Integrating the Metabolic Function and Population Dynamics of Gut Microbiota for Host Nutritional Health

项目摘要 人类肠道微生物群落的扰动与各种胃肠道疾病有关。 疾病和代谢性疾病，特别是肥胖，但这个系统的复杂性阻碍了 开发可靠的微生物疗法，例如益生菌。自然简单的肠道 果蝇中的微生物群落为整个研究目标提供了一个极好的模型， 确定肠道微生物群与宿主代谢健康之间相互作用的机制基础。 基于肠道微生物群保护果蝇免受高脂血症和 高血糖症，本项目的第一个目的是鉴定肠道微生物发酵产物 保护宿主免受过度能量储存（即高水平的脂质、糖原 和糖），通过识别微生物群落释放的代谢物， 储存指数;这些功能性代谢物可能包括多微生物代谢的产物。 第二个目标将测试假设（基于初步数据），即微生物介导的 通过增强游离糖、脂质和糖原的动员促进能量储存的减少 在肠道上皮中。宿主对肠道微生物群的代谢反应及其代谢 产物将通过对定殖有以下物质的苍蝇的饮食葡萄糖代谢的同位素分析来定量： 不同的微生物，以及候选代谢酶在减少能量储存中的作用 将通过果蝇肠道中的RNAi表达敲低来鉴定。这些数据将告知第三个目标， 建立益生乳酸菌降低能量储存功效的机制基础， 与未被操纵的微生物群相关的苍蝇，其能力不同，以减少能量储存。 使用由转录组学和代谢组学数据提供信息的代谢建模， 以及介导微生物群介导的能量减少的途径（在宿主和微生物群中） 储存将被确定;和代谢功能的贡献，丰度和持久性 口服乳酸杆菌在肠道中对益生菌介导的高血糖症的保护作用 和高脂血症。总的来说，该项目将确定微生物产品和宿主 支持肠道微生物群介导的抗高血糖保护的代谢反应， 高脂血症，人类代谢疾病的关键指标，定量代谢模型， 外推到哺乳动物系统;并提供对代谢的系统理解 和形成乳酸杆菌（广泛用作人类益生菌）功效的群体过程 食物）代谢健康。它还将为益生菌研究提供果蝇模型， 扩展到研究与不同组成的肠道微生物的相互作用的影响， 该项目旨在解决其他至关重要的变量，包括宿主基因型和饮食。

Project Summary Perturbation to the human gut microbial community is associated with various gastro-intestinal diseases and metabolic ill-health, especially obesity, but the complexity of this system is hampering the development of reliable microbiological therapies, e.g. probiotics. The naturally simple gut microbial community in Drosophila fruit flies offers a superb model for the overall research goal to determine the mechanistic basis of interactions between gut microbiota and host metabolic health. Building on evidence that the gut microbiota protects Drosophila against hyperlipidemia and hyperglycemia, the first aim of this project is to identify the microbial fermentation products of gut microbiota that protect the host against excessive energy storage (i.e. high levels of lipid, glycogen and sugars), by identifying the metabolites released from microbial communities that reduce energy storage indices; these functional metabolites likely include the products of polymicrobial metabolism. The second aim will test the hypothesis (based on preliminary data) that microbial-mediated reduction in energy storage is promoted by enhanced mobilization of free sugar, lipid and glycogen in the gut epithelium. The metabolic response of the host to the gut microbiota and their metabolic products will be quantified by isotopic analysis of dietary glucose metabolism in flies colonized with different microorganisms, and the role of candidate metabolic enzymes in reducing energy storage will be identified by RNAi-expression knockdown in the fly gut. These data will inform the third aim, to establish the mechanistic basis of the efficacy of probiotic Lactobacillus to reduce energy storage in flies associated with unmanipulated microbiotas that vary in capacity to reduce energy storage. Using metabolic modeling informed by transcriptomic and metabolomic data, the metabolic reactions and pathways (in the host and microbiota) that mediate microbiota-mediated reduction in energy storage will be identified; and the contribution of metabolic function, abundance and persistence of orally-administered Lactobacillus in the gut to probiotic-mediated protection against hyperglycemia and hyperlipidemia will be determined. Overall, this project will identify microbial products and host metabolic responses that underpin gut microbiota-mediated protection against hyperglycemia and hyperlipidemia, key indices of human metabolic disease, with quantitative metabolic models that can be extrapolated to the mammalian system; and provide a systematic understanding of the metabolic and population processes shaping the efficacy of Lactobacillus (widely used as probiotic in human foods) for metabolic health. It will also provide a Drosophila model for probiotic research that can be extended beyond study of the impacts of interactions with gut microbiotas of different composition in this project to address other critically-important variables, including host genotype and diet.