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

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

doi:10.1038/srep16148

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.

Highlights

System at even lower concentrations[10]
To determine the expression pattern of Short-chain fatty acids (SCFA) receptors on human monocyte-derived dendritic cells (DC), we performed qPCR assays for the main SCFA receptors genes such as GPR43, GPR41, and GPR109A
One largely used mechanism is via metabolite-sensing G-protein-coupled receptors (GPCRs) such as, GPR43, GPR41, and GPR109A, all of which can act as receptors, with different specificity and affinity, for SCFA16,18,20,21,30

Summary

Introduction

System at even lower concentrations[10]. Experiments carried out on mice models allowed dissection of the multifactorial role of these metabolites on the host immunological phenotype. The major GPCRs activated by SCFA are GPR43 (FFAR2) and GPR41 (FFAR3), and GPR109A (HCAR2) for both murine and human immune cells[16,17,18,19,20,21]. Propionate was shown to affect mouse dendritic cells (DC) and macrophage biology in the bone marrow and affect T helper 2 (Th2) cell responses in the airway[22] confirming the important role of SCFA on the mouse immune system. The aim of this study was to investigate the gene transcription modulation by Affymetrix GeneChip and potential pathways in human immature and mature human monocyte-derived DC after exposure to acetate, butyrate, or propionate. The results revealed distinct transcriptional responses elicited by these bacterial metabolites indicating that butyrate and propionate exerts important immunomodulatory roles by down-regulating genes involved in inflammation and immune cell trafficking

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