Redirection of Epithelial Immune Responses by Short-Chain Fatty Acids through Inhibition of Histone Deacetylases

• Published in: Frontiers in immunology Vol. 6; p. 554
• Main Authors: Lin, May Young, de Zoete, Marcel R., van Putten, Jos P. M., Strijbis, Karin
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 03.11.2015
• Subjects: Butyrate; Flagellin; HDAC; histone acetylation; Immunology; NF-κB; Toll-Like Receptors; NF-κB; butyrate; toll-like receptors; SCFAs; flagellin; TLR5; histone acetylation; HDAC
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2015.00554

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 tumor necrosis factor α (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. 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 reprograming of cytokine/chemokine expression.