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.

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation, and reduced neuroplasticity

“…Secondary BAs are produced by gut microbiota. Moreover, gut bacteria generate butyrate via fermentation, which, in turn, increases the production of RA in the gut dendritic cells (111). Thus, WD-associated dysbiosis, accompanied by dysregulated BA synthesis in the digestive tract, likely has significant roles in cognitive health and dysfunction.…”

Oral administration of propionic acid during lactation enhances the colonic barrier function

“…The major mechanisms involves the direct inhibition of histone deacetylases (HDACs) to directly regulate gene expression [28–30] and signaling through G-protein-coupled receptors (GPCRs) [31–33]. Propionic acid was the most potent and efficacious ligand for GPCR4 [34].…”

Novel insights into microbiome in colitis and colorectal cancer

“…Using the AOM/DSS CAC mouse model, Bhattacharya et al demonstrated that atRA protects against tumorigenesis by enhancing anti-tumor CD8+ T cell response and that microbiota-induced inflammatory cytokines promote differential expression of ALDH1 and CYP26A1 as observed in patients (31*). The microbiota metabolite butyrate was recently shown to stimulate ALDH1 expression, thereby increasing atRA levels in epithelial cells (32). …”