Short-Chain Fatty Acids Promote Intracellular Bactericidal Activity in Head Kidney Macrophages From Turbot (Scophthalmus maximus L.) via Hypoxia Inducible Factor-1α

Short-chain fatty acids (SCFAs) are mainly produced by microbiota through the fermentation of carbohydrates in the intestine. Acetate, propionate, and butyrate are the most abundant SCFA metabolites and have been shown to be important in the maintenance of host health. In this study, head kidney macrophages (HKMs) were isolated and cultured from turbots. We found that the antibacterial activity of HKMs was increased after these cells were incubated with sodium butyrate, sodium propionate or sodium acetate. Interestingly, our results showed that all three SCFAs enhanced the expression of hypoxia inducible factor-1 α (HIF-1α) in HKMs, and further study confirmed that butyrate augmented the oxygen consumption of these cells. Moreover, HIF-1α inhibition diminished the butyrate-promoted intracellular bacterial killing activity of macrophages, and SCFAs also raised the gene expression and activity of lysozymes in HKMs via HIF-1α signaling. In addition, our results suggested that butyrate induced HIF-1α expression and the bactericidal activity of HKMs through histone deacetylase inhibition, while G protein-coupled receptors did not contribute to this effect. Finally, we demonstrated that butyrate induced a similar response in the murine macrophage cell line RAW264.7. In conclusion, our results demonstrated that SCFAs promoted HIF-1α expression via histone deacetylase inhibition, leading to the enhanced production of antibacterial effectors and increased bacterial killing of macrophages.

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154 – Gut Microbe-Produced Short Chain Fatty Acids Entrain Circadian Rhythms in Murine Enteroids by Histone Deacetylase Inhibition

Gastroenterology ◽

10.1016/s0016-5085(19)36867-2 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-36

Author(s):

Jibraan A. Fawad ◽

Deborah Luzader ◽

Thomas J. Moutinho ◽

Paul Mitchell ◽

Kathleen Brown-Steinke ◽

...

Keyword(s):

Fatty Acids ◽

Circadian Rhythms ◽

Histone Deacetylase ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Histone Deacetylase Inhibition ◽

Gut Microbe ◽

Chain Fatty Acids

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Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity

Nature Communications ◽

10.1038/s41467-020-18262-6 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Wenjing Yang ◽

Tianming Yu ◽

Xiangsheng Huang ◽

Anthony J. Bilotta ◽

Leiqi Xu ◽

...

Keyword(s):

Fatty Acids ◽

T Cells ◽

Immune Cell ◽

Hypoxia Inducible Factor ◽

Short Chain Fatty Acids ◽

Lymphoid Cells ◽

Short Chain ◽

Intestinal Immunity ◽

Protein Receptor ◽

Chain Fatty Acids

Abstract Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.

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Histone Deacetylase Inhibition and Dietary Short-Chain Fatty Acids

ISRN Allergy ◽

10.5402/2011/869647 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 29

Author(s):

Paul V. Licciardi ◽

Katherine Ververis ◽

Tom C. Karagiannis

Keyword(s):

Fatty Acids ◽

Histone Deacetylase ◽

Biological Effects ◽

Short Chain Fatty Acids ◽

Dietary Factors ◽

Short Chain ◽

Dietary Interventions ◽

Important Relationship ◽

Health And Disease ◽

Chain Fatty Acids

Changes in diet can also have dramatic effects on the composition of gut microbiota. Commensal bacteria of the gastrointestinal tract are critical regulators of health and disease by protecting against pathogen encounter whilst also maintaining immune tolerance to certain allergens. Moreover, consumption of fibre and vegetables typical of a non-Western diet generates substantial quantities of short-chain fatty acids (SCFAs) which have potent anti-inflammatory properties. Dietary interventions such as probiotic supplementation have been investigated for their pleiotropic effects on microbiota composition and immune function. Probiotics may restore intestinal dysbiosis and improve clinical disease through elevated SCFA levels in the intestine. Although the precise mechanisms by which such dietary factors mediate these effects, SCFA metabolites such as butyrate also function as histone deacetylase inhibitors (HDACi), that can act on the epigenome through chromatin remodeling changes. The aim of this review is to provide an overview of HDAC enzymes and to discuss the biological effects of HDACi. Further, we discuss the important relationship between diet and the balance between health and disease and how novel dietary interventions such as probiotics could be alternative approach for the prevention and/or treatment of chronic inflammatory disease through modulation of the intestinal microbiome.

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Zn2+-Chelating Motif-Tethered Short-Chain Fatty Acids as a Novel Class of Histone Deacetylase Inhibitors

Journal of Medicinal Chemistry ◽

10.1021/jm0303655 ◽

2004 ◽

Vol 47 (2) ◽

pp. 467-474 ◽

Cited By ~ 77

Author(s):

Qiang Lu ◽

Ya-Ting Yang ◽

Chang-Shi Chen ◽

Melanie Davis ◽

John C. Byrd ◽

...

Keyword(s):

Fatty Acids ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Chain Fatty Acids

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P021 The influence of short-chain fatty acids produced by commensal bacteria on macrophage phenotype

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.150 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S141-S142 ◽

Cited By ~ 1

Author(s):

C Jukes ◽

L Ricci ◽

E von Coburg ◽

M Nasr ◽

A W Walker ◽

...

Keyword(s):

Fatty Acids ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Intracellular Bacteria ◽

Macrophage Phenotype ◽

Bacterial Isolates ◽

Bacterial Killing ◽

Wide Range ◽

Chain Fatty Acids

Abstract Background Macrophages are dynamic immune cells that react to environmental signals to adapt to their environment. Among this diverse array of signals are multiple bacterially derived metabolites including short-chain fatty acids (SCFAs) in the gastrointestinal tract. It has been previously shown that butyrate, one of several SCFAs produced by bacteria, is able to drive an antimicrobial phenotype in macrophages. However, it is still unknown which bacterial species are able to drive this impact and whether this effect can be recapitulated in vivo. The identification of a common molecular signature that drives this phenotype may allow us to easily identify bacteria with this beneficial phenotype and give insight into potential therapeutic strains. Methods Monocytes were differentiated into macrophages in the presence of SFCAs or bacterial supernatants from a wide range of gut commensals isolated from healthy human donors. RNA was isolated post-differentiation and gene expression screened using a defined gene panel using the Fluidgm Biomark system. In addition, cytokines present in the supernatant were measured by ELISA and the ability of the macrophages to kill intracellular bacteria determined. Currently, we are carrying out the same procedure using bone marrow-derived macrophages (BMDM) from mice in order to expand this work flow into the mouse system so that we can determine if bacteria identified can elicit their impact in vivo. Results We have screened numerous SCFAs alone and in combination in the bacterial killing assay to determine how these are able to influence macrophage phenotype. From these experiments, we have repeated the earlier observation that butyrate can increase macrophage killing of intracellular bacteria. In addition, we have identified four bacterial isolates that induce significantly increased microbial killing in macrophages. This is associated with the production of butyrate, acetate and formate. Using RNA from these different conditions, we are in the process of determining if there is a common molecular pathway by which this increased antimicrobial phenotype is driven. Conclusion Both SCFAs and SCFA producing bacteria are able to induce an antimicrobial phenotype in macrophages that increased the ability of these cells to kill intracellular pathogens. Identification of a common signature that drives these changes could help to screen bacterial isolates for this beneficial trait. Ongoing work hopes to identify such a signature, to enable us to screen large numbers of commensals using high-throughput molecular methods. This can then be verified using both in vitro and in vivo techniques.

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

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2007.08.002 ◽

2008 ◽

Vol 19 (9) ◽

pp. 587-593 ◽

Cited By ~ 267

Author(s):

Markus Waldecker ◽

Tanja Kautenburger ◽

Heike Daumann ◽

Cordula Busch ◽

Dieter Schrenk

Keyword(s):

Fatty Acids ◽

Histone Deacetylase ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Chain Fatty Acids

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CML Blasts Modify the Acetylation Pattern of Non Histone Proteins after Short Chain Fatty Acid Histone Deacetylase Inhibitor Treatment.

Blood ◽

10.1182/blood.v106.11.2884.2884 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2884-2884 ◽

Cited By ~ 1

Author(s):

Roberta Pastorelli ◽

Germano Ferrari ◽

Antonella Gozzini ◽

Donatella Tombaccini ◽

Valeria Santini ◽

...

Keyword(s):

Fatty Acids ◽

Valproic Acid ◽

Western Blot ◽

Histone Deacetylase ◽

Short Chain Fatty Acids ◽

Drug Binding ◽

Short Chain ◽

Histone Proteins ◽

Imatinib Resistant ◽

Chain Fatty Acids

Abstract Imatinib is an effective therapy for chronic phase CML, but patients may became irresponsive due to the development of resistance, caused by amplification of the BCR-ABL genomic locus or by point mutations within the kinase domain of BCR-ABL, which prevents drug binding. Novel dual SRC/ABL kinase inhibitors with higher potency against native and imatinib-resistant mutants of BCR-ABL have substantial clinical utility, but at least one mutation remains resistant to any kinase inhibitor (T315I). Thus, the search for alternative drugs effective in CML is still cogent. Treatment of CML cells with histone deacetylase inhibitors (HDIs) of the class of hydroxamic acid analogues promotes proteasomal degradation of Bcr-Abl, associated with apoptosis, in synergy with imatinib. We evaluated whether HDIs of other classes, namely short chain fatty acids like butyrates and valproic acid, could exert the same effects and we intended to dissect the determining molecular mechanisms. The human CML cell lines K562, KBM, LAMA-84 S and LAMA-84 R and primary imatinib-resistant CML-BC cells were grown in the presence of valproic acid (VPA) at the escalating doses 0.2 mM to 2mM or the mannose ester of butyric acid D1 (0.2–1mM) for 24 and 48 hrs. Apoptosis was induced in a time and dose dependent manner by VPA and D1 (annexin V test and flow cytometric analysis after propidium iodide uptake). Imatinib was synergistic with both HDIs in inducing apoptosis and cell proliferation arrest (MTT-assay). VPA and D1 were able to induce after 48 hrs of incubation a significant decrease in the number of copies of BCR-ABL determined by real time-PCR, paralleled by a substantial decrease in Bcr-Abl protein expression, shown in western blots of total cell lysates from CML cells. This decrease in the expression of protein kinase could account for the synergy with imatinib, but also for the reversal of resistance in mutated Bcr-Abl CML cells and is consistent with what previously observed. We also analysed the expression of Hsp-90 (protein chaperone of Bcr-Abl) and found it quantitatively unmodified but hyperacetylated by the treatment with both HDIs. As little is known of the ability of short chain fatty acids to induce acetylation of non-histone proteins, we compared the acetylated proteome of CML cells treated and not treated with HDIs, alone and in combination with imatinib, by 2D western blot versus a pan-acetylated antibody, followed by MALDI-TOF mass spectrometry for protein identification. 22 proteins were positively identified with a high degree of confidence, with the majority of these being cytoplasmic. At least two chaperone proteins were identified as target of acetylation after VPA and D1 treatment of CML cells, other targets were proteins involved in the synthesis and stability of RNA. Phosphorylation of proteins, evaluated by 2D western blot, was not significantly affected by HDIs. Short chain fatty acids are indeed not the most potent HDIs, but have been used successfully in clinical trials. Our observations contribute to the dissection of proteome modifications by HDIs and may help extrapolate the molecular effects of different HDIs on CML cells so to improve their use as single drugs or in combination with imatinib or new SRC/ABL inhibitors.

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