Molecular characterization of mixed-species bacterial biofilms in the gastrointestinal tract

肠道菌群（寄生在胃肠道中的微生物群落）在人类健康和疾病中起着重要作用，但人们对脊椎动物肠道中宿主-微生物共生相互作用的基本原理知之甚少。特别是，多物种肠道生物膜细菌成员之间的相互作用尚未得到研究，但这些知识对于制定调节肠道微生物群以改善健康的策略至关重要。利用非生物小鼠（具有确定微生物群的小鼠），申请人的小组开发了一种独特的模型，通过该模型来解开有助于胃肠道生物膜形成的细菌功能。利用该模型，我们已经证明了小鼠胃中选择性生物膜的形成是促进罗伊氏乳杆菌宿主特异性的关键机制，并且已经开始阐明生物膜形成的分子过程。然而，我们对这些生物膜如何在自然界中发生的混合物种种群的背景下发挥作用和进化知之甚少。

The gut microbiota (the community of microbes that colonizes the gastrointestinal tract) plays important roles in human health and disease, but little is known about the basic principles that underlie host-microbial symbiotic interactions in the vertebrate gut. In particular, the interactions between the bacterial members of multi-species intestinal biofilms have not been studied at all, but such knowledge is essential for the development of strategies that modulate the gut microbiota to improve health. Capitalizing on gnotobiotic mice (mice with a defined microbiota), the applicant’s group has developed a unique model by which to disentangle the bacterial functions that contribute to biofilm formation in the gastrointestinal tract. Using this model, we have demonstrated that selective biofilm formation in the mouse stomach as a key mechanism by which host specificity is facilitated in the species Lactobacillus reuteri, and have begun to elucidate the molecular processes that underlie formation of biofilms. However, we know little about how these biofilms function and evolve in the context of the mixed species populations that occur in nature. The long-term objective of this research program is to identify the mechanisms by which multi-species Lactobacillus biofilms evolved and function, and characterize the interactions between the individual members on a molecular level. In the proposed study, we will use an innovative combination of experiments with mice that harbor defined Lactobacillus populations and genomic approaches to specifically identify bacterial interactions among mixed-species biofilms in the intestinal tract. The project is innovative in that it uses Lactobacillus isolates that coexisted in the gut of wild mice, a powerful genomic approach (transposon sequencing) that allows the identification of relevant genes directly in the environment, and an experimental model (gnotobiotic mice) that allow to study gene function in real-life ecological context. The experiments are therefore likely to identify genes that contribute to bacterial biofilms that have not been described so far. The benefit to the research field and Canada: The work will likely provide unprecedented insight into the mechanisms by which mixed-species bacterial biofilms in nature are established and how the members evolve, and it is likely to discover novel processes that remain elusive in other models of biofilms. The findings have the potential to provide the basis for strategies to modulate biofilms with both beneficial and detrimental roles in human and animal health. The project will train six HQP, three of which have citizenship or permanent residency in Canada, and will provide a unique interdisciplinary experience that makes them uniquely qualified to contribute to progress in the gut microbiome field (a field that is currently considered one of the frontiers in biology and medicine).