Ultra-Deep Single-Cell Analyses Reveals Novel Mechanisms of Gut Enteroendocrine Cell Sensing Dysfunction in Human Obesity

We sought to investigate the transcriptomic profile of native human EECs at an ultra-deep single-cell level from endoscopic biopsies of patients with normal weight, and obesity with and without abnormal satiety. EECs transcriptomic revealed several molecular signatures of obesity in the form of both single-gene and pathway level alterations, including terminal differentiation, hormone processing, negative feedback circuits, and GPCR-signaling. The aberrant GPCR-signal is mediated by over-expression of the regulator of G-protein receptor signaling (RGS) pathway, a global negative regulator of GPCRs signaling. We confirmed co-expression of RGS9 in human EECs, and its expression is negatively correlated postprandial PYY blood levels. Furthermore inhibition of RGS9 in primary culture of human colonic tissue increased GLP-1 and PYY release from EECs ex vivo. Our study provides a rich data source and describes a novel aberrant pathway in EEC-signaling in human obesity. Single cell RNA-Sequencing from thirteen sigmoid mucosal biopsies of patients with obesity and lean