“We are investigating how the intestine controls energy homeostasis and makes nutritional decisions”
The gastrointestinal (GI) tract is a key regulator of appetite and metabolism. Dysregulation of signals emanating from the GI tract or its neurons contributes to increasingly prevalent conditions such as diabetes and metabolic syndrome. As well as signalling, the GI tract can also undergo dramatic functional remodelling in response to environmental or internal change – for example, during reproduction.
Our lab is exploring mechanisms of intestinal plasticity and their functional significance. We have described extensive differences between the intestinal epithelium of males and females. We showed that such sex differences played key roles during reproduction and also increased gut tumour susceptibility in females (Hudry et al (2016) Nature, Reiff et al (2015) eLife). We also observed that sex and reproductive differences are not confined to the intestinal epithelium, and have explored their significance in gut-innervating neurons (Hadjieconomou et al (2020) Nature, in press). Along the way, we discovered local communication between the intestine and adjacent organs (Hudry et al (2019) Cell): an observation that we are now pursuing further by systematically investigating organ positioning and inter-organ contacts. Finally, we are also interested in how the intestine senses and responds to nutrients, and recently revealed roles for an intestinal zinc sensor in food intake regulation via Tor signalling (Redhai et al (2020) Nature). Collectively, our studies illustrate how a fully developed adult organ continues to develop and adjust to its environment with (patho)physiological consequences.
Most of our work has taken advantage of the genetic amenability of 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 if 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 investigating 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 (Perea et al (2017) EMBO J) 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, resist 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 and preventing tumour formation.
Transcriptional differences between male and female guts revealed by next-generation sequencing
The different cell types of the digestive system, immunostained and visualised using confocal microscopy
Irene Miguel-Aliaga holds an ERC Advanced grant.
Hadjieconomou D, King G, Gaspar P, Mineo A, Blackie L, Ameku T, Studd C, de Mendoza A, Diao F, White BH, Brown AEX, Plaçais P, Preat T, Miguel-Aliaga I. (2020). Enteric neurons increase maternal food intake during reproduction. Nature, in press.
Redhai S, Pilgrim C, Gaspar P, van Giesen L, Lopes T, Riabinina O, Grenier T, Milona A, Chanana B, Swadling JB, Wang Y-F, Dahalan F, Yuan M, Wilsch-Brauninger M, Lin W-H, Dennison N, Capriotti P, Lawniczak MKN, Baines RA, Warnecke T, Windbichler N, Leulier F, Bellono N, Miguel-Aliaga I (2020). An intestinal zinc sensor regulates food intake and developmental growth. Nature; 580, 263–268.
Hudry B, de Goeij E, Mineo A, Gaspar P, Hadjieconomou D, Studd C, Mokochinski JB, Kramer HB, Plaçais P-Y, Preat T and Miguel-Aliaga I. (2019). Sex differences in intestinal carbohydrate metabolism promote food intake and sperm maturation. Cell 178(4), 901-918.
Hudry B, Khadayate S, Miguel-Aliaga I. (2016). The sexual identity of adult intestinal stem cells controls organ size and plasticity. Nature 530(7590), 344-348.
Reiff T, Jacobson J, Cognigni P, Antonello Z, Ballesta E, Tan KJ, Yew JY, Dominguez M, Miguel-Aliaga I. (2015). Endocrine remodelling of the adult intestine sustains reproduction in Drosophila. eLife 4, e06930.
Linneweber GA, Jacobson J, Busch KE, Hudry B, Christov CP, Dormann D, Yuan M, Otani T, Knust E, de Bono M, Miguel-Aliaga I. (2014). Neuronal control of metabolism through nutrient-dependent modulation of tracheal branching. Cell 156(1-2), 69–83.