The Anti-inflammatory Effects of Short Chain Fatty Acids on Lipopolysaccharide- or Tumor Necrosis Factor α-Stimulated Endothelial Cells via Activation of GPR41/43 and Inhibition of HDACs

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Abstract

Background and Aim: Previously, we found that short chain fatty acids (SCFA) inhibit LPS or TNFα-induced endothelial inflammatory responses and excessive vascular cell adhesion molecule-1 (VCAM-1) expression, two important steps in the development of atherosclerosis. However, the mechanisms involved are still unclear. We hypothesized that the effects of SCFA are associated with activation of G-protein coupled receptor 41/43 (GPR41/43) and/or inhibition of histone deacetylases (HDACs).

Methods: The expression and location of GPR41/43 and HDAC3 in human umbilical vein endothelial cells (HUVEC) were confirmed. HUVEC were pre-incubated with acetate, butyrate or propionate alone or in combination with GLPG0974 (GLPG, antagonist of GPR43) or β-hydroxybutyrate (SHB, antagonist of GPR41) and then exposed to LPS or TNFα. Interleukin (IL)-6 and IL-8 levels and VCAM-1 expression were measured. HDAC activity was measured after treatment with butyrate, propionate and trichostatin A (TSA, HDAC inhibitor). The peripheral blood mononuclear cell (PBMC) adhesive level was also determined after TSA treatment.

Results: GPR41/43 were expressed on the membrane of HUVEC and HDAC3 was located in cytoplasm and nucleus. The GLPG and/or SHB treatments restored the inhibitory effects of acetate on IL-6 and IL-8 production and the inhibitory effects of butyrate or propionate on IL-6 production, but not on IL-8. In contrast, GLPG and/or SHB treatments did not affect the inhibitory effects of butyrate or propionate on TNFα-induced VCAM-1 expression. TSA showed similar effects on IL-8 production and VCAM-1 expression as butyrate and propionate. In addition, TSA significantly inhibited the adhesion of PBMC to an endothelial monolayer.

Conclusion: Activation of GPR41/43 mediates the effects of acetate on IL-6 and IL-8 production and the effects of butyrate and propionate on IL-6 production. Furthermore, inhibition of HDACs mediates the effects of butyrate and propionate on IL-8 production, VCAM-1 expression, and PBMC adhesion to an endothelial monolayer. These data indicate the beneficial roles of SCFA in preventing vascular inflammation and relevant diseases by activation of GPR41/43 and inhibition of HDACs.

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Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

Ikuo Kimura, Daisuke Inoue, Takeshi Maeda … (2011)

The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.

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Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon.

Markus Waldecker, Tanja Kautenburger, Heike Daumann … (2008)

Colorectal cancer is the most abundant cause of cancer mortality in the Western world. Nutrition and the microbial flora are considered to have a marked influence on the risk of colorectal cancer, the formation of butyrate and other short-chain fatty acids (SCFAs) possibly playing a major role as chemopreventive products of microbial fermentation in the colon. In this study, we investigated the effects of butyrate, other SCFAs, and of a number of phenolic SCFA and trans-cinnamic acid derivatives formed during the intestinal degradation of polyphenolic constituents of fruits and vegetables on global histone deacetylase (HDAC) activity in nuclear extracts from colon carcinoma cell cultures using tert-butoxycarbonyl-lysine (acetylated)-4-amino-7-methylcoumarin (Boc-Lys(Ac)-AMC) as substrate. Inhibition of HDAC activity, e.g., by butyrate, is related to a suppression of malignant transformation and a stimulation of apoptosis of precancerous colonic cells. In nuclear extracts from HT-29 human colon carcinoma cells, butyrate was found to be the most potent HDAC inhibitor (IC50=0.09 mM), while other SCFAs such as propionate were less potent. In the same assay, p-coumaric acid (IC50=0.19 mM), 3-(4-OH-phenyl)-propionate (IC50=0.62 mM) and caffeic acid (IC50=0.85 mM) were the most potent HDAC inhibitors among the polyphenol metabolites tested. Interestingly, butyrate was also the most potent HDAC inhibitor in a whole-cell HeLa Mad 38-based reporter gene assay, while all polyphenol metabolites and all other SCFAs tested were much less potent; some were completely inactive. The findings suggest that butyrate plays an outstanding role as endogenous HDAC inhibitor in the colon, and that other SCFAs and HDAC-inhibitory polyphenol metabolites present in the colon seem to play a much smaller role, probably because of their limited levels, their marked cytotoxicity and/or their limited intracellular availability.

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Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health?

Marion G. Priebe, K Meijer, Paul Vos (2010)

High-fiber diets have been shown to reduce plasma concentrations of inflammation markers. Increased production of fermentation-derived short-chain fatty acids (SCFAs) is one of the factors that could exert these positive effects. This review examines the effects of SCFAs on immune cells and discusses the relevance of their effects on systemic inflammation, as frequently seen in obesity. SCFAs have been shown to reduce chemotaxis and cell adhesion; this effect is dependent on type and concentration of SCFA. In spite of conflicting results, especially butyrate seems to have an anti-inflammatory effect, mediated by signaling pathways like nuclear factor-κB and inhibition of histone deacetylase. The discrepancies in the results could be explained by differences in cell types used and their proliferative and differentiation status. SCFAs show anti-inflammatory effects and seem to have the potency to prevent infiltration of immune cells from the bloodstream in, for example, the adipose tissue. In addition, their ability to inhibit the proliferation and activation of T cells and to prevent adhesion of antigen-presenting cells could be important as it recently has been shown that obesity-associated inflammation might be antigen-dependent. More studies with concentrations in micromolar range are needed to approach more physiological concentrations.

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Author and article information

Contributors

Meng Li: URI : http://loop.frontiersin.org/people/504471/overview

Betty C. A. M. van Esch: URI : http://loop.frontiersin.org/people/457545/overview

Paul A. J. Henricks: URI : http://loop.frontiersin.org/people/171681/overview

Gert Folkerts: URI : http://loop.frontiersin.org/people/31987/overview

Johan Garssen: URI : http://loop.frontiersin.org/people/184524/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 23 May 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 533

Affiliations

[1] ¹Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University , Utrecht, Netherlands

[2] ²Nutricia Research, Immunology , Utrecht, Netherlands

Author notes

Edited by: Annalisa Bruno, Università degli Studi “G. d’Annunzio” Chieti-Pescara, Italy

Reviewed by: Annalisa Trenti, Università degli Studi di Padova, Italy; Jiiang-Huei Jeng, National Taiwan University, Taiwan

*Correspondence: Gert Folkerts, G.Folkerts@ 123456uu.nl

This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

Article

DOI: 10.3389/fphar.2018.00533

PMC ID: 5974203

PubMed ID: 29875665

SO-VID: 30fd6775-e2b1-498f-a9e5-0c36b4df5304

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 13 March 2018

Date accepted : 02 May 2018

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Figures: 6, Tables: 0, Equations: 0, References: 47, Pages: 12, Words: 0

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The Anti-inflammatory Effects of Short Chain Fatty Acids on Lipopolysaccharide- or Tumor Necrosis Factor α-Stimulated Endothelial Cells via Activation of GPR41/43 and Inhibition of HDACs

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Most cited references 31

Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon.

Butyrate and other short-chain fatty acids as modulators of immunity: what relevance for health?

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