Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling

Abstract

Enteroendocrine cells (EECs) produce hormones that regulate food absorption, insulin secretion and appetite. Both EECs and their peptide products are foci of drug discovery programmes for diabetes and obesity. We compared the human and mouse EEC transcriptome and peptidome to validate mouse as a model of the human enteroendocrine axis. We present the first RNA sequencing analysis of human EECs, and demonstrate strong correlation with mouse, although with outliers including some low abundance G-protein coupled receptors. Liquid chromatography mass spectrometry (LC-MS) identified peptide hormone gradients along the human and mouse gut that should enhance progress in gut physiology and therapeutics.

Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery

“…(collected by endoscopy) and performed transcriptomic analysis by RNA sequencing. EEC purity estimated from the FACS profiles ranged from 10% to 50%, compared with $0.1% in the starting cell populations, so to prevent bias introduced from non-EECs, we restricted the analysis to genes known to be differentially expressed and enriched in human EECs (Roberts et al, 2018a). By PCA, the pre-and post-surgical samples did not show any distinct clustering ( Figure 4A), and the relatively few EEC genes that did exhibit significant differential expression between pre-and post-operative samples ( Figure 4B) were not suggestive of major functional differences between the groups.…”

“…GLP-1 and PYY are produced from enteroendocrine cells (EECs), which comprise $1% of the intestinal epithelium (Gribble and Reimann, 2016). These cell types have been extensively characterized in mice, because they can be tagged with fluorescent reporters driven by cell-specific hormonal or transcription factor promoters in transgenic mouse models (Gribble and Reimann, 2016), but data on human EECs are limited, because cell purification requires antibody staining for identification (Roberts et al, 2018a). One potential explanation for the post-surgical changes in gut hormone release is that EECs undergo adaptive changes, producing more GLP-1 and PYY that can be mobilized after food intake, or changing their response to nutrients due to different receptor expression.…”

“…An alternative explanation is that ingested nutrients make contact with and thereby stimulate more EECs from the distal gut after surgery, due to anatomic intestinal rearrangement and/or increased intestinal transit. In both humans and mice, GLP-1 and PYY production is higher in more distal regions of the small intestine (Roberts et al, 2018a), so increased distal nutrient delivery has the potential to activate a greater number of GLP-1 and PYY-producing EECs.…”

Modern Methods of Transcriptomic and Peptidomic Profiling of Enteroendocrine Cells Promise Progress for a Better Understanding of (Patho)physiology and New Therapies for Obesity and Diabetes

“…Heidenhain predicted in 1888 that "even an only limited clue about the processes in the gut mucosa deserves many more years of studies" (author's translation) (3). In fact, only 130 years later, facing an impressive diversity of enteroendocrine cells, researchers became capable of employing transcriptomic and peptidomimetic profiling techniques, revealing a complexity rarely expected by the earlier reports (5,6).…”

“…In this issue of Diabetes, Roberts et al (6) present an interesting and timely piece of work dealing with the comparison of human and murine enteroendocrine cells utilizing these new state-of-the-art technologies. They focus on certain gut peptides, such as the proglucagonderived glucagon-like peptide 1 (GLP-1), recently highly acclaimed as candidates for new therapies of diabetes and other metabolic diseases (7).…”