“We are investigating how the intestine controls energy homeostasis and makes nutritional decisions”
The digestive system is emerging as a key regulator of appetite and metabolism. It is now recognised that 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 dramatic functional remodelling in response to environmental or internal change – 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, using targeted genetic experiments, 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, and 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 lack of lack of specific nutrients (Linneweber et al (2014) Cell).
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.
Grmai L, Hudry B, Miguel-Aliaga I, Bach EA. (2018). Chinmo prevents transformer alternative splicing to maintain male sex identity. PLOS GENETICS 14.
Perea D, Guiu J, Hudry B, Konstantinidou C, Milona A, Hadjieconomou D, Carroll T, Hoyer N, Natarajan D, Kallijarvi J, Walker JA, Soba P, Thapar N, Burns AJ, Jensen KB, Miguel-Aliaga I. (2017). Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia. EMBO Journal 36, 3029-3045.
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.
Talsma AD, Christov CP, Terriente-Felix A, Linneweber GA, Perea D, Wayland M, Shafer OT, Miguel-Aliaga I. (2012). Remote control of renal physiology by the intestinal neuropeptide pigment-dispersing factor in drosophila. Proceedings of the National Academy of Sciences 109(30), 12177–12182.
Cognigni P, Bailey AP, Miguel-Aliaga I. (2011). Enteric neurons and systemic signals couple nutritional and reproductive status with intestinal homeostasis. Cell Metabolism 13(1), 92–104.