Remote control: How do microbiota promote animal health? Defining signalling circuits and mechanisms.

在英国和全球范围内，我们受到两种长期流行病的困扰：衰老和代谢性疾病。两者都是天文数字般的有害和昂贵。随着平均年龄的增长，疾病患病率上升，预计医疗费用将达到数万亿美元。与此同时，三分之一的成年人现在超重或肥胖，最近的头条新闻强调了预测到2050年将有13亿糖尿病成年人的研究。破坏性的健康影响和惊人的财务成本提供了一个非常强大的动力来了解代谢疾病的原因，以及我们如何促进健康的老龄化。肠道微生物群与代谢疾病和衰老有关。我们在动物身上看到了相同的微生物群效应，这表明了基础生物学的原因。因此，了解动物模型中宿主-微生物群相互作用的生物学可能有助于我们对抗代谢疾病并促进人类健康衰老。衰老和代谢是整个生物体的过程。微生物群改变这些过程的事实，尽管被物理限制在肠腔中，表明微生物发挥“远程控制”-通过长距离分子串扰改变系统功能。起作用的分子可能是从肠道释放到循环中的激素和代谢物。我们正在研究果蝇中的这些分子，果蝇与包括人类在内的其他动物在生物学方面有许多共同之处。在苍蝇身上工作的优势在于，我们对微生物群、饮食和苍蝇的功能有着非凡的控制力，使我们能够精确而快速地研究动物之间发生的机制;产生我们期望在物种之间推广的预测。我们在这个项目的第一阶段取得了两个突破。首先，我们已经生成了特定微生物群在特定组织中诱导的代谢变化的图谱，这表明了在整个动物中发挥基本作用的化合物的调节。其次，我们已经确定了一种特定的激素-速激肽-由特定的细菌调节，特别是在肠道中，我们认为它向苍蝇大脑中的特定受体发出信号。敲除这一电路使苍蝇组成长寿，甚至显着逆转微生物群对脂肪储存的影响，表明作为微生物对衰老和代谢影响的介导者的核心作用。这种激素在人类中是保守的，靶向其受体的药物已经获得许可，这表明我们可能能够转化我们的发现。在这个项目的更新中，我将联合收割机结合现有的和新的方法来最终测试从肠道到大脑的速激肽中继是否介导微生物群对衰老和代谢的影响。我将使用尖端技术来识别果蝇大脑中的特定细胞群，速激肽受体对肠道细菌的存在做出反应，这取决于速激肽激素的肠道表达。最后，我将根据我研究衰老和代谢的经验，研究微生物群如何通过速激肽改变死亡率，以及速激肽如何诱导脂肪代谢如何响应肠道细菌的代谢开关。这些信息将为长期、大规模、多模型的研究计划奠定基础，这些研究计划将生物学描述得如此重要，以至于我们预计我们可以将其用于促进人类健康。

In the UK and globally, we are beset by two long-term pandemics: ageing, and metabolic disease. Both are astronomically harmful and costly. As average ages increase, disease prevalence rises, with projected healthcare costs in $trillions. At the same time, one in three adults are now overweight or obese, and recent headlines have highlighted studies predicting 1.3bn diabetic adults by 2050. The devastating health impacts and staggering financial costs provide a very strong motivation to understand the causes of metabolic disease, and how we can promote healthy ageing. Gut microbiota are linked to both metabolic disease and ageing. We see the same effects of microbiota across animals, suggesting causes in fundamental biology. Thus, understanding the biology of host-microbiota interactions in animal models may help us to both fight metabolic disease and promote healthy ageing in humans.Ageing and metabolism are whole-organism processes. The fact that microbiota alter these processes, despite being physically confined to the gut lumen, suggests that microbes exert "remote control" - altering systemic function through long-distance molecular cross-talk. The molecules in play are likely to be hormones and metabolites released from the gut into circulation. We are studying these molecules in fruitflies, which share many aspects of biology with other animals, including humans. Advantages of working in flies are that we have extraordinary control of the microbiota, diet, and the fly's function, allowing us to study mechanisms that occur across animals precisely and rapidly; generating predictions that we expect to generalise across species. We have made two breakthroughs in the first phase of this project. First, we have generated an atlas of metabolic changes that specific microbiota induce in specific tissues, which has indicated regulation of compounds that play fundamental roles throughout animals. Second, we have identified a specific hormone - tachykinin - modulated by specific bacteria, specifically in the gut, which we think signals to a specific receptor in the fly brain. Knocking down this circuit makes flies constitutively long-lived and even dramatically reverses the impact of microbiota on fat storage, indicating a central role as a mediator of microbial effects on ageing and metabolism. This hormone is conserved in humans, and drugs targeting its receptor are already licenced, suggesting we may be able to translate our findings.In the renewal of this project, I will combine both established and new methods to test conclusively whether a tachykinin relay from gut to brain mediates impacts of microbiota on ageing and metabolism. I will use cutting edge technologies to identify specific populations of cells in the fly brain where the tachykinin receptor responds to presence of gut bacteria, depending on gut expression of tachykinin hormone. Finally I will build on my experience of studying ageing and metabolism to investigate how microbiota alters mortality through tachykinin, and how tachykinin appears to induce a metabolic switch in how fat metabolism responds to gut bacteria. This information will lay the foundation for a long-term, large-scale, multi-model research program, characterising biology so fundamental that we anticipate we can target it to promote human health.