Regulation of immune cell function by short-chain fatty acids

Eosinophils are key components of our host defense and potent effectors in allergic and inflammatory diseases. Once recruited to the inflammatory site, eosinophils release their cytotoxic granule proteins as well as cytokines and lipid mediators, contributing to parasite clearance but also to exacerbation of inflammation and tissue damage. However, eosinophils have recently been shown to play an important homeostatic role in different tissues under steady state. Despite the tremendous progress in the treatment of eosinophilic disorders with the implementation of biologics, there is an unmet need for novel therapies that specifically target the cytotoxic effector functions of eosinophils without completely depleting this multifunctional immune cell type. Recent studies have uncovered several endogenous molecules that decrease eosinophil migration and activation. These include short chain fatty acids (SCFAs) such as butyrate, which are produced in large quantities in the gastrointestinal tract by commensal bacteria and enter the systemic circulation. In addition, high-density lipoprotein-associated anti-inflammatory apolipoproteins have recently been shown to attenuate eosinophil migration and activation. Here, we focus on the anti-pathogenic properties of SCFAs and apolipoproteins on eosinophil effector function and provide insights into the potential use of SCFAs and apolipoproteins (and their mimetics) as effective agents to combat eosinophilic inflammation.

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Short Chain Fatty Acids Prevent Glyoxylate-Induced Calcium Oxalate Stones by GPR43-Dependent Immunomodulatory Mechanism

Frontiers in Immunology ◽

10.3389/fimmu.2021.729382 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xi Jin ◽

Zhongyu Jian ◽

Xiaoting Chen ◽

Yucheng Ma ◽

Hongwen Ma ◽

...

Keyword(s):

Fatty Acids ◽

Calcium Oxalate ◽

Rna Sequencing ◽

Immune Cells ◽

Kidney Stones ◽

Immune Cell ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Crystal Formation ◽

Chain Fatty Acids

Calcium oxalate (CaOx) stones are the most common type of kidney stones and are associated with high recurrence, short chain fatty acids (SCFAs), and inflammation. However, it remains uncertain whether SCFAs affect the formation of CaOx stones through immunomodulation. We first performed mass cytometry (CyTOF) and RNA sequencing on kidney immune cells with glyoxylate-induced CaOx crystals (to elucidate the landscape of the associated immune cell population) and explored the role of SCFAs in renal CaOx stone formation through immunomodulation. We identified 29 distinct immune cell subtypes in kidneys with CaOx crystals, where CX3CR1+CD24- macrophages significantly decreased and GR1+ neutrophils significantly increased. In accordance with the CyTOF data, RNA sequencing showed that most genes involved were related to monocytes and neutrophils. SCFAs reduced kidney CaOx crystals by increasing the frequency of CX3CR1+CD24- macrophages and decreasing GR1+ neutrophil infiltration in kidneys with CaOx crystals, which was dependent on the gut microbiota. GPR43 knockdown by transduction with adeno-associated virus inhibited the alleviation of crystal formation and immunomodulatory effects in the kidney, due to SCFAs. Moreover, CX3CR1+CD24- macrophages regulated GR1+ neutrophils via GPR43. Our results demonstrated a unique trilateral relationship among SCFAs, immune cells, and the kidneys during CaOx formation. These findings suggest that future immunotherapies may be used to prevent kidney stones using SCFAs.

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Evidence for the Gut Microbiota Short-Chain Fatty Acids as Key Pathophysiological Molecules Improving Diabetes

Mediators of Inflammation ◽

10.1155/2014/162021 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 101

Author(s):

Alessandra Puddu ◽

Roberta Sanguineti ◽

Fabrizio Montecucco ◽

Giorgio Luciano Viviani

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Fatty Acids ◽

Cell Function ◽

Serum Levels ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Bacterial Fermentation ◽

Chain Fatty Acids

In type 2 diabetes, hyperglycemia, insulin resistance, increased inflammation, and oxidative stress were shown to be associated with the progressive deterioration of beta-cell function and mass. Short-chain fatty acids (SCFAs) are organic fatty acids produced in the distal gut by bacterial fermentation of macrofibrous material that might improve type 2 diabetes features. Their main beneficial activities were identified in the decrease of serum levels of glucose, insulin resistance as well as inflammation, and increase in protective Glucagon-like peptide-1 (GLP-1) secretion. In this review, we updated evidence on the effects of SCFAs potentially improving metabolic control in type 2 diabetes.

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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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Postprandial Glycemic, Insulinemic, and Short-Chain Fatty Acids Responses Following the Consumption of Okara and Biovalorized Okara Incorporated Biscuits

Current Developments in Nutrition ◽

10.1093/cdn/nzab041_022 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 507-507

Author(s):

Delia Pei Shan Lee ◽

Alicia Xinli Gan ◽

Clarinda Sutanto ◽

Kate Qi Xuan Toh ◽

Jung Eun Kim

Keyword(s):

Fatty Acids ◽

Cell Function ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Metabolic Clearance ◽

Soluble Fiber ◽

Β Cell ◽

Glucose Response ◽

Β Cell Function ◽

Chain Fatty Acids

Abstract Objectives Okara is a fiber-rich food processing by-product. However, it is underutilized as food due to its rapid putrefaction and poor sensorial properties. Valorization via fermentation (biovalorization) can alleviate its undesirable qualities while augmenting its soluble fiber content. The increase in soluble fiber may improve postprandial glycemic and insulinemic responses, potentially via generation of short-chain fatty acids (SCFAs) from colonic bacteria fermentation. This study aimed to assess the effect of consuming okara and biovalorized okara-containing biscuits on postprandial glucose, insulin and SCFAs responses in older Singaporeans. Methods Fifteen healthy middle-aged and older Singaporeans participated in a randomized controlled crossover trial. Subjects underwent a 4-hour mixed meal tolerance test with 100 g ingestion of 3 types of biscuits – control (C, no okara), biovalorised okara (RO) and autoclaved okara (AOK). RO and AOK biscuits were produced by 20% substitution of wheat flour with okara powder that was fermented with Rhizopus oligosporus (7% w/w) or autoclaved. The 4-hour incremental area under the curve (iAUC) of glucose, insulin and SCFAs (acetate, propionate and butyrate) were assessed. β-cell function was evaluated based on glucose stimulated insulin secretion, using a ratio of 4-hour AUC of insulin to glucose. Estimated insulin sensitivity (ISI) and metabolic clearance rate (MCR) were assessed with Stumvoll Index. Results Although no difference in glucose response was noted, RO showed significantly lower insulin iAUC (RO: 8931 ± 1058 mU/L × min, mean ± SE; C: 10271 ± 866 mU/L × min, p = 0.021) and improved β-cell function (p = 0.028) compared to C. AOK yielded significantly greater ISI and MCR compared to C (pISI = 0.016, pMCR = 0.009) while RO showed no difference against AOK or C. Significantly higher acetate and total SCFAs iAUC were evident for both RO and AOK relative to C (C vs RO: pacetate = 0.012, ptotal SCFA = 0.001; C vs AOK: pacetate = 0.015, ptotal SCFA = 0.001). AOK also had significantly greater propionate and butyrate iAUC compared to C (C vs AOK: pacetate = 0.002, pbutyrate = 0.001). Conclusions Consumption of okara and biovalorized okara-containing biscuits offers the benefit of attenuating postprandial insulinemic response possibly via SCFAs modulation. Funding Sources Singapore Ministry of Education

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