title: Redirection of Epithelial Immune Responses by Short-Chain Fatty Acids through Inhibition of Histone Deacetylases.
abstract: 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.
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University , Utrecht , Netherlands.
authors.forename: May Young
authors.initials: MY
authors.lastname: Lin
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University , Utrecht , Netherlands.
authors.forename: Marcel R
authors.initials: MR
authors.lastname: de Zoete
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University , Utrecht , Netherlands.
authors.forename: Jos P M
authors.initials: JP
authors.lastname: van Putten
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University , Utrecht , Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Strijbis
keywords: HDAC; NF-κB; SCFAs; TLR5; butyrate; flagellin; histone acetylation; toll-like receptors