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. 2015 Nov 6:5:16148.
doi: 10.1038/srep16148.

The effect of short-chain fatty acids on human monocyte-derived dendritic cells

Claudia Nastasi  1 , Marco Candela  2 , Charlotte Menné Bonefeld  1 , Carsten Geisler  1 , Morten Hansen  3 , Thorbjørn Krejsgaard  1 , Elena Biagi  2 , Mads Hald Andersen  3 , Patrizia Brigidi  2 , Niels Ødum  1 , Thomas Litman  4 , Anders Woetmann  1
Affiliations

The effect of short-chain fatty acids on human monocyte-derived dendritic cells

Claudia Nastasi et al. Sci Rep. .

Abstract

The gut microbiota is essential for human health and plays an important role in the pathogenesis of several diseases. Short-chain fatty acids (SCFA), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients that distribute systemically via the blood. The aim of this study was to investigate the transcriptional response of immature and LPS-matured human monocyte-derived DC to SCFA. Our data revealed distinct effects exerted by each individual SCFA on gene expression in human monocyte-derived DC, especially in the mature ones. Acetate only exerted negligible effects, while both butyrate and propionate strongly modulated gene expression in both immature and mature human monocyte-derived DC. An Ingenuity pathway analysis based on the differentially expressed genes suggested that propionate and butyrate modulate leukocyte trafficking, as SCFA strongly reduced the release of several pro-inflammatory chemokines including CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11. Additionally, butyrate and propionate inhibited the expression of lipopolysaccharide (LPS)-induced cytokines such as IL-6 and IL-12p40 showing a strong anti-inflammatory effect. This work illustrates that bacterial metabolites far from the site of their production can differentially modulate the inflammatory response and generally provides new insights into host-microbiome interactions.

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Figures

Figure 1
Figure 1. Expression of SCFA receptors by human monocyte-derived DC and primary CD141 + and CD1c + DC.
(a) qPCR for SCFAs receptors on monocyte-derived DC compared to MCF-7 cell line as internal control. Shown are the averages ± standard deviations (SD) (n = 3). (b) Flow cytometry analysis of GPR41 and GPR109A surface expression on monocyte-derived DC and (c) primary CD141 + and CD1c + DC. Mean fluorescence intensity (MFI) averages ± standard deviations (SD) (n = 3) are reported below each histogram. Gates for GPR41- or GPR190A-positive cells in both figures (b,c) has been placed according to their respective isotype control. The different shades of grey represent cells from three different donors used for the experiments.
Figure 2
Figure 2
(a) Flow cytometry DC gating and SCFA effect. The figure is representative of the gating strategy for DC for HLA-DR, CD83, and CD86 markers for both monocyte-derived im-DC and m-DC. (b) A representative example of SCFA effect on im-DC and m-DC expression of CD86 and CD83 markers by flow cytometry. (c) Effect of SCFA on DC maturation markers. Numbers calculated represented by flow cytometry indicate the mean fluorescence intensity (MFI) of each sample. Shown are the averages ± standard deviations (SD) (n = 3); Mann-Whitney U t-test, *P < 0.05.
Figure 3
Figure 3
(a) Heat-map and unsupervised hierarchical clustering based on the top 200 differentially expressed genes (DEG). (b) Principal component analysis (PCA) sample plot based on the 737 most variable genes across experiments. Primary clustering is seen according to im-/m-dendritic cells (DC). The samples are colored according to treatment with either acetate (a), propionate (P), or butyrate (b). Each dot represents one pooled sample from three donors. (c) Venn diagrams showing the number of overlapping up-(red) and down-(green) regulated genes by im-DC and m-DC after exposure to A (acetate), P (propionate), or B (butyrate).
Figure 4
Figure 4. IL6 and IL12B qPCR
((a,b) respectively) and IL-6 and IL-21p40 ELISA ((c,d) respectively) on monocyte-derived m-DC and im-DC treated with acetate, propionate, and butyrate. Shown are the averages ± standard deviations (SD) (n = 3); Mann-Whitney U t-test p values: *P ≤ 0.05; **P ≤ 0.01.
Figure 5
Figure 5. Chemokine patterns by im-DC and m-DC treated with acetate, propionate, and butyrate.
Shown are the averages ± standard deviations (SD) (n = 3); Unpaired t test with Welch’s correction, *P 
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