Dietary inhibitors of histone deacetylases in intestinal immunity and homeostasis

Abstract

Intestinal epithelial cells (IECs) are integral players in homeostasis of immunity and host defense in the gut and are under influence of the intestinal microbiome. Microbial metabolites and dietary components, including short chain fatty acids (acetate, propionate, and butyrate, SCFAs), have an impact on the physiology of IECs at multiple levels, including the inhibition of deacetylases affecting chromatin remodeling and global changes in transcriptional activity. The number and diversity of butyrate-producing bacteria is subject to factors related to age, disease, and to diet. At physiological levels, SCFAs are inhibitors of histone deacetylases (HDACs) which may explain the transcriptional effects of SCFAs on epithelial cells, although many effects of SCFAs on colonic mucosa can be ascribed to mechanisms beyond HDAC inhibition. Interference with this type of post-translational modification has great potential in cancer and different inflammatory diseases, because HDAC inhibition has anti-proliferative and anti-inflammatory effects in vitro, and in in vivo models of intestinal inflammation. Hence, the influence of dietary modulators on HDAC activity in epithelia is likely to be an important determinant of its responses to inflammatory and microbial challenges.

Keywords: HDAC; butyrate; inflammatory bowel diseases; intestinal epithelium; short chain fatty acids.

Figure 1

The effects of SCFA butyrate on epithelial cell responses in Caco-2 enterocyte-like cells. Cells were stimulated with 10 ng/mL of ILlb and tested against indicated butyrate concentrations added simultaneously. Expression levels of IL-8, and CCL2, were measured after 24 h treatment. Butyrate modulates the epithelial responses to cytokines at relevant concentrations. Tytgat Institute, 2013.

Figure 2

Intestinal SCFA receptors and transporters. SCFAs are taken up by the epithelial cells by diffusion, H⁺ coupled transport by monocarboxylate transporters (MCT) or by Na⁺ coupled transport by SLC5A8. Other receptors that are activated by SCFA are localized on colonocytes, peptide YY expressing enteroendocrine cells, or different immune cells. Receptor FFAR2 is involved in neutrophil chemotaxis toward sources of SCFA.