Credit: Ninouk Akkerman and Mike Nikolaev, Institute of Human Biology 17 October 2024 Gut instincts: Intestinal nutrient sensors Back to news A multi-institutional 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. Rare hormone producing cells in the gut secrete hormones in response to incoming food and play key roles in managing digestion and appetite. The team has developed new tools to identify potential ‘nutrient sensors’ on these hormone producing cells and study their function. This could result in new strategies to interfere with the release of these hormones and provide avenues for the treatment of a variety of metabolic or gut motility disorders. The work is presented in an article in Science, on October 17th. The intestine acts as a vital barrier. It protects the body from harmful bacteria and highly dynamic pH levels, while allowing nutrients and vitamins to enter the bloodstream. The gut is also home to endocrine cells, which secrete many hormones that regulate bodily functions. These enteroendocrine cells (endocrine cells of the gut) are very rare cells that release hormones in response to various triggers, such as stretching of the stomach, energy levels and nutrients from food. These hormones in turn regulate key aspects of physiology in response to the incoming food, such as digestion and appetite. Thus, enteroendocrine cells are the body’s first responders to incoming food, and instruct and prepare the rest of the body for what is coming. Understanding hormone release Medications that mimic gut hormones, most famously GLP-1, are promising for the treatment of multiple metabolic diseases. The ability to directly manipulate endocrine cells to adjust hormone secretion could open up new therapeutic options. However, it has been challenging to understand how gut hormone release can be influenced effectively. Researchers have had trouble identifying the sensors on cells. Enteroendocrine cells represent less than 1% of cells in the intestinal epithelium. In addition, the sensors on these cells are expressed in low amounts. Current studies mainly rely on mouse models, but the signals to which mouse cells respond are likely different from those to which human cells respond. Therefore, new models and approaches were required to study these signals. A human intestinal organoid, displaying typical ‘budding crypts’ and a central ‘villus-like’ domain. The main intestinal cell types are shown in green, blue, red and purple. Membranes are yellow and nuclei cyan. Credit: Ninouk Akkerman, Yannik Bollen and Jannika Finger, Institute of Human Biology Enteroendocrine cells in organoids The Hubrecht team has previously developed methods to derive large quantities of enteroendocrine cells in human organoids. OrganoidsOrganoids are essentially miniature organs (around 1mm), complex miniature 3D tissue cultures that are grown in the lab from a small biopsy, and mimic the organ they were derived from. contain the same cell types of the organ they are derived from. Therefore, they are useful to explore the development and function of cells. Using a special protein, Neurogenin-3, the researchers could generate high numbers of endocrine cells in organoids of the intestine. Enteroendocrine cells have different sensors and hormone profiles in different regions of the gut. In order to study these rare cells, the researchers needed to make organoids of all these different regions. Stomach organoids In the current study, the team managed to enrich enteroendocrine cells in organoids of other parts of the digestive system, including the stomach. Like the real stomach, stomach organoids respond to known inducers of hormone release and secrete large amounts of the hormone Ghrelin. Ghrelin is also called the ‘hunger hormone’ because it plays a key role in signaling hunger to the brain. The Ghrelin production of the stomach organoids confirms that these organoids can be used to study hormone secretion in enteroendocrine cells. In this human stomach organoid, you see a rare purple Ghrelin producing cell. Credit: Ninouk Akkerman and Mike Nikolaev, Institute of Human Biology Enteroendocrine cell sensors Since enteroendocrine cells are rare, researchers have struggled to profile many of these cells. In the current study, the team identified a so-called surface marker, called CD200, on human cells. The researchers used this surface marker to isolate a large number of human enteroendocrine cells from organoids and study their sensors. This revealed numerous receptor proteins that had not yet been identified in enteroendocrine cells. The team stimulated the organoids with molecules that would activate these receptors and identified multiple new sensory receptors that control hormone release. When the researchers inactivated these receptors using CRISPRA technique that researchers can use to cut the DNA in a very specific place, to make a change there. This way, researchers can study the effect of a specific change in the DNA.-based gene editing, hormone secretion was often blocked. Therapeutic applications With these data, the researchers can now predict how human enteroendocrine cells respond when certain sensory receptors are activated. Their findings thus pave the way for additional studies to explore the effects of these receptor activations. The enteroendocrine cell-enriched organoids will allow the team to perform larger, unbiased studies to identify new regulators of hormone secretion. These studies may eventually lead to therapies for metabolic diseases and gut motility disorders. Publication Description and functional validation of human enteroendocrine cell sensors. Joep Beumer, Maarten H. Geurts, Veerle Geurts, Amanda Andersson-Rolf, Ninouk Akkerman, Franziska Völlmy, Daniel Krueger, Georg A. Busslinger, Adriana Martínez-Silgado, Charelle Boot, Fjodor A. Yousef Yengej, Jens Puschhof, Wiline J. Van de Wetering, Kevin Knoops, Carmen López-Iglesias, Peter J. Peters, Judith A. Vivié, Dylan Mooijman, Johan H. van Es, Hans Clevers Hans Clevers is advisor/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 from the Utrecht University and is Investigator at Oncode Institute. Hans Clevers has been the Head of Pharma Research and Early Development (pRED) at Roche since 2022. He previously held directorship/President positions at the Hubrecht Institute, the Royal Netherlands Academy of Arts and Sciences and the Princess Máxima Center for pediatric oncology.
