Redirection of epithelial immune responses by short chain fatty acids through inhibition of histone deacetylases

Abstract

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Short-Chain Fatty Acids (SCFAs) are products of microbial fermentation that are important for intestinal epithelial health. Here we describe that SCFAs have rapid and reversible effects on Toll-like receptor (TLR) responses in epithelial cells. Incubation of HEK293 or HeLa epithelial cells with the SCFAs butyrate or propionate at physiological concentrations enhanced NF-κB activation induced by TLR5, TLR2/1, TLR4 and TLR9 agonists. NF-κB activation in response to TNFα was also increased by SCFAs. Comparative transcript analysis of HT-29 colon epithelial cells revealed that SCFAs enhanced TLR5-induced transcription of TNFα but dampened or even abolished the TLR5-mediated induction of IL-8 and monocyte chemotactic protein 1 (MCP-1). SCFAs are known inhibitors of histone deacetylases (HDACs). Butyrate or propionate caused a rapid increase in histone acetylation in epithelial cells, similar to the small molecule HDAC inhibitor Trichostatin A (TSA). TSA also mimicked the effects of SCFAs on TLR-NF-κB responses. This study shows that bacterial SCFAs rapidly alter the epigenetic state of host cells resulting in redirection of the innate immune response and selective reprogramming of cytokine/chemokine expression.

Keywords

• Flagellin
• Toll-Like Receptors
• NF-κB
• histone acetylation
• Butyrate
• HDAC