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.
Highlights
The intestinal microbiota is essential for fermentation of complex carbohydrates
Cells were transfected with the TLR5 gene and an NF-κB dependent luciferase reporter construct and incubated with 10 mM butyrate or propionate for 30 min followed by stimulation with the TLR5 agonist flagellin for 5 h
The modulatory effect of the short-chain fatty acids (SCFA) was accompanied by a change in histone acetylation and could be mimicked by the known histone deacetylase (HDAC) inhibitor trichostatin A (TSA)
Summary
As a result of this process, the microbiota produces a multitude of metabolites that can cross the mucus barrier and exert local and systemic regulatory functions. Such metabolites have been shown to play a role in the development of inflammatory bowel diseases (IBD) and even impact brain function [1]. One group of bacterial metabolites with pleiotropic effects on host immune and energy state are short-chain fatty acids (SCFAs). SCFAs are the major end products of bacterial degradation of soluble fiber in the large intestine, with acetate (C2), propionate (C3), and butyrate (C4) as the main SCFAs produced during carbohydrate and amino acid fermentation [2]. The major butyrate-producing bacteria are a phylogenetically diverse group of Gram-positive
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