Miguel-Aliaga LabGut Signalling and Metabolism

Research

Our interests

We are interested in the plasticity of adult organs: how and why organs that we commonly regard as fully developed change in size or function in response to environmental or internal challenges.

We use the intestine and its neurons to explore these questions because they allow us to explore organ plasticity from an integrated perspective: how an organ senses and integrates signals from both its internal milieu and the environment (e.g. nutrients, microbiota), how its adult progenitors respond by either maintaining or resizing the organ, and how different cell types within the organ (epithelial, muscle, neural) communicate to achieve coordinated, organ-level remodelling.

Our work is at the interface of developmental biology and physiology. We use genetic approaches to interfere with specific gene or cell functions using genome editing and/or genetically encoded tools such as thermo/optogenetics to interfere with neuronal activity. We assess the consequences at the levels of molecules (transcriptomics, metabolomics), cells (imaging), organ (peristalsis, modelling), and whole animal (behavioural assays and physiological readouts).

We typically use Drosophila melanogaster for discovery; since the identification of adult somatic stem cells in the Drosophila intestine, there has been a surge of studies using this invertebrate organ to investigate various aspects of physiology. Like its mammalian counterpart, the digestive tract of Drosophila is functionally regionalised. It harbours a resident microbiota, and consists of cell types similar to those found in the human gastrointestinal tract, including digestive/absorptive enterocytes and hormone-secreting enteroendocrine cells.

Informed by our Drosophila work, we sometimes explore specific questions in mice (in vivo or using intestinal organoids) and/or humans – for example, when our Drosophila research suggests new or unexpected explanations for certain aspects of mammalian physiology, such as contributions of cell-intrinsic mechanisms to sexual dimorphisms in the intestine.

Current projects

Our ongoing work is exploring these questions:

Sex differences in the intestine

We found that the intestine has its own sexual identity, which must be actively maintained in adults and subserves reproduction. In females, cell-intrinsic female identity makes intestinal stem cells divide more often, enabling reproductive resizing but increasing tumour susceptibility (Hudry 2016 Nature, Reiff 2015 eLife). In males, the adjacent testes masculinise the gut leading to gut secretion of citrate, which sustains sperm production (Hudry 2019 Cell). Hence, adjacent organs communicate with physiological consequences.

Intestinal remodelling during reproduction

In both flies and mice, the intestine is extensively remodelled during reproduction. Our work in flies showed that a reproductive hormone promotes adult intestinal stem cell proliferation and differentiation, increasing gut size, and adjusts lipid handling in enterocytes. Collectively, these changes are required to sustain reproductive output (Reiff 2015 eLife). Ongoing work in mice is characterising the striking remodelling of the female intestine during pregnancy and lactation.

Functions of enteric neurons

Our ongoing characterisation of the different neuronal cell types that innervate the intestine has revealed their key roles in regulating food intake, fluid balance, renal function and mating-triggered intestinal adaptations (Cognigni 2011 Cell Metab, Talsma 2012 Proc Natl Acad USA). We are currently exploring how plastic enteric neurons are, and whether such plasticity may be adaptive (Ameku 2020 Curr Opin Neurobiol).

Intestinal nutrient sensing

The gut is known to sense nutrients via its neurons or enteroendocrine cells. However, we have revealed a nutrient-sensing role for a subset of enterocytes - gut epithelial cells known for their digestive/absorptive roles. A zinc sensor within them is required to sustain food intake and developmental growth (Redhai 2020 Nature). This is exciting because micronutrients are commonly regarded as passive “building blocks”, and had received little attention in the context of development or whole-body physiology.

Support

We work in brand new laboratories and fly facilities. Our research is supported by a range of core facilities, including genomics, bioinformatics, proteomics, metabolomics and imaging.

We are core-funded by the MRC, and receive additional funding from ERC.