Supporting healthy ageing through the microbiota: A Drosophila model

肠道菌群的变化（生态失调）与年龄相关的衰退有关，与老年人的虚弱程度有关。然而，简单的干预措施，如饮食或益生菌，也凸显了这些微生物群体作为维持终身健康的伙伴的潜力。针对微生物群的干预措施的合理设计将需要对微生物在整个生命过程中对宿主健康影响的机制基础有更深入的了解。果蝇（Drosophila melanogaster）是衰老研究的主要模式生物之一，它携带着一种简单的肠道微生物群，其中包含了在人类肠道中发现的许多分类群。我们已经证明，衰老的果蝇微生物群的变化与老年人的变化大致相同，并且也与年龄相关的衰退密切相关（Clark et al 2015）。该项目将利用这些相似性和果蝇模型的优势，以表征驱动生态失调对宿主健康影响的分子机制。该项目的第一阶段将利用与年龄相关的衰退的多种标记物的详细时间过程研究。我们的重点将是微生物对衰退的影响的特征，并将包括肠道和多个远端组织。除了我们在克拉克实验室使用的与年龄相关的衰退分析外，该学生还将在Sanz实验室（纽卡斯尔）进行轮换，以测量微生物暴露和衰老对许多组织中线粒体功能的影响。接下来，我们将使用代谢组学和转录组学方法来测量宿主衰老过程中肠道微生物群的代谢和基因表达的变化。这些数据将为我们提供一些候选代谢途径或单基因，这些代谢途径或单基因随着年龄的增长而改变，并可能驱动微生物群对宿主健康的影响。因此，这些数据将构成这个项目最后阶段的基础，在这个阶段，我们将使用强大的果蝇遗传工具，结合细菌遗传学来测试我们的候选基因对宿主年龄相关衰退的影响。所使用的技术和工具将由感兴趣的基因/途径的性质决定，但将侧重于确定干预的潜在目标，以防止或延迟跨多个组织的衰退。

Changes in the intestinal microbiota (dysbiosis) have been implicated in age-related decline, being correlated with measures of frailty in the elderly. However, the accessibility of this microbial population to simple interventions, such as diet or probiotics, has also highlighted its potential as a partner in the maintenance of life-long health. The rational design of interventions targeting the microbiota will require a greater understanding of the mechanistic basis of microbial influence on host health throughout the life course. The fruit fly, Drosophila melanogaster, is one of the premier model organisms for ageing research and carries a simple intestinal microbiota containing a number of taxa found in the human intestine. We have shown that shifts in the aging Drosophila microbiota broadly echo those seen in ageing people, and are also strongly implicated in age-related decline (Clark et al 2015). This project will capitalize on these similarities, and the strengths of the Drosophila model, in order to characterise the molecular mechanisms that drive the impact of dysbiosis on host healthThe first stage of this project will utilise detailed time-course studies of multiple markers of age-related decline. Our focus will be the characterisation of microbial influence on decline and will encompass the intestine and multiple distal tissues. In addition to the assays of age-related decline that we use in the Clark lab, the student will take a rotation in the Sanz lab (Newcastle) in order to measure the impact of microbial exposure and ageing on mitochondrial function in a number of tissues.Following this, we will use metabolomic and transcriptomic approaches to measure change in metabolism and gene expression of the intestinal microbiota during host aging. These data will provide us with a number of candidate metabolic pathways or single genes that are modified with age and may drive the influence of the microbiota on host health. These data will therefore form the basis of the final stage of this project in which we will use the powerful genetic tools available in Drosophila in combination with bacterial genetics to test the impact of our candidates on age-related decline in the host. The techniques and tools used will be determined by the nature of the gene/pathway of interest, but will focus on identifying potential targets for interventions to prevent or delay decline across multiple tissues.