A selective and augmentable butyrate-FFAR2 signal circuitry programs the cellular identity of enteroendocrine L-cells
File(s)
Published version
Author(s)
Hirdaramani, Aanya
Cheng, Chia-Wei
Hanyaloglu, Aylin
Frost, Gary
Type
Journal Article
Abstract
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-Gai 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 Gai 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.
Date Issued
2026-05-06
Date Acceptance
2026-02-26
Citation
Communications Biology, 2026, 9
ISSN
2399-3642
Publisher
Nature Portfolio
Journal / Book Title
Communications Biology
Volume
9
Copyright Statement
Copyright © 2026 Copyright Owner. This is the author’s accepted manuscript made available under a CC-BY licence in accordance with Imperial’s Research Publications Open Access policy (www.imperial.ac.uk/oa-policy)
License URL
Identifier
10.1038/s42003-026-09830-5
Publication Status
Published
Article Number
ARTN 606
Date Publish Online
2026-03-17