Leveraging synthetic gut microbiomes to understand the host and microbial determinants that promote dysbiosis

人类胃肠道是最密集的微生物生态系统之一，尽管可能被低估了。肠道微生物群通过提供独特的酶和生化途径，调节宿主生理的多个方面，包括代谢、免疫和神经系统的发育和功能，以及对病原体感染的抵抗力。微生物群结构和代谢能力的不利改变，通常被称为生态失调，与许多疾病有关，包括炎症性肠病（IBD）、癌症、自身免疫性疾病和代谢紊乱。然而，在组成和功能水平上定义生态失调意味着什么已被证明是困难的，因为在多个队列中并不总是一致地检测到疾病特异性分类特征。事实上，鉴于肠道生态系统中微生物间和微生物-宿主相互作用网络的复杂性，很难破译自然群落中个体成员的生理作用。由于多个分类群具有相似的代谢能力，因此在功能上是冗余的，这一事实使情况进一步复杂化。另一方面，培养一定比例肠道细菌的技术和实践限制阻碍了尚未培养或未知分类群的功能表征，这些分类群可能在复杂的微生物群落中发挥重要的生物学作用。此外，由于肠道微生物群的固有变异性可能导致表型变异，因此对微生物-宿主串扰的实验动物研究显示可重复性有限。由于这些原因，有一个新兴的兴趣在开发标准化的微生物群落减少和已知的复杂性，通常被称为合成或定义的微生物群落。在这个项目中，我们计划利用合成微生物组的使用来描述肠道环境如何影响微生物生态系统，以及来自受干扰群落的微生物因子如何影响宿主。代表健康或疾病条件下人类或小鼠衍生群落的合成微生物组将在趋化生物反应器中构建，其中宿主模拟环境鼓励这些群落的稳定生长。然后将这些微生物群落灌入无菌小鼠中，这将提供一种方法来测试生物反应器在肠道环境中如何很好地反映给定微生物群落的组成和功能，以及确定哪些宿主因素影响微生物生态系统，哪些微生物因素有助于在受控和可处理的系统中宿主的结果。

The human gastrointestinal tract represents one of the most dense microbial ecosystems and, although likely underestimated. By providing unique enzymes and biochemical pathways, the gut microbiota regulates multiple aspects of host physiology, including metabolism, development and function of the immune and nervous system, as well as resistance to infection by pathogens. Adverse alterations of the structure and metabolic capacity of the microbiota, often referred to as dysbiosis, have been linked to numerous diseases, including inflammatory bowel disease (IBD), cancer, autoimmune diseases and metabolic disorders. However, defining what dysbiosis means on a compositional and functional level has proven to be difficult since disease-specific taxonomic signatures are not always consistently detected across multiple cohorts. Indeed, given the complexity of inter-microbe and microbe-host interaction networks within the gut ecosystem, it is difficult to decipher the physiological roles of individual members in natural communities. This is further complicated by the fact that multiple taxa possess similar metabolic capacities and are thereby functionally redundant. On the other hand, technical and practical constraints in culturing a proportion of gut bacteria have hindered the functional characterization of not-yet culturable or unknown taxa, which could play an important biological role in the complex microbial community. In addition, experimental animal studies of microbe-host crosstalk have shown limited reproducibility because of the inherent variability of the gut microbiota that can cause phenotypic variations. For these reasons, there is an emerging interest in developing standardized microbiota communities of reduced and known complexity, generally referred to as synthetic or defined microbial communities. In this project, we plan to leverage the use of synthetic microbiomes in order to delineate how the gut environment impacts the microbial ecosystem as well as how microbial factors from a perturbed community impact the host. Synthetic microbiomes representing human- or mouse-derived communities, either in conditions of health or disease, will be constructed in chemostat bioreactors where host-simulated environments encourage the stable growth of these communities. These communities will then be gavaged into germ-free mice, which provide the means to test the effectiveness of how well the bioreactors reflect composition and function of a given microbial community once within the gut environment as well as to determine what host factors impact the microbial ecosystem and which microbial factors contribute to host outcomes in a controlled and tractable system.