title: The SCFA butyrate stimulates the epithelial production of retinoic acid via inhibition of epithelial HDAC.
abstract: In the intestinal mucosa, retinoic acid (RA) is a critical signaling molecule. RA is derived from dietary vitamin A (retinol) through conversion by aldehyde dehydrogenases (aldh). Reduced levels of short-chain fatty acids (SCFAs) are associated with pathological microbial dysbiosis, inflammatory disease, and allergy. We hypothesized that SCFAs contribute to mucosal homeostasis by enhancing RA production in intestinal epithelia. With the use of human and mouse epithelial cell lines and primary enteroids, we studied the effect of SCFAs on the production of RA. Functional RA conversion was analyzed by Adlefluor activity assays. Butyrate (0-20 mM), in contrast to other SCFAs, dose dependently induced aldh1a1 or aldh1a3 transcript expression and increased RA conversion in human and mouse epithelial cells. Epithelial cell line data were replicated in intestinal organoids. In these organoids, butyrate (2-5 mM) upregulated aldh1a3 expression (36-fold over control), whereas aldh1a1 was not significantly affected. Butyrate enhanced maturation markers (Mucin-2 and villin) but did not consistently affect stemness markers or other Wnt target genes (lgr5, olfm4, ascl2, cdkn1). In enteroids, the stimulation of RA production by SCFA was mimicked by inhibitors of histone deacetylase 3 (HDAC3) but not by HDAC1/2 inhibitors nor by agonists of butyrate receptors G-protein-coupled receptor (GPR)43 or GPR109A, indicating that butyrate stimulates RA production via HDAC3 inhibition. We conclude that the SCFA butyrate inhibits HDAC3 and thereby supports epithelial RA production.
authors.affiliation: Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands;
authors.forename: Ronald
authors.initials: R
authors.lastname: Schilderink
authors.affiliation: Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands;
authors.forename: Caroline
authors.initials: C
authors.lastname: Verseijden
authors.affiliation: Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands;
authors.forename: Jurgen
authors.initials: J
authors.lastname: Seppen
authors.affiliation: Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands;
authors.forename: Vanesa
authors.initials: V
authors.lastname: Muncan
authors.affiliation: Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands; and.
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
authors.affiliation: Mead Johnson Pediatric Nutrition Institute, Nijmegen, the Netherlands.
authors.forename: Tim T
authors.initials: TT
authors.lastname: Lambers
authors.affiliation: Mead Johnson Pediatric Nutrition Institute, Nijmegen, the Netherlands.
authors.forename: Eric A
authors.initials: EA
authors.lastname: van Tol
authors.affiliation: Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands; and w.j.dejonge@amc.nl.
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: de Jonge
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D018938:Caco-2 Cells; D002478:Cells, Cultured; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D008840:Microfilament Proteins; D055262:Mucin-2; C026615:villin; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; D006655:Histone Deacetylases
keywords: butyrate; epithelial cells; immune tolerance; retinoic acid; short-chain fatty acids