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

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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.