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

Aanya Hirdaramani; Chia-Wei Cheng; Aylin C. Hanyaloglu; Gary Frost

doi:10.1038/s42003-026-09830-5

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

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

Aanya Hirdaramani, Chia-Wei Cheng, Aylin C. Hanyaloglu and Gary Frost

Communications biology, Vol.9(1), 606

2026

DOI: https://doi.org/10.1038/s42003-026-09830-5

PMID: 41844830

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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-Gαi axis that does not require dynamin-dependent receptor internalisation. 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 Gαi 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.

Details

Title: A selective and augmentable butyrate-FFAR2 signal circuitry programs the cellular identity of enteroendocrine L-cells
Authors/Creators: Aanya Hirdaramani - Imperial College London
Chia-Wei Cheng - Columbia University Irving Medical Center
Aylin C. Hanyaloglu - Imperial College London
Gary Frost - Imperial College London
Publication Details: Communications biology, Vol.9(1), 606
Publisher: Nature Publishing Group
Identifiers: 991005884952707891
Murdoch Affiliation: Centre for Computational and Systems Medicine
Language: English
Resource Type: Journal article

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