A collaborative effort between the Hubrecht Institute and Roche’s Institute of Human Biology has led to the creation of methods aimed at pinpointing the regulators involved in the secretion of intestinal hormones. These hormones, produced by specialized and scarce cells in the gut, are released in response to food intake and are crucial for regulating digestion and appetite. To further this understanding, the research team has developed innovative tools to locate potential ‘nutrient sensors’ on these hormone-secreting cells and to examine their functionality. This could pave the way for new tactics to modify hormone release, potentially opening doors to treatments for various metabolic and gut motility conditions. Their findings will be detailed in an upcoming article in Science, set for publication on October 18th.
The intestine plays a crucial protective role, safeguarding the body from harmful bacteria and fluctuating pH levels while allowing nutrients and vitamins to be absorbed into the bloodstream. The gut is also home to specialized endocrine cells that release hormones to regulate various bodily functions. These enteroendocrine cells (EECs), which are quite rare, react to various stimuli such as stomach expansion, energy levels, and the nutrients present in food, resulting in hormone release that influences key physiological processes related to food intake, like digestion and appetite. Hence, EECs serve as the body’s initial responders to food, preparing and directing other bodily systems accordingly.
Medications that simulate gut hormones, particularly GLP-1, show great promise for treating a range of metabolic disorders. Directly modifying EECs to alter hormone secretion could lead to new therapeutic possibilities. However, effectively understanding how gut hormone release can be influenced remains complex. Researchers face challenges in identifying the sensors present on EECs since they constitute less than 1% of the cells in the intestinal epithelium, and the sensors themselves are produced in minimal quantities. Studies primarily focus on mouse models, although the signals that activate mouse EECs may differ from those affecting human EECs. Hence, there is a need for new models and methods to explore these signaling pathways.
Enteroendocrine Cells in Organoids
The Hubrecht team has previously devised strategies to produce significant quantities of EECs using human organoids. These organoids replicate the cell types found in their original organs, making them an excellent tool for investigating the development and functions of cells like EECs. By employing a specialized protein, Neurogenin-3, the researchers were able to significantly increase the number of EECs generated.
Moreover, the researchers have enhanced the EEC content in organoids from various parts of the digestive system, including the stomach. These stomach organoids exhibited responses to known stimuli that induce hormone release, producing substantial amounts of the hormone Ghrelin, commonly referred to as the ‘hunger hormone’ due to its role in signaling hunger to the brain. This supports the use of these organoids for studying hormone secretion in EECs.
EEC Sensors
Due to the rarity of EECs, researchers have faced difficulties in profiling them extensively. In this study, the team discovered a specific surface marker, CD200, on human EECs, which enabled them to isolate a larger number of these cells from organoids for further analysis. This process revealed numerous receptor proteins previously unidentified in EECs. The team then stimulated these organoids with molecules designed to activate these receptors, leading to the identification of several new sensory receptors that regulate hormone release. Notably, inactivating these receptors through CRISPR-based gene editing often halted hormone secretion.
With this information, researchers can now anticipate how human EECs will respond when specific sensory receptors are activated. Their discoveries offer a foundation for further investigations into the impacts of these receptor activations. The EEC-enriched organoids will facilitate broader and more objective studies to uncover new regulators of hormone secretion, which may eventually lead to therapeutic strategies for metabolic disorders and issues related to gut motility.
About Hans Clevers
Hans Clevers serves as an advisor and guest researcher at the Hubrecht Institute for Developmental Biology and Stem Cell Research (KNAW) and at the Princess Máxima Center for Pediatric Oncology. He holds a professorship in Molecular Genetics at Utrecht University and is an investigator at Oncode Institute. Since 2022, Hans Clevers has been the Head of Pharma Research and Early Development (pRED) at Roche. He has previously held various leadership roles, including director and president positions at the Hubrecht Institute, the Royal Netherlands Academy of Arts and Sciences, and the Princess Máxima Center for Pediatric Oncology.
