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

我现在19岁的NSERC项目的首要目标是使用贾第虫病模型来理解宿主-微生物以及微生物-微生物相互作用的基本机制，这些相互作用调节了肠道的健康状态功能。***十二指肠贾第鞭毛虫感染是一种世界性的水源性腹泻原因，在包括牲畜在内的多种动物中传播，使这种寄生虫成为粮食生产行业经济损失的重要原因。除了对肠道功能的直接影响外，最近的证据表明，贾第虫病通过尚不清楚的机制（狗/马荨麻疹、跛行、体重增加受损）导致肠道和肠外的感染后破坏。我们最近的研究结果还表明，贾第鞭毛虫可能通过直接的抗炎特性来预防肠道细菌感染。肠道共生微生物群落在称为生物膜的空间组织中以高度结构化的联盟形式生活。肠道菌群与宿主之间的相互作用越来越被认为是宿主免疫、发育和生理的关键；然而，人们对其生物膜表型的稳态意义以及这对稳态的贡献知之甚少。***假设：菌群生物膜的结构和功能是肠道内稳态的关键，贾第鞭毛虫对这一状态的破坏可能具有一定的生理意义。因此，这项研究将使我们能够揭示基本肠道生理学的新方面。***长期目标：提高我们对微生物-微生物相互作用和宿主因子如何调节胃肠道生物学的理解。利用猪或人肠道样本的互补微生物群模型，结合猪和人肠道细胞，线虫秀丽隐杆线虫或小鼠，本应用的总体目标是确定由肠道病原体（贾第鞭毛虫）引起的共生肠道微生物群生物膜和粘液的破坏如何导致感染后肠道破坏的新机制。并在动物模型系统中评估一种原型h2s释放化合物对这些异常的稳定作用。******具体目的将描述：***1)十二指肠弧菌对猪和人粘膜微生物群、生物膜和粘液的影响。***2)十二指肠梭菌对肠道共生菌、致病菌及肠道炎症的影响。***3)十二指肠鸡半胱氨酸蛋白酶组织蛋白酶B在上述作用中的作用。***4)一种新的h2s释放化合物（我们开发的）对这些异常的好处。******该项目将有助于扩大我们在贾第鞭毛虫原生动物方面公认的国际合作专业知识。通过提高我们对贾第鞭毛虫对微生物群生物膜结构和功能的影响的理解，该项目将为肠道生理学的基本方面提供新的视角********

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.********