inflammation. 3) the role of G. duodenalis cysteine protease cathepsin B in these effects. 4) the benefits of a new H2S-releasing compound (which we developed) on these abnormalities. This program will help expand upon our well-recognized international collaborative expertise on the Protozoan Giardia sp. By improving our understanding of the effects of Giardia sp. on the structure and function of microbiota biofilms, this project will shed new light on fundamental aspects of intestinal physiology.