Enteroendocrine cells (EECs) produce hormones such as glucagon-like peptide-1 (GLP-1) and peptideYY (PYY) that regulate food absorption, insulin secretion and appetite. Based on the success of GLP-1 based therapies for type 2 diabetes and obesity, EECs are themselves the focus of drug discovery programmes to enhance gut hormone secretion. The aim of this study was to identify the transcriptome and peptidome of human EECs, and to provide a cross-species comparison between humans and mice. By RNA sequencing of human EECs purified by flow cytometry after cell fixation and staining, we present a first transcriptomic analysis of human EEC populations, and demonstrate strong correlation with murine counterparts. RNA sequencing was deep enough to enable identification of low abundance transcripts such as G-protein coupled receptors and ion channels, revealing expression in human EECs of GPCRs previously found to play roles in post-prandial nutrient detection. By liquid chromatography mass spectrometry (LC-MS) we profiled the gradients of peptide hormones along the human and mouse gut, including their sequences and post-translational modifications. The transcriptomic and peptidomic profiles of human and mouse EECs, and cross-species comparison, will be valuable tools for drug discovery programmes and for understanding human metabolism and the endocrine impacts of bariatric surgery.

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