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

Abstract

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 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 analysed. SCFA-responsive regions and cis-elements within the MUC2 promoter were identified by transfection and gel-shift assays. The effects of butyrate on histone H3/H4 status at the MUC2 promoter were established by chromatin immunoprecipitation. Butyrate (at 1 mM), 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 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 butyrate and 1-15 mM 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.

Ketogenesis contributes to intestinal cell differentiation

“…Treatment with butyrate, an HDAC inhibitor, induces differentiation as noted by the increased expression of intestinal alkaline phosphatase (IAP), an enterocyte differentiation marker, and Mucin2 (MUC2), a goblet cell differentiation marker in LS174T cells. 26,27 We have shown that βHB inhibits HDAC in Caco-2 cells. To determine whether βHB also increases goblet cell differentiation, we treated LS174T cells with βHB.…”

Streptozotocin-induced type-1-diabetes disease onset in Sprague–Dawley rats is associated with an altered intestinal microbiota composition and decreased diversity

“…Lactic acid producers such as Lactobacillus, Lactococcus, Bifidobacterium and Streptococcus were higher in the faeces of children pre-diagnosed with autoimmune diabetes (Brown et al, 2011). The fate of lactate is crucial in determining intestinal health as conversion to butyrate results in mucin synthesis (Barcelo et al, 2000;Burger-van Paassen et al, 2009;Finnie et al, 1995;Shimotoyodome et al, 2000) and tighter junctions (Peng et al, 2007(Peng et al, , 2009, while conversion to other SCFA, such as propionate and acetate does not induce mucin synthesis (Brown et al, 2011). Mucin is a glycoprotein made by the host that maintains the integrity of intestinal epithelium (Brown et al, 2011).…”

Peptides: Production, bioactivity, functionality, and applications

“…In healthy mammas, there is a dynamic balance between mucin release by goblet cells and mucin loss through physical and proteolytic processes (Mart ınez-Maqueda et al, 2013a, b). In addition to internal factors such as hormones and cytokines, dietary regulation of mucin secretion has also been mentioned (Morel et al, 2003;Burger-van et al, 2009;Moughan et al, 2013).…”