Effects of short-chain fatty acids in inhibiting HDAC and activating p38 MAPK are critical for promoting B10 cell generation and function

AbstractB10 cells are regulatory B cells capable of producing IL-10 for maintaining immune homeostasis. Dysregulation of B10 cells occurs in autoimmune and inflammatory diseases. Modulation or adoptive transfer of B10 cells is a promising therapeutic strategy. The short-chain fatty acids (SCFAs), the metabolites of microbiota, play a critical role in maintaining immune homeostasis and are the potential drugs for the modulation of B10 cells. It is not clear whether and how SCFAs upregulate the frequency of B10 cells. Here, we found that SCFAs could promote murine and human B10 cell generation in vitro. Upregulation of B10 cells by butyrate or pentanoate was also observed in either healthy mice, mice with dextran sodium sulfate (DSS)-induced colitis, or mice with collagen-induced arthritis. Moreover, SCFA treatment could ameliorate clinical scores of colitis and arthritis. Adoptive transfer of B cells pretreated with butyrate showed more alleviation of DSS-induced colitis than those without butyrate. A further study demonstrates that SCFAs upregulate B10 cells in a manner dependent on their histone deacetylase (HDAC) inhibitory activity and independent of the G-protein-coupled receptor pathway. Transcriptomic analysis indicated that the MAPK signaling pathway was enriched in B10 cells treated with butyrate. A study with inhibitors of ERK, JNK, and p38 MAPK demonstrated that activating p38 MAPK by butyrate is critical for the upregulation of B10 cells. Moreover, HDAC inhibitor has similar effects on B10 cells. Our study sheds light on the mechanism underlying B10 cell differentiation and function and provides a potential therapeutic strategy with SCFAs and HDAC inhibitors for inflammation and autoimmune diseases.

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B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber-derived short-chain fatty acids

Nature Communications ◽

10.1038/s41467-019-13603-6 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 24

Author(s):

Helia N. Sanchez ◽

Justin B. Moroney ◽

Huoqun Gan ◽

Tian Shen ◽

John L. Im ◽

...

Keyword(s):

Fatty Acids ◽

B Cells ◽

B Cell ◽

Dna Recombination ◽

Short Chain Fatty Acids ◽

Histone Deacetylation ◽

Antibody Responses ◽

Short Chain ◽

Autoantibody Production ◽

Chain Fatty Acids

AbstractShort-chain fatty acids (SCFAs) butyrate and propionate are metabolites from dietary fiber's fermentation by gut microbiota that can affect differentiation or functions of T cells, macrophages and dendritic cells. We show here that at low doses these SCFAs directly impact B cell intrinsic functions to moderately enhance class-switch DNA recombination (CSR), while decreasing at higher doses over a broad physiological range, AID and Blimp1 expression, CSR, somatic hypermutation and plasma cell differentiation. In human and mouse B cells, butyrate and propionate decrease B cell Aicda and Prdm1 by upregulating select miRNAs that target Aicda and Prdm1 mRNA-3′UTRs through inhibition of histone deacetylation (HDAC) of those miRNA host genes. By acting as HDAC inhibitors, not as energy substrates or through GPR-engagement signaling in these B cell-intrinsic processes, these SCFAs impair intestinal and systemic T-dependent and T-independent antibody responses. Their epigenetic impact on B cells extends to inhibition of autoantibody production and autoimmunity in mouse lupus models.

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Conserved Polar Residues in Transmembrane Domains V, VI, and VII of Free Fatty Acid Receptor 2 and Free Fatty Acid Receptor 3 Are Required for the Binding and Function of Short Chain Fatty Acids

Journal of Biological Chemistry ◽

10.1074/jbc.m805601200 ◽

2008 ◽

Vol 283 (47) ◽

pp. 32913-32924 ◽

Cited By ~ 69

Author(s):

Leigh A. Stoddart ◽

Nicola J. Smith ◽

Laura Jenkins ◽

Andrew J. Brown ◽

Graeme Milligan

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Free Fatty Acid ◽

Short Chain Fatty Acids ◽

Transmembrane Domains ◽

Short Chain ◽

Acid Receptor ◽

Free Fatty Acid Receptor ◽

And Function ◽

Fatty Acid Receptor

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Dietary lipids, gut microbiota and lipid metabolism

Reviews in Endocrine and Metabolic Disorders ◽

10.1007/s11154-019-09512-0 ◽

2019 ◽

Vol 20 (4) ◽

pp. 461-472 ◽

Cited By ~ 40

Author(s):

Marc Schoeler ◽

Robert Caesar

Keyword(s):

Fatty Acids ◽

Lipid Metabolism ◽

Liver Disease ◽

Gut Microbiota ◽

Short Chain Fatty Acids ◽

Dietary Lipids ◽

Lipid Levels ◽

And Function ◽

Host Metabolism ◽

Secondary Bile Acids

Abstract The gut microbiota is a central regulator of host metabolism. The composition and function of the gut microbiota is dynamic and affected by diet properties such as the amount and composition of lipids. Hence, dietary lipids may influence host physiology through interaction with the gut microbiota. Lipids affect the gut microbiota both as substrates for bacterial metabolic processes, and by inhibiting bacterial growth by toxic influence. The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans. Furthermore, diseases linked to dyslipidemia, such as non-alcoholic liver disease and atherosclerosis, are associated with changes in gut microbiota profile. The influence of the gut microbiota on host lipid metabolism may be mediated through metabolites produced by the gut microbiota such as short-chain fatty acids, secondary bile acids and trimethylamine and by pro-inflammatory bacterially derived factors such as lipopolysaccharide. Here we will review the association between gut microbiota, dietary lipids and lipid metabolism

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Short-Chain Fatty Acids

10.32545/encyclopedia202005.0006.v2 ◽

2020 ◽

Author(s):

Paulina Markowiak-Kopeć ◽

Katarzyna Śliżewska

Keyword(s):

Fatty Acids ◽

Volatile Fatty Acids ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Intestinal Microbiome ◽

Test Results ◽

And Function ◽

The Relationship ◽

Normal Health ◽

Chain Fatty Acids

The relationship between diet and the diversity and function of the intestinal microbiomeand its importance for human health is currently the subject of many studies. The type and proportionof microorganisms found in the intestines can determine the energy balance of the host. Intestinalmicroorganisms perform many important functions, one of which is participation in metabolicprocesses, e.g., in the production of short-chain fatty acids—SCFAs (also called volatile fatty acids).These acids represent the main carbon flow from the diet to the host microbiome. Maintainingintestinal balance is necessary to maintain the host’s normal health and prevent many diseases.The results of many studies confirm the beneficial effect of probiotic microorganisms on the balanceof the intestinal microbiome and produced metabolites, including SCFAs. The aim of this review is tosummarize what is known on the effects of probiotics on the production of short-chain fatty acidsby gut microbes. In addition, the mechanism of formation and properties of these metabolites isdiscussed and verified test results confirming the effectiveness of probiotics in human nutrition bymodulating SCFAs production by intestinal microbiome is presented.

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Metformin Affects Gut Microbiome Composition and Function and Circulating Short-Chain Fatty Acids: A Randomized Trial

Diabetes Care ◽

10.2337/dc20-2257 ◽

2021 ◽

pp. dc202257

Author(s):

Noel T. Mueller ◽

Moira K. Differding ◽

Mingyu Zhang ◽

Nisa M. Maruthur ◽

Stephen P. Juraschek ◽

...

Keyword(s):

Fatty Acids ◽

Randomized Trial ◽

Gut Microbiome ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Microbiome Composition ◽

And Function ◽

Chain Fatty Acids

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Perturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation

Mucosal Immunology ◽

10.1038/s41385-020-0296-4 ◽

2020 ◽

Vol 14 (1) ◽

pp. 113-124 ◽

Cited By ~ 6

Author(s):

Aida Iljazovic ◽

Urmi Roy ◽

Eric J. C. Gálvez ◽

Till R. Lesker ◽

Bei Zhao ◽

...

Keyword(s):

Fatty Acids ◽

Steady State ◽

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Short Chain Fatty Acids ◽

Host Susceptibility ◽

Mucosal Inflammation ◽

Microbial Ecosystem ◽

Systemic Autoimmunity ◽

And Function

AbstractDiverse microbial signatures within the intestinal microbiota have been associated with intestinal and systemic inflammatory diseases, but whether these candidate microbes actively modulate host phenotypes or passively expand within the altered microbial ecosystem is frequently not known. Here we demonstrate that colonization of mice with a member of the genus Prevotella, which has been previously associated to colitis in mice, exacerbates intestinal inflammation. Our analysis revealed that Prevotella intestinalis alters composition and function of the ecosystem resulting in a reduction of short-chain fatty acids, specifically acetate, and consequently a decrease in intestinal IL-18 levels during steady state. Supplementation of IL-18 to Prevotella-colonized mice was sufficient to reduce intestinal inflammation. Hence, we conclude that intestinal Prevotella colonization results in metabolic changes in the microbiota, which reduce IL-18 production and consequently exacerbate intestinal inflammation, and potential systemic autoimmunity.

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Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function

Nature Metabolism ◽

10.1038/s42255-020-0188-7 ◽

2020 ◽

Vol 2 (9) ◽

pp. 840-848 ◽

Cited By ~ 6

Author(s):

James Frampton ◽

Kevin G. Murphy ◽

Gary Frost ◽

Edward S. Chambers

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Muscle Metabolism ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Skeletal Muscle Metabolism ◽

And Function ◽

Chain Fatty Acids

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Short-chain fatty acids increase TNFα-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAPK

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00306.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. L157-L174 ◽

Cited By ~ 7

Author(s):

Sandra Rutting ◽

Dia Xenaki ◽

Monique Malouf ◽

Jay C. Horvat ◽

Lisa G. Wood ◽

...

Keyword(s):

Fatty Acids ◽

P38 Mapk ◽

Human Lung ◽

Short Chain Fatty Acids ◽

Mapk Signaling ◽

Mesenchymal Cells ◽

Short Chain ◽

Lung Fibroblasts ◽

Anti Inflammatory ◽

Chain Fatty Acids

Short-chain fatty acids (SCFAs), produced as by-products of dietary fiber metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against tumor necrosis factor (TNF)α-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0), and butyrate (C4:0) (0.01–25 mM) with or without TNFα, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNFα-induced cytokine release. On the contrary, challenge with supraphysiological concentrations (10–25 mM), as might be used therapeutically, of propionate or butyrate in combination with TNFα resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFα alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNFα-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signaling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAPK signaling. This study demonstrates that proinflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells.

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Three main short-chain fatty acids inhibit the activation of THP-1 cells by Mycoplasma pneumoniae

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbaa110 ◽

2020 ◽

Author(s):

Xia Wen ◽

Dai Xiaoyue ◽

Ding Longkun ◽

Xi Yue ◽

Yan Man ◽

...

Keyword(s):

Fatty Acids ◽

Mycoplasma Pneumoniae ◽

Therapeutic Strategy ◽

Inflammatory Diseases ◽

Cell Activity ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Chronic Inflammatory Diseases ◽

Ifn Γ ◽

Chain Fatty Acids

ABSTRACT The overactivation of macrophages causes chronic inflammatory diseases. Short-chain fatty acids (SCFAs), potential drugs for clinical treatment, are modulators of macrophage inflammatory reaction. Therefore, the modulation of macrophage-mediated cell activity is expected to become a new therapeutic strategy for inflammatory diseases caused by Mycoplasma pneumoniae. In this study, 2 kinds of SCFAs (propionate and butyrate) were found to have anti-inflammatory effects in M. pneumoniae-stimulated THP-1 cells inflammatory. They inhibited the expressions of IL-4, IL-6, ROS, and NLRP3 inflammasome, while enhancing the expressions of IL-10 and IFN-γ. Our study revealed these 2 agents to repress transcriptional activities of NF-κB, which are important modulators of inflammation. Meanwhile, SCFAs can significantly enhance the autophagy induced by M. pneumoniae. Considering that SCFAs have few side effects, they might be the promising adjuvant therapy for the prevention and/or treatment of various inflammatory diseases.

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