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

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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MP03-11 GUT MICROBIOME AND SHORT CHAIN FATTY ACIDS IN RENAL CALCIUM OXALATE STONES FORMATION

The Journal of Urology ◽

10.1097/01.ju.0000554943.49324.a5 ◽

2019 ◽

Vol 201 (Supplement 4) ◽

Author(s):

Kunjie Wang* ◽

Yu Liu ◽

Liang Zhou ◽

Yi Li ◽

Qun Sun ◽

...

Keyword(s):

Fatty Acids ◽

Calcium Oxalate ◽

Gut Microbiome ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Calcium Oxalate Stones ◽

Chain Fatty Acids

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The role of gut microbiome and short chain fatty acids in renal calcium oxalate stones formation

European Urology Supplements ◽

10.1016/s1569-9056(19)30200-3 ◽

2019 ◽

Vol 18 (1) ◽

pp. e276

Author(s):

Y. Liu ◽

Z. Chen ◽

Q. Jiang ◽

L. Cheng ◽

L. Zhou ◽

...

Keyword(s):

Fatty Acids ◽

Calcium Oxalate ◽

Gut Microbiome ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Calcium Oxalate Stones ◽

Chain Fatty Acids

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Role of Short Chain Fatty Acids and Apolipoproteins in the Regulation of Eosinophilia-Associated Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22094377 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4377

Author(s):

Eva Maria Sturm ◽

Eva Knuplez ◽

Gunther Marsche

Keyword(s):

Fatty Acids ◽

Immune Cell ◽

Inflammatory Diseases ◽

Unmet Need ◽

Density Lipoprotein ◽

Parasite Clearance ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Eosinophil Migration ◽

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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Immunomodulatory potential of gut microbiome-derived short-chain fatty acids (SCFAs)

Acta Biochimica Polonica ◽

10.18388/abp.2018_2648 ◽

2019 ◽

Cited By ~ 30

Author(s):

Weronika Ratajczak ◽

Aleksandra Rył ◽

Arnold Mizerski ◽

Kinga Walczakiewicz ◽

Olimpia Sipak ◽

...

Keyword(s):

Fatty Acids ◽

Immune System ◽

Intestinal Microbiota ◽

Immune Cells ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Intestinal Microbiome ◽

16S Rrna Analysis ◽

Immunomodulatory Potential ◽

Chain Fatty Acids

Intestinal microbiota is an element of the bacterial ecosystem in all mammalian organisms. These microorganisms play a very important part in the development, functioning, and modulation of the immune system from the moment of birth. In recent years, owing to the use of modern sequencing techniques, the microbiome composition in healthy people has been identified based on bacterial 16S rRNA analysis. Currently, more and more attention is being given to the influence of microorganisms on the host’s cellular metabolism. Analysis of microbial metabolites, among them short-chain fatty acids (SCFAs), and disruption of intestinal microbiota homeostasis in terms of their effects on molecular regulatory mechanisms of immune reactions will surely improve the understanding of the etiology of many common diseases. SCFAs, mainly butyrate, propionate, and acetate, occur in specific amounts, and their proportions can change, depending on the diet, age and diseases. The levels of SCFAs are substantially influenced by the ratio of commensal intestinal bacteria, the disturbance of which (dysbiosis) can lead to a disproportion between the SCFAs produced. SCFAs are regarded as mediators in the communication between the intestinal microbiome and the immune system. The signal they produce is transferred, among others, in immune cells via free fatty acid receptors (FFARs), which belong to the family of G protein-coupled receptors (GPCRs). It has been also confirmed that SCFAs inhibit the activity of histone deacetylase (HDAC) – an enzyme involved in post-translational modifications, namely the process of deacetylation and, what is new, the process of histone crotonylation. These properties of SCFAs have an effect on their immunomodulatory potential i.e. maintaining the anti/pro-inflammatory balance. SCFAs act not only locally in the intestines colonized by commensal bacteria, but also influence the intestinal immune cells, and modulate immune response by multi-protein inflammasome complexes. SCFAs have been confirmed to contribute to the maintenance of the immune homeostasis of the urinary system (kidneys), respiratory system (lungs), central nervous system, and the sight organ.

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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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Short chain fatty acids reduce renal calcium oxalate stones by regulating oxalate transporters SLC26A2/3/6 expression in intestine

European Urology Open Science ◽

10.1016/s2666-1683(20)32852-4 ◽

2020 ◽

Vol 19 ◽

pp. e432

Author(s):

K.J. Wang ◽

Y. Liu ◽

Y.C. Ma ◽

Q.Y. Jiang ◽

Z.D. Chen ◽

...

Keyword(s):

Fatty Acids ◽

Calcium Oxalate ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Calcium Oxalate Stones ◽

Oxalate Transporters ◽

Chain Fatty Acids

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Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis

Scientific Reports ◽

10.1038/s41598-021-84881-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Stephanie Trend ◽

Jonatan Leffler ◽

Anderson P. Jones ◽

Lilian Cha ◽

Shelley Gorman ◽

...

Keyword(s):

Multiple Sclerosis ◽

Fatty Acids ◽

B Cells ◽

Immune Cells ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Bioactive Metabolites ◽

Healthy Controls ◽

Serum Factors ◽

Chain Fatty Acids

AbstractAltered composition of gut bacteria and changes to the production of their bioactive metabolites, the short-chain fatty acids (SCFAs), have been implicated in the development of multiple sclerosis (MS). However, the immunomodulatory actions of SCFAs and intermediaries in their ability to influence MS pathogenesis are uncertain. In this study, levels of serum SCFAs were correlated with immune cell abundance and phenotype as well as with other relevant serum factors in blood samples taken at first presentation of Clinically Isolated Syndrome (CIS; an early form of MS) or MS and compared to healthy controls. There was a small but significant reduction in propionate levels in the serum of patients with CIS or MS compared with healthy controls. The frequencies of circulating T follicular regulatory cells and T follicular helper cells were significantly positively correlated with serum levels of propionate. Levels of butyrate associated positively with frequencies of IL-10-producing B-cells and negatively with frequencies of class-switched memory B-cells. TNF production by polyclonally-activated B-cells correlated negatively with acetate levels. Levels of serum SCFAs associated with changes in circulating immune cells and biomarkers implicated in the development of MS.

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