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

我现在已经19岁的NSERC项目的首要目标是使用贾第虫病的模型来了解宿主-微生物以及微生物-微生物相互作用的基本机制，这些机制调节肠道内的健康状态功能。*感染十二指肠贾第鞭毛虫是包括牲畜在内的各种动物水源性腹泻的世界性原因，使这种寄生虫成为食品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，贾第鞭毛虫病通过尚不清楚的机制(狗/马荨麻疹、跛行、体重增加受损)导致肠道和肠外感染后的紊乱。我们最近的发现也证明了贾第鞭毛虫。可通过直接抗炎作用预防肠道细菌感染。*肠道共生微生物群落作为高度结构化的联合体生活在称为生物膜的空间组织中。肠道微生物区系和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，人们对它们的生物膜表型的动态平衡意义以及这如何有助于动态平衡知之甚少。*假设：微生物区系生物膜的结构和功能是肠道动态平衡的关键，贾第虫引起的这种状态的破坏可能证明其生理意义。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素如何调节胃肠道生物学的理解。使用来自猪或人肠道样本的免费微生物区系模型，结合猪和人肠道细胞、线虫或小鼠，本申请的总体目标是识别肠道病原体(贾第鞭毛虫)对共生肠道微生物区系生物膜和粘液的破坏如何可能导致感染后肠道破坏的新机制，并在动物模型系统中评估硫化氢释放化合物原型对这些异常的稳定作用。*具体目标将表现为：*1)十二指肠明胶对猪和人粘膜微生物区系生物膜和粘液的影响。*2)十二指肠明胶对共生菌和肠道致病菌以及肠道炎症的影响。*3)十二指肠明胶半胱氨酸蛋白酶组织蛋白B在这些影响中的作用。*4)一种新的硫化氢释放化合物(我们开发的)对这些异常的益处。*这个项目将有助于扩大我们在原生动物贾第鞭毛虫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的影响的认识。关于微生物生物膜的结构和功能，该项目将为肠道生理学的基本方面提供新的线索。

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.********