A group of researchers led by the Hubrecht Institute and Roche’s Institute of Human Biology has developed strategies to identify regulators of intestinal hormone secretion. These hormones are secreted by rare hormone producing cells in the gut in response to incoming food, playing critical roles in managing digestion and appetite. The team has developed new tools to identify potential ‘nutrient sensors’ on these cells and study their function, which could lead to new strategies for interfering with hormone release and treating metabolic or gut motility disorders. Their work will be published in an article in Science on October 18th.
The intestine serves as a vital barrier protecting the body from harmful bacteria and dynamic pH levels, while allowing nutrients to enter the bloodstream. The gut is also home to endocrine cells known as enteroendocrine cells (EECs) that release hormones in response to various triggers, such as food energy levels and stretching of the stomach. These hormones regulate key aspects of physiology including digestion and appetite, making EECs the body’s first responders to incoming food and preparing the rest of the body for what is to come.
Medications that mimic gut hormones, such as GLP-1, show promise for treating metabolic diseases, but manipulating EECs to adjust hormone secretion has been challenging. Identifying sensors on EECs has been difficult due to their rarity and low expression levels of sensors. Studies have mainly relied on mouse models, despite differences in signals to which mouse and human EECs respond. New models and approaches were needed to study these signals and identify potential therapies.
The Hubrecht team has developed methods to derive large quantities of EECs in human organoids, which contain the same cell types as the organ they are derived from. Using a protein called Neurogenin-3, they were able to generate high numbers of EECs. By enriching EECs in organoids from different regions of the digestive system, including the stomach, the researchers were able to study hormone secretion. Stomach organoids responded to inducers of hormone release by secreting the hormone Ghrelin, known as the ‘hunger hormone’, confirming their usefulness for studying EEC function.
Researchers identified a surface marker, CD200, on human EECs which allowed them to isolate a large number of EECs from organoids and study their sensors. This led to the identification of numerous receptor proteins not previously known in EECs. By stimulating the organoids with molecules that activate these receptors, the team identified new sensory receptors that control hormone release. Inactivating these receptors using CRISPR-based gene editing often blocked hormone secretion, providing insight into how human EECs respond to receptor activation.
The data from these studies allow researchers to predict how human EECs respond to activation of specific sensory receptors, paving the way for further studies on the effects of receptor activation. The EEC-enriched organoids enable larger, unbiased studies to identify new regulators of hormone secretion, which may ultimately lead to therapies for metabolic diseases and gut motility disorders. Hans Clevers, an advisor and guest researcher at the Hubrecht Institute, has played a key role in these efforts, alongside his work in developmental biology and stem cell research, as well as his position at Roche in Pharma Research and Early Development.
