Human Organoids Provide Insights Into Gut Hormone Release

A collaborative team of researchers from the Hubrecht Institute and Roche’s Institute of Human Biology has formulated strategies to identify the regulators involved in intestinal hormone secretion.

Rare hormone-producing cells in the gut release hormones in response to food intake, playing crucial roles in digestion and appetite regulation. The team has developed innovative tools to identify potential "nutrient sensors" on these hormone-producing cells and to investigate their functions.

This research may lead to new approaches for modulating hormone release, offering potential treatments for various metabolic and gut motility disorders. The findings are detailed in an article published in Science on October 17^th, 2024.

The intestine serves as a crucial barrier, safeguarding the body from harmful bacteria and fluctuating pH levels while permitting the absorption of nutrients and vitamins into the bloodstream. It also houses endocrine cells that produce various hormones essential for regulating bodily functions.

These enteroendocrine cells are rare and respond to different stimuli, including stomach stretching, energy levels, and nutrients from food, by releasing hormones. These hormones then regulate vital physiological processes, such as digestion and appetite, in response to food intake.

As a result, enteroendocrine cells act as the body's first responders to incoming food, signaling and preparing the rest of the body for what is to come.

Understanding Hormone Release

Drugs that imitate gut hormones, particularly GLP-1, show potential for treating various metabolic disorders. The direct manipulation of endocrine cells to modify hormone secretion could lead to innovative therapeutic possibilities.

Nevertheless, understanding how to effectively influence gut hormone release has proven difficult. Researchers have faced challenges in pinpointing the sensors present in these cells.

Enteroendocrine cells account for less than 1% of the cells in the intestinal epithelium, and the sensors found on these cells are present in minimal quantities.

Current research primarily utilizes mouse models; however, the signals that activate mouse cells may differ from those affecting human cells. As a result, there is a need for new models and methodologies to investigate these signals.

Enteroendocrine Cells in Organoids

The Hubrecht team has previously established techniques to produce substantial quantities of enteroendocrine cells from human organoids. Organoids replicate the same cell types as the organs from which they are derived, making them valuable for investigating cell development and function.

By utilizing a specific protein, Neurogenin-3, the researchers were able to generate a large number of endocrine cells within intestinal organoids.

Enteroendocrine cells possess distinct sensors and hormone profiles across various regions of the gut. To investigate these rare cells effectively, the researchers needed to create organoids representing each of these different regions.

Stomach Organoids

In the current study, the team successfully enriched enteroendocrine cells in organoids from various parts of the digestive system, including the stomach. Similar to the actual stomach, these stomach organoids respond to established inducers of hormone release and secrete significant amounts of the hormone Ghrelin.

Often referred to as the "hunger hormone," Ghrelin is crucial for signaling hunger to the brain. The production of Ghrelin by the stomach organoids validates their potential as models for studying hormone secretion in enteroendocrine cells.

Enteroendocrine Cell Sensors

Due to the rarity of enteroendocrine cells, researchers have faced challenges in profiling a substantial number of these cells. In the current study, the team identified a specific surface marker, known as CD200, on human cells.

This surface marker was utilized to isolate a significant quantity of human enteroendocrine cells from organoids, allowing the researchers to investigate their sensors. This approach uncovered several receptor proteins that had not previously been identified in enteroendocrine cells.

The team stimulated the organoids with molecules designed to activate these receptors, leading to the identification of several new sensory receptors that regulate hormone release. When the researchers employed CRISPR-based gene editing to deactivate these receptors, they frequently observed a blockage in hormone secretion.

Therapeutic Applications

With this data, the researchers are now able to predict the responses of human enteroendocrine cells upon activation of specific sensory receptors. Their findings open the door for further investigations into the effects of these receptor activations.

The organoids enriched with enteroendocrine cells will enable the team to conduct larger, unbiased studies aimed at discovering new regulators of hormone secretion. Ultimately, these studies may contribute to the development of therapies for metabolic diseases and gut motility disorders.