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Butyrate stimulates the epithelial potential to produce retinoic acid demonstrated in primary epithelial enteroid systems
Author(s) -
Verseijden Caroline,
Schilderink Ronald,
Lambers Tim,
Tol Eric,
Jonge wouter
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.847.1
Subject(s) - butyrate , retinoic acid , downregulation and upregulation , microbiology and biotechnology , lgr5 , wnt signaling pathway , biology , butyric acid , short chain fatty acid , tretinoin , chemistry , biochemistry , signal transduction , fermentation , gene
Reduced levels of the short chain fatty acid (SCFA) butyrate are associated with microbial dysbiosis and disease development. Butyrate serves as main energy source in colonocytes and is purported to exert anti‐inflammatory effects. Using enteroid cultures for primary intestinal epithelia, we studied effects of butyrate on the production of retinoic acid (RA) as intestinal epithelia dictate homeostasis and immune tolerance by stimulating tolerogenic CD103+DCs through release of RA. Retinal dehydrogenases (aldha1a1 and aldh1a3) are gatekeeping enzymes for retinoic acid production. Mouse CMT93, human CACO2 epithelial cell lines, and mouse intestinal enteroids were incubated with SCFA and analyzed for RA metabolic enzyme expression, stemness, and maturation markers. Functional RA conversion was analyzed by Aldefluor activity assays. Butyrate (0‐5mM) dose dependently induced aldh1a1 and ‐3 expression in CACO2 and CMT93 cells (up to 10‐30 fold at 5mM for aldh1a1 and ‐3 resp.) coinciding with increased functional conversion of retinol to RA. Moreover, in enteroids butyrate (2‐5mM) upregulated aldh1a3 expression 50 fold over control. RA receptor alpha was upregulated two‐fold, indicating enhanced RA signaling. Butyrate (2‐5mM) reduced stemness marker (LGR5, OLMF4) expression but upregulated Wnt target genes (CD44, ASCL2, CDKN1), indicating that enhanced RA conversion did not reflect dedifferentiation. We conclude butyrate can support epithelial conversion of dietary retinoic acid thereby enhancing the capacity to generate tolerogenic DCs and drive immune tolerance in the gut.