“We are investigating the nature and significance of the signals mediating the crosstalk between the nervous and digestive systems”
The gastrointestinal (GI) tract and its neurons are emerging as key regulators of nutrient intake and utilisation. Their involvement in prevalent metabolic conditions such as obesity and diabetes is becoming increasingly recognized, although the underlying mechanisms are not completely understood. Our main goal is to understand how the GI tract senses and responds to nutritional information in order to maintain or perturb homeostasis. We are tackling the study of brain-gut inter-organ signalling primarily in the fruit fly Drosophila melanogaster, taking advantage of three key features: 1) it can be utilized in medium-throughput screens to systematically investigate the potential contribution of hundreds of candidate genes to the modulation of nutrient intake and utilization, using publicly available fly strains; 2) gene expression and/or neuronal activity can be modulated with both single cell (or cell type) resolution and temporal control; and 3) over 60% of its genes are shared with humans. Together, these properties allow us to identify metabolically significant – and, potentially, evolutionarily conserved – signals, their cellular sources and tissue targets.
Currently, we are using a combination of genetic labelling and manipulation to identify and characterise nutrient-sensing enteric neurons or epithelial cells. To assess their possible roles, we have developed new physiological assays and biomarkers, which we combine with confocal microscopy, behavioural assays and metabolic quantifications. We are also characterising the transcriptional and metabolic plasticity of the intestinal epithelium in response to environmental or internal nutritional challenges. Finally, building on our recent finding, where we reveal a fly equivalent of “neurovascular” interactions, we are currently investigating the signalling mechanisms mediating communication between the gut, its neurons and trachea (a system of oxygen delivering tubes analogous to the mammalian lung/vasculature).
The anatomical, genetic and physiological similarities between the fly and human gut make us confident that the signals we identify will be relevant to humans, and should lead to the identification of new regulators of appetite and metabolism. Given that many of the enteric neuromodulators, receptors and transporters present in the Drosophila intestine are conserved in humans, we expect our findings to provide candidate new targets for the treatment of metabolic conditions in which the digestive tract is suspected to be involved.
Figure 1: Insulinergic innervation of the Drosophila gut. A subset of enteric nerves (in green) secrete an insulin-like peptide (in blue). Enteric muscles are highlighted in red with an actin staining.
Figure 2: The digestive and reproductive systems of an adult female fly.
Hudry, B., Khadayate, S. and Miguel-Aliaga, I. (2016) The sexual identity of adult intestinal stem cells controls organ size and plasticity. Nature. In press. 530, 344-48. doi:10.1038/nature16953.
Reiff, T., Jacobson, J., Cognigni, P., Antonello, Z., Ballesta, E., Tan, K.J., Yew, J.Y., Dominguez, M., & Miguel-Aliaga, I. (2015) Endocrine remodelling of the adult intestine sustains reproduction in Drosophila. eLife, 4, doi: 10.7554/eLife.06930.
Linneweber, G. A., Jacobson, J., Busch, K. E. E., Hudry, B., Christov, C. P., 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, A. D., Christov, C. P., Terriente-Felix, A., Linneweber, G. A., Perea, D., Wayland, M., Shafer, O. T., & 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, A. P., & Miguel-Aliaga, I. (2011). Enteric neurons and systemic signals couple nutritional and reproductive status with intestinal homeostasis. Cell Metabolism, 13(1), 92–104.