Biochemical controls: very many in the gut (Introduction)

by David Turell , Wednesday, October 30, 2024, 17:05 (22 days ago) @ David Turell

Using organoids to study specific controlling cells:

https://www.science.org/doi/10.1126/science.adl1460?utm_source=sfmc&utm_medium=emai...

"Enteroendocrine cells are a collection of cell types found throughout the gastrointestinal tract that secrete various hormones involved in digestion and metabolism. These cells are relatively rare, and they vary in their locations and the types of hormones they secrete, making it difficult to fully characterize their subtypes and biological functions. To address this difficulty, Beumer et al. developed a method of culturing organoids composed of human gastric cells. The authors then studied organoids derived from the stomach, small intestine, and colon cells of human patients with or without targeted mutations inactivating specific receptors to delineate the functions of various metabolite sensors and to identify potential pharmacological targets.

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"Enteroendocrine cells (EECs) are gut epithelial cells that respond to intestinal contents by secreting hormones, including the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory protein (GIP), which regulate multiple physiological processes. Hormone release is controlled through metabolite-sensing proteins. Low expression, interspecies differences, and the existence of multiple EEC subtypes have posed challenges to the study of these sensors. We describe differentiation of stomach EECs to complement existing intestinal organoid protocols. CD200 emerged as a pan-EEC surface marker, allowing deep transcriptomic profiling from primary human tissue along the stomach-intestinal tract. We generated loss-of-function mutations in 22 receptors and subjected organoids to ligand-induced secretion experiments. We delineate the role of individual human EEC sensors in the secretion of hormones, including GLP-1. These represent potential pharmacological targets to influence appetite, bowel movement, insulin sensitivity, and mucosal immunity.

"Enteroendocrine cells (EECs) are gastrointestinal (GI) epithelial cells that constitute part of the gut-brain axis. They regulate physiological responses related to metabolism such as appetite, insulin release, and bowel movement, as well mucosal immunity (1). EECs are relatively rare (~1% of the epithelium) and can be subdivided into five major subtypes, each producing a different set of peptide hormones and/or neurotransmitters (2). Each subtype has a distinct distribution along the GI tract. The major EEC subtype, the enterochromaffin cell (EC), produces ~90% of the body’s serotonin (5-HT) and regulates gut motility and inflammation. The other EECs are coded with letters: L cells produce glucagon-like peptide 1 (GLP-1), neurotensin (NTS), peptide YY (PYY), and cholecystokinin (CCK); MX cells produce ghrelin (GHRL) and motilin (MLN); D cells produce somatostatin (SST); K cells produce gastric inhibitory protein (GIP); and G cells produce gastrin (GAST) (3). K, MX, and G cells are most abundant in the proximal small intestine (SI), whereas L cells are enriched in the distal SI and colon. The stomach corpus contains an EEC subset called enterochromaffin-like (ECL) cells. In addition to producing some 5-HT, ECL cells produce histamine to regulate acid secretion by nearby parietal cells (4). Important differences exist between mouse and human EECs. For instance, human MX cells express motilin only in the SI but not in the stomach (where these are called X cells), whereas the pertinent gene is a pseudogene in rodents.

"EECs are electrically excitable and control hormone secretion through elevation of intracellular calcium (5). Calcium levels are controlled through G protein–coupled receptors (GPCRs), as well as nutrient status, regulating the activity of adenosine triphosphate (ATP)–sensitive potassium channels. Their products can signal to local neurons, potentially through diffusion or through synaptic interactions (called neuropods) with nearby neurons (6), immune cells and to other epithelial cells.

Here are the scientist's thoughts:

https://mail.google.com/mail/u/0/#inbox/FMfcgzQXJswcxrBPRJQjRJnBBshhKQzr

"...everyone knows that the intestine is where nutrient uptake happens. But what I think is much less known is that it’s also the largest endocrine organ. The intestine has the most hormone-producing cells of any tissue—the enteroendocrine cells. Even though they’re very rare within it—they’re less than 1% of the epithelium, or the layer that lines the intestine—because the intestine is so large, it’s still a lot of cells. And these cells act as first responders. Whenever you eat, they are sitting there and watching what comes into the lumen of the gut, or the inside of that intestinal tube. They chemically “see” that food, and they prepare the body for what’s coming by secreting hormones. These cells can even respond to the stretching of the tissue." (my bold)

"They do a lot—they can tell your brain to eat more or less. They regulate gut motility and blood glucose levels. And because of these physiologically important roles, they’re of course very interesting targets for therapies as well."

Comment: This is high powered research which I have introduced here with direct quotes from a science journal. It is not meant to educate at that level, but to show that extremely complex design exists to run our bodies.