The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection

SCFAs (short-chain fatty acids). fermentation products of bacteria, influence epithelial-Specific gene expression. We hypothesize that SCFAs affect goblet-cell-specific mucin MUC2 expression and thereby alter epithelial protection. In the present study, our aim was to investigate the mechanisms that regulate butyrate-mediated effects oil MUC2 synthesis. Human goblet cell-like LS174T cells were treated with SCFAs, after which MUC2 mRNA levels and stability, and MUC2 protein expression were analysed. SCFA-responsive regions and cis-elements within the MUC2 promoter were identified by transfection and gel-shift assays. The effects elf butyrate on historic H3/H4 status at the MUC2 promoter were established by chromatin immunoprecipitation. Butyrate (at 1mM), as well as propionate, induced an increase in MUC2 mRNA levels. MUC2 mRNA levels returned to basal levels after incubation with 5-15 mM butyrate. Interestingly, this decrease was not due to loss of RNA stability. In contrast, at concentrations of 5-15 mM propionate, MUC2 mRNA levels remained increased. Promoter-regulation studies revealed active butyrate-responsive region at -947/-371 within the, an MUC2 promoter. In this region we identified an active API (c-Fos/c-Jun) cis-element at -818/-808 that mediates butyrateinduced activation of the promoter. Finally, MUC2 regulation by butyrate at 10-15 mM was associated with increased acetylation of historic H3 and H4 and methylation of H3 at the MUC2 promoter. Ill Conclusion, 1mM butyrate and 1-15 mM propionate increase MUC2 expression. The effects of butyrate oil MUC2 mRNA are mediated via AP-1 and acetylation/methylation of histories at the MUC2 promoter.