The intestinal tract is a complex organ system in which a single layer of specialized epithelium, replaced every week by the stem cells, performs its primary functions of digestion, absorption, protection and excretion. The intestinal epithelium consists, therefore, of different epithelial cells that secrete digestive enzymes and mucus (goblet cells), anti-bacterial agents (Paneth cells), absorb food particles (enterocytes) or produce hormones (entero-endocrine cells).
The rare EECs, also present in the stomach and colon, are subclassified by the (>20) different hormones they produce. Generally, EECs sense intestinal content and regulate gastrointestinal activity, systemic metabolism and food intake. While one EEC hormone, GLP1, has been developed into a highly successful diabetes drug, a paucity of laboratory models has complicated human EEC studies.
We have previously identified the adult intestinal stem cell and established conditions to grow ‘gut organoids’ (mini-organs in a dish) from these stem cells. These organoids have been used to resolve the complex EEC subtype hierarchy. Moreover, we developed protocols in which gut organoids can be manipulated to contain all EEC lineages and can be genetically modified using CRISPR technology. E.g. individual hormones can be tagged by a fluorescent marker. These cells can subsequently isolated and/or analyzed on basis of the fluorescent marker.
The ERC grant GutHormones exploits the technologies described above to generate a detailed picture of the biology of EECs, their triggers, their interconnectivity and their products.
Successful completion of this project will generate a comprehensive characterization of EECs. This will inspire new therapeutic approaches to reshape the EEC landscape for the treatment of metabolic diseases (obesity, diabetes, fatty liver disease, atherosclerosis).
