Researchers from the Hubrecht Institute and Utrecht University generated an in-depth description of the human hormone-producing cells of the gut, in a large collaborative effort with other research teams. These cells are hard to study, as they are very rare and unique to different species of animals. The researchers developed an extensive toolbox to study human hormone-producing cells in tiny versions of the gut grown in the lab, called organoids. These tools allowed them to uncover secrets of the human gut, for example which potential hormones can be made by the gut and how the secretion of these hormones is triggered. These findings offer potential new avenues for the treatment of diseases such as type 2 diabetes and obesity.Did you ever wonder where that sudden feeling of hunger comes from when your empty stomach rumbles? Thousands of hormone-producing cells, or enteroendocrine cells, scattered throughout your stomach and intestine just released millions of tiny vesicles filled with the hunger hormone ghrelin into your bloodstream.

Another effect to these hormones can be to increase the release of insulin from the pancreas, which is especially interesting in patients with type II diabetes. These patients are unable to produce sufficient insulin to stabilize their glucose levels on their own. One of the most successful treatments for type 2 diabetes is actually based on a gut hormone, called GLP1. With this treatment some patients are able to control their blood glucose without the need of insulin injections.

Most of our knowledge on enteroendocrine cells is derived from studies in mice. However, mice have a different diet and are therefore likely to sense other signals from their food. The differences are so striking that the counterparts of some human gut hormones do not even exist in mice.

To be able to study all the specific types of enteroendocrine cells, the researchers used another trick that was recently developed in the group of Hans Clevers. Clevers: "In our lab, we have optimized genetic engineering of organoids. We were therefore able to label the hormones that are made by the enteroendocrine cells in different colors and create a biobank of mini-intestines, called the EEC-Tag biobank, in which different hormones are tagged with different colors." When an enteroendocrine cell starts producing a labeled hormone, that cell will appear in the corresponding color. The researchers can use the EEC-Tag biobank to study ten major hormones and different combinations of these hormones within the same organoid.

Joep Beumer (Hubrecht Institute): "Marking all major gut hormones with colors allows us to selectively collect any subset of enteroendocrine cells and study even the rarest enteroendocrine cell types. Combining the EEC-Tag biobank with other cutting-edge techniques allowed us to gain deep insights into the biology of hormone production in the human intestine."

"With the EEC-Tag biobank we can measure hundreds of cells for each enteroendocrine cell subtype. The resulting atlas is a gold mine full of fascinating relationships between hormones, receptors and other genes used by well-defined subsets of enteroendocrine cells, which opens many new directions for future studies," says Jens Puschhof (Hubrecht Institute).

The key characteristic of enteroendocrine cells are the active hormones they secrete. To directly measure these hormones, the researchers collaborated with the group of Wei Wu at Utrecht University. The researchers in this group are specialists at mass spectrometry, a very sensitive method to identify different molecules. In the collection of molecules produced by the mini-intestines, they found many new molecules for which it was unknown that they are secreted in the intestine. These new molecules may have functions in our bodies' response to food that are so far unknown. This discovery underlines our limited knowledge of the hormones produced in our gut and will inspire more detailed studies into the functions of these molecules.

Wei Wu (Utrecht University): "Gut secretions contain a mix of hormones that can be either active or inactive. For the first time, we characterize this diversity in human mini-intestines, to reveal also if these hormones are processed into active functional pieces. Hormone activation is not determined by genes, but rather by the processing of the hormones afterwards. Therefore, this may also hint at an exciting route of intervention for broad-spectrum applications, such as controlling hunger or treating diabetes."

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