In the intestinal mucosa, retinoic acid (RA) is a critical signalling molecule to maintain immune tolerance. RA is derived from dietary vitamin A (retinol) through conversion by aldehyde dehydrogenases (aldh). Reduced levels of short-chain fatty acids (SCFA) are associated with pathological microbial dysbiosis, inflammatory disease, and allergy. We hypothesized that SCFA contribute to mucosal homeostasis by enhancing RA production in intestinal epithelia. Using human and mouse epithelial cell lines, and primary enteroids, we studied the effect of SCFA on the production of RA. Functional RA conversion was analysed by Aldefluor activity assays. Butyrate (0-5mM), in contrast to other SCFA, dose dependently affected cyto- and chemokine production, and induced aldh1a1 and aldh1a3 transcript expression in epithelial cells. We functionally validated that butyrate increased conversion to RA. Epithelial cell line data were replicated in mouse enteroid culture systems. In these enteroids, butyrate (2-5mM) upregulated aldh1a3 expression (50 fold over control), whereas aldh1a1 was not significantly affected. Butyrate enhanced maturation markers (muc2 and villin) but did not affect stemness markers or other Wnt target genes (lgr5, olfm4, CD44, ascl2, cdkn1). The stimulation of RA production by SCFA was mimicked by inhibition of HDAC, rather than by agonists of butyrate receptors GPR43 or GPR109a, suggesting that butyrate stimulates RA production via class I HDAC inhibition.
- Short-chain fatty acids
- retinoic acid
- immune tolerance
- epithelial cells
- Copyright © 2015, American Journal of Physiology- Gastrointestinal and Liver Physiology