Researchers are developing strategies to identify regulators of intestinal hormone secretion

A multi-institutional team of researchers led by the Hubrecht Institute and the Roche Institute of Human Biology has developed strategies to identify regulators of intestinal hormone secretion. In response to incoming food, these hormones are secreted by rare hormone-producing cells in the gut and play a key role in managing digestion and appetite. The team has developed new tools to identify potential “nutrient sensors” in these hormone-producing cells and study their function. This could lead to new strategies to interfere with the release of these hormones and provide avenues for treating a variety of metabolic or gut motility disorders. The work will be presented in an article at Scienceon October 18.

The gut acts as a vital barrier. It protects the body from harmful bacteria and extremely dynamic pH levels, while allowing nutrients and vitamins to enter the bloodstream. The gut also houses endocrine cells, which secrete many hormones that regulate bodily functions. These enteroendocrine cells (EECs, gut endocrine cells) are very rare cells that release hormones in response to various triggers, such as stomach distention, energy levels, and nutrients from food. These hormones in turn regulate key aspects of physiology in response to incoming food, such as digestion and appetite. Thus, EECs are the body’s first responders to incoming food and guide and prepare the rest of the body for what is to come.

Drugs that mimic gut hormones, most famously GLP-1, are promising for the treatment of multiple metabolic diseases. Direct manipulation of EECs to regulate hormone secretion could open new therapeutic options. However, it has been difficult to understand how the release of gut hormones can be effectively affected. Researchers have had difficulty identifying the sensors in EECs because EECs themselves represent less than 1% of the cells in the intestinal epithelium, and furthermore the sensors in these EECs are expressed in low amounts. Current studies are primarily based on mouse models, although the signals to which mouse EECs respond are likely different compared to those to which human EECs respond. Therefore, new models and approaches were required to study these signals.

Enteroendocrine cells in organoids

Hubrecht’s group has previously developed methods to produce large quantities of EECs in human organoids. Organoids contain the same cell types as the organ from which they are derived, and are therefore useful for investigating the growth and function of cells such as EECs. Using a special protein Neurogenin-3, the researchers could generate large numbers of EECs.

Previously, Hubrecht researchers developed a way to increase the number of EECs in gut organoids. Considering that EECs have different sensors and hormone profiles in different regions of the gut, studying these rare cells requires researchers to make organoids enriched with EECs from all these different regions. In the current study, the team was able to enrich EECs in organelles of other parts of the digestive system, including the stomach. Like the real stomach, these stomach organoids respond to known inducers of hormone release and secrete large amounts of the hormone Ghrelin, also called the “hunger hormone” because it plays a key role in signaling hunger to the brain. This confirms that these organoids can be used to study hormone secretion in EEC.

EEC sensors

Since EECs are rare, researchers have had difficulty profiling many EECs. In the current study, the team identified a so-called surface marker, called CD200, on human EECs. The researchers used this surface marker to isolate large numbers of human EECs from organelles and study their sensors. This revealed numerous receptor proteins that had not yet been identified in EEC. The team then stimulated the organoids with molecules that would activate these receptors and identified multiple new sensory receptors that control hormone release. When these receptors were disabled using CRISPR-based gene editing, hormone secretion was often blocked.

With this data, researchers can now predict how human EECs react when certain sensory receptors are activated. Their findings thus pave the way for additional studies to investigate the effects of these receptor activations. The EEC-enriched organoids will allow the team to conduct larger, unbiased studies to identify new regulators of hormone secretion. These studies may eventually lead to treatments for metabolic diseases and gut motility disorders.