A selective and augmentable FFAR2 signal circuitry programs a butyrate-induced cellular identity of enteroendocrine L-cells

Activation of free fatty acid receptor 2 (FFAR2) on enteroendocrine L-cells mediates secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), key regulators of central appetite control with therapeutic relevance to obesity. Here, we show that butyrate, a metabolite derived from fermentation of dietary fibre and an FFAR2 agonist, stimulates a PYY-biased profile in a human L-cell model at the transcriptional, morphological and secretory level via an FFAR2-Gi axis that does not require dynamin-dependent receptor internalization. We observe that butyrate modulates active Notch cascades within a Hes1-GFP mouse organoid model, which are antagonistic to secretory differentiation, and identify butyrate-dependent regulation of late-stage human enteroendocrine maturation markers, NeuroD1 and Pax6. Butyrate-mediated upregulation of Pyy and Pax6 is enhanced by the FFAR2-selective Gi biased allosteric agonist AZ-1729. Our study reveals functions of spatiotemporally-regulated butyrate-activated FFAR2 signalling mechanisms that could be pharmacologically amplified to fine-tune L-cell populations in the human colon. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=160 HEIGHT=200 SRC="FIGDIR/small/659710v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@14b9620org.highwire.dtl.DTLVardef@16d4c10org.highwire.dtl.DTLVardef@9cb031org.highwire.dtl.DTLVardef@f3a0e1_HPS_FORMAT_FIGEXP M_FIG C_FIG