Gut Signalling and Metabolism

We are exploring how the digestive system listens and responds to signals sent by other organs, and why this matters. We tackle these questions using Drosophila flies; simpler organisms with which we share over 60% of our genes. Like us, flies have a gut populated by nerve cells. They also get fat and can have diabetes. Importantly, the fly allows us to do technically challenging experiments easily and rapidly; we can turn fly genes on and off in specific cells at specific times in order to learn about how these genes affect metabolism. Using such genetic approaches, we recently found that the intestine can adapt to challenges in striking and unexpected ways. For example, during reproduction, the mother’s intestine grows dramatically and changes the way she handles nutrients to ensure reproductive success. Even before reproduction, the intestines of males and females are very different; female gut stem cells are more active than their male counterparts. This helps the female gut grow during reproduction, but also renders it more vulnerable to tumorigenic insults. Informed by our findings in flies, we are now investigating whether similar intestinal mechanisms and sex differences can affect the ability of humans to reproduce, handle nutrient overload/scarcity, suffer from certain diseases and respond to their treatment. If they do, they may inform the development of genetic or drug treatments in the areas of fertility, weight gain/loss and/or cancer.

We are investigating how the intestine controls energy homeostasis and nutritional decisions. The digestive system is emerging as a key regulator of appetite and metabolism. Indeed, signals emanating from the gastrointestinal tract and its neurons can contribute to increasingly prevalent conditions such as diabetes and metabolic syndrome. In addition to signalling, the digestive tract can also undergo striking functional remodelling in response to environmental or internal changes – for example, during reproduction. Our lab has been exploring the mechanisms underlying intestinal plasticity and their functional significance. We recently identify a sex hormone required for intestinal remodelling during reproduction and demonstrated that such remodelling was required to sustain reproductive output (Reiff et al (2015) eLife). We also described extensive differences between the intestine of males and females, and showed that the intrinsic sexual identity of intestinal somatic stem cells played key roles during reproduction, but also increased gut tumour susceptibility in females (Hudry et al (2016) Nature). Finally, we described a new mechanism, key during malnutrition, by which enteric neurons sense the lack of specific nutrients (Linneweber et al (2014) Cell). Most of our work has taken advantage of the genetic amenability of the fruit fly Drosophila. Over 60% of our genes have equivalent counterparts in Drosophila. Fruit flies also offer two key advantages to investigate the genetic control of physiology and metabolic adaptations: 1) they allow rapid mutation or misexpression of large numbers of genes (allowing for rapid identification of metabolically significant genes) and 2) they allow temporal and spatial control of gene expression (key to establishing directionality of signalling when investigating organ crosstalk). While flies continue to be our primary discovery tool, we are also exploring whether the mechanisms of intestinal plasticity that the fly has revealed are evolutionarily conserved; are our organs sexually dimorphic and capable of similar remodelling? We are using mouse models and human cells to explore these questions. Conservation of these mechanisms and sex differences may have important implications for our ability to reproduce, handle nutrient overload/scarcity, suffer from certain diseases and respond to their treatment. Genetic or pharmacological interventions aimed at modulating similar pathways in humans may be advantageous in the contexts of fertility, weight gain/loss or preventing tumour formation.