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

在英国和全球，我们受到两种长期流行病的困扰：衰老和代谢性疾病。两者都是有害的，而且代价高昂。随着平均年龄的增长，疾病患病率上升，预计医疗成本将达到数万亿美元。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研究预测到2050年将有13亿糖尿病人。毁灭性的健康影响和惊人的财务成本为了解代谢性疾病的原因以及我们如何促进健康老龄化提供了非常强大的动力。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微生物群的相同影响，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和促进人类健康衰老。衰老和新陈代谢是整个有机体的过程。事实上，微生物群改变了这些过程，尽管它们在物理上被限制在肠道内，这表明微生物通过远距离分子串扰来施加“远程控制”——改变系统功能。起作用的分子很可能是从肠道释放到循环中的激素和代谢物。我们正在果蝇身上研究这些分子，果蝇与包括人类在内的其他动物在生物学上有许多共同之处。在果蝇身上工作的优势在于，我们对微生物群、饮食和果蝇的功能有非凡的控制，使我们能够精确、快速地研究动物身上发生的机制；产生我们期望在物种间推广的预测。在这个项目的第一阶段，我们已经取得了两个突破。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图谱，这表明了在动物体内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殊的激素——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。敲除这个回路可以使果蝇长寿，甚至显著地逆转微生物群对脂肪储存的影响，这表明微生物在衰老和代谢过程中起着中介作用。这种激素在人体中是保守的，针对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，我将结合现有的和新的方法，最终测试从肠道到大脑的速激肽传递是否介导了微生物群对衰老和代谢的影响。我将使用最先进的技术来识别苍蝇大脑中特定的细胞群，其中速激肽受体对肠道细菌的存在做出反应，这取决于肠道速激肽激素的表达。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，以及速激肽如何在脂肪代谢对肠道细菌的反应中诱导代谢开关。这些信息将为一个长期的、大规模的、多模型的研究项目奠定基础，使生物学的特征变得如此基本，以至于我们预计我们可以将其作为促进人类健康的目标。

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.