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

Nanda Burger-van Paassen , Audrey Vincent , Patrycja J Puiman , Maria van Der Sluis , Janneke Bouma , Günther Boehm , Johannes B van Goudoever , Isabelle van Seuningen , Ingrid B Renes (1)

1 Laboratory of Pediatrics, Division of Neonatology

Short chain fatty acids (SCFAs), 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. Our aim was to study the mechanisms that regulate butyrate-mediated effects on MUC2 synthesis. Human goblet cell-like LS174T cells were treated with SCFAs, after which MUC2 mRNA levels and stability and MUC2 protein expression were analyzed. SCFA-responsive regions and cis-elements within the MUC2 promoter were identified by transfection and gel shift assays. Effects of butyrate on histone H3/H4 status at the MUC2 promoter were established by chromatin immunoprecipitation. One mM butyrate as well as propionate induced an increase in MUC2 mRNA levels. MUC2 mRNA levels returned to basal levels after incubation with 5-15 mM of butyrate. Interestingly, this decrease was not due to loss of RNA stability. In contrast, at concentrations of 5-15 mM of propionate MUC2 mRNA levels remained increased. Promoter regulation studies revealed an active butyrate-responsive region at -947/-371 within the MUC2 promoter. In this region we identified an active AP1 (c-Fos/c-Jun) cis-element at –818/-808 that mediates butyrate-induced activation of the promoter. Finally, MUC2 regulation by butyrate at 10-15 mM was associated with increased acetylation of histone H3 and H4 and methylation of H3 at the MUC2 promoter. In conclusion, 1 mM of butyrate and 1-15 mM of propionate increase MUC2 expression. The effects of butyrate on MUC2 mRNA are mediated via AP-1 and acetylation/methylation of histones at the MUC2 promoter.

Mots clés: Life Sciences

Nanda Burger-van Paassen, Audrey Vincent, Patrycja J Puiman, Maria van Der Sluis, Janneke Bouma, et al.. The regulation of the intestinal mucin MUC2 expression by short chain fatty acids: implications for epithelial protection. Biochemical Journal, 2009, 420 (2), pp.211-219. ⟨10.1042/BJ20082222⟩. ⟨hal-00479129⟩