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New Research Sheds Light on Intestinal Hormone Regulation
A collaborative effort among researchers from the Hubrecht Institute and Roche’s Institute of Human Biology has led to the development of innovative strategies aimed at identifying the regulators that oversee the secretion of intestinal hormones. These hormones, secreted by specialized but scarce hormone-producing cells in the gut in response to food intake, are pivotal for managing digestion and appetite. With newly devised tools, the team is exploring potential ‘nutrient sensors’ on these cells, which may open the door to novel methods for modulating hormone release and could offer new treatment pathways for various metabolic and gastrointestinal disorders. This research will be detailed in an article published in Science on October 18th.
The intestine serves as a crucial barrier for the human body, protecting against harmful bacteria and fluctuations in pH levels while facilitating the absorption of essential nutrients and vitamins into the bloodstream. Within the gut, enteroendocrine cells (EECs)—rarified endocrine cells—play a significant role by secreting hormones that influence various bodily functions. These EECs respond to multiple stimuli, such as stomach distension, energy levels, and the presence of nutrients, guiding physiological responses like appetite regulation and digestion. As the gut’s first responders, EECs prepare the body for incoming food.
Medications that mimic gut hormones, particularly GLP-1, have shown promise in treating several metabolic conditions. Directly manipulating EECs to fine-tune hormone secretion could create new therapeutic strategies. However, understanding the precise mechanisms that influence gut hormone release has proven challenging. The rarity of EECs—comprising less than 1% of intestinal epithelial cells—along with the low expression levels of sensors on these cells complicates research efforts. Current knowledge primarily derives from mouse models, which may not accurately reflect human EEC responses to various stimuli. This gap highlights the need for new investigative models and methodologies.
Advancements in EEC Research
Enteroendocrine Cells in Organoids
The Hubrecht Institute team has previously made strides in generating significant quantities of EECs using human organoids, which mirror the cellular composition of their source organs. Utilizing a specific protein known as Neurogenin-3 allowed researchers to increase EEC yields substantially. As different regions of the gut house EECs with varying sensory profiles, the team has focused on creating EEC-enriched organoids that represent multiple gastrointestinal locales. Recent developments allowed for the enrichment of EECs not only in intestinal organoids but also in stomach organoids, which react to known hormonal triggers and secrete substantial amounts of Ghrelin, a hormone integral to hunger signaling. This capability confirms the usefulness of these organoids for studying hormone secretion in EECs.
EEC Sensors
Due to their rarity, comprehensive profiling of EECs has previously been a challenge. In their recent work, the team successfully identified a surface marker named CD200 on human EECs, facilitating the isolation and detailed study of these cells. This investigation unveiled numerous receptor proteins unrecognized in EECs to date. Upon stimulating the organoids with molecules that activate these receptors, the researchers discovered several new sensory receptors crucial for hormone secretion. When CRISPR-based gene editing techniques were employed to deactivate these receptors, a significant inhibition of hormone release was observed.
These findings empower researchers to anticipate how human EECs will react when specific sensory receptors are activated. With this knowledge, further investigations can explore the effects of receptor activation, and the enriched EEC organoids will enable larger, unbiased studies aimed at identifying additional regulatory factors in hormone secretion. Such advancements might ultimately lead to innovative treatments for metabolic diseases and gut motility disorders.
About Hans Clevers
Hans Clevers is a researcher/advisor 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 the Oncode Institute. Since 2022, he has also served as the Head of Pharma Research and Early Development (pRED) at Roche. Previously, Clevers held key positions as director and president at the Hubrecht Institute, the Royal Netherlands Academy of Arts and Sciences, and the Princess Máxima Center for Pediatric Oncology.
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