Diversity of enteroendocrine cells investigated at cellular and subcellular levels: the need for a new classification scheme

Abstract

Enteroendocrine cells were historically classified by a letter code, each linked to a single hormone, deduced to be the only hormone produced by the cell. One type, the L cell, was recognised to store and secrete two products, peptide YY (PYY) and glucagon-related peptides. Many other exceptions to the one cell – one hormone classifications have been reported over the last 40 years or so, and yet the one hormone dogma has persisted. In the last 6 years, a plethora of data has appeared that makes the concept unviable. Here we describe the evidence that multiple hormone transcripts and their products reside in single cells and evidence that the hormones are often, but not always, processed into separate storage vesicles. It has become clear that most enteroendocrine cells contain multiple hormones. For example, most secretin cells contain 5-hydroxytryptamine (5-HT), and in mouse many of these also contain cholecystokinin (CCK). Furthermore, CCK cells also commonly store ghrelin, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), neurotensin, and PYY. Several hormones, for example secretin and 5-HT, are in separate storage vesicles at a subcellular level. Hormone patterns can differ considerably between species. Another complication is that relative levels of expression vary substantially. This means that data are significantly influenced by the sensitivities of detection techniques. For example, a hormone that can be detected in storage vesicles by super-resolution microscopy may not be above threshold for detection by conventional fluorescence microscopy. New nomenclature for cell clusters with common attributes will need to be devised and old classifications abandoned.

Single cell transcriptomic profiling of large intestinal enteroendocrine cells in mice – Identification of selective stimuli for insulin-like peptide-5 and glucagon-like peptide-1 co-expressing cells

“…Peptide YY, PYY; GLP-1; Insulin-like peptide-5, INSL5) [3]. Recent transcriptomic analyses have challenged the traditional notion that distinct EEC subtypes exist, which produce separate and non-overlapping sets of gut hormones [4]. Characterization of individual EECs in the small intestine by single cell RNA-sequencing (scRNA-seq), led to the identification of distinct EEC subgroups by cluster analysis, exhibiting overlapping expression profiles for known gut hormones [5], [6], [7].…”

Review: Nutritional regulation of intestinal starch and protein assimilation in ruminants

“…The gastrointestinal hormones that are secreted from the neuroendocrine cells containing taste receptors in response to stimulation of the taste receptors include secretin (S-cells), CCK (I-cells), ghrelin (X/A-like cells), GIP (K-cells), and peptide YY, glucagon peptide 1 and glucagon peptide 2 (GLP-2; L-cells) (Calvo and Egan, 2015). There is also a recent evidence suggesting that multiple gastrointestinal regulatory proteins can be co-localized within the enteroendocrine cells of the small intestine (Fothergill and Furness, 2018). The primary functions of the gastrointestinal hormones are to regulate feed intake, feed digestion and whole animal metabolism (Gribble and Reimann, 2017;Fothergill and Furness, 2018).…”

“…There is also a recent evidence suggesting that multiple gastrointestinal regulatory proteins can be co-localized within the enteroendocrine cells of the small intestine (Fothergill and Furness, 2018). The primary functions of the gastrointestinal hormones are to regulate feed intake, feed digestion and whole animal metabolism (Gribble and Reimann, 2017;Fothergill and Furness, 2018).…”

Tryptophan Metabolites Along the Microbiota-Gut-Brain Axis: An Interkingdom Communication System Influencing the Gut in Health and Disease

“…152 These hormones comprise 5-HT, chromogranin/secretogranin family, somatostatin, neuropeptide Y (NPY ), vasoactive intestinal peptide (VIP), substance P (SP), cholecystokinin (CKK), glucagon-like peptide (GLP)-1/2, and ghrelin. 153,154 The apical surface of enteroendocrine cells (ECCs) comes into contact with luminal constituents, including bacterial metabolites, and takes part in modulation of local neuronal and glial networks by releasing peptides and biological active molecules towards the intestinal submucosa. 155,156 Gut signalling molecules from EECs may influence also the brain function, via hormonal and humoral routes, thus participating in the gutbrain communication axis.…”