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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-G\u03b1i 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,\n                    <jats:italic>NeuroD1<\/jats:italic>\n                    and\n                    <jats:italic>Pax6<\/jats:italic>\n                    . Butyrate-mediated upregulation of\n                    <jats:italic>Pyy<\/jats:italic>\n                    and\n                    <jats:italic>Pax6<\/jats:italic>\n                    is enhanced by the FFAR2-selective G\u03b1i 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.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-09830-5","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:05:36Z","timestamp":1773749136000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A selective and augmentable butyrate-FFAR2 signal circuitry programs the cellular identity of enteroendocrine L-cells"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9101-1527","authenticated-orcid":false,"given":"Aanya","family":"Hirdaramani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1088-923X","authenticated-orcid":false,"given":"Chia-Wei","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4206-737X","authenticated-orcid":false,"given":"Aylin C.","family":"Hanyaloglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0529-6325","authenticated-orcid":false,"given":"Gary","family":"Frost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"9830_CR1","doi-asserted-by":"publisher","first-page":"8752","DOI":"10.1080\/10408398.2022.2061909","volume":"63","author":"IS Waddell","year":"2023","unstructured":"Waddell, I. 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