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

远程控制：微生物群如何促进动物健康？

• 批准号: MR/Y019660/1
• 负责人: Adam Dobson
• 金额: $ 75.6万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY019660%2F1
• 关键词: Remote; control; How; do; microbiota

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.

在英国和全球，我们受到两种长期大流行的困扰：衰老和代谢疾病。两者在天文学上有害和昂贵。随着平均年龄的增长，疾病患病率上升，预计医疗保健成本为数万亿美元。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年到2050年的13亿糖尿病成年人的研究。毁灭性的健康影响和惊人的财务成本为了解新陈代谢疾病的原因提供了非常强大的动机，以及我们如何促进健康的老化。肠道微生物群与代谢疾病和衰老都有联系。我们看到微生物群在动物上的影响相同，这表明基本生物学的原因。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抗击新陈代谢疾病并促进人类的健康衰老。年龄和代谢是整体生物过程。尽管物理局限于肠道，但微生物群改变了这些过程，这一事实表明，微生物通过长距离分子交叉词来施加“遥控器” - 改变全身功能。发挥的分子可能是从肠道释放到循环的激素和代谢产物。我们正在研究水果中的这些分子，这些分子与包括人类在内的其他动物共享生物学的许多方面。在苍蝇中工作的优点是，我们对微生物群，饮食和苍蝇的功能具有极大的控制，使我们能够精确，快速地研究跨动物的机制。产生我们期望跨物种的预测。在该项目的第一阶段，我们取得了两个突破。首先，我们已经产生了特定微生物群在特定组织中诱导的代谢变化的地图集，这表明对整个动物的基本作用的化合物进行了调节。其次，我们已经确定了一种特定的激素 - 速素 - 由特定细菌（特别是肠道）调节，我们认为这是蝇脑中特定受体的信号。击倒该电路使苍蝇组成寿命长，甚至显着逆转了微生物群对脂肪储存的影响，这表明是微生物对衰老和代谢的介体的中心作用。这种激素在人类中是保守的，针对其受体的药物已经获得许可，这表明我们可能能够翻译我们的发现。在此项目的更新中，我将结合既定的方法和新方法，以最终测试从肠道中的速度相关性，是否会从肠道中介导aging aging aging aging and aging and aging and aging and aging and aging and aging and necabolism。我将使用尖端技术来鉴定速气蛋白受体受体对肠道细菌的存在反应的特定细胞群，这取决于速氨酸激素的肠道表达。最后，我将基于研究衰老和代谢的经验，以研究微生物群如何通过速旋蛋白改变死亡率，以及速齿如何在脂肪代谢对肠道细菌反应的方式中诱导代谢转换。该信息将为长期，大规模的多模型研究计划奠定基础，其特征是生物学如此基本，以至于我们预计我们可以针对它来促进人类健康。