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Cell Metabolism Nov 2021As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on...
As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFAs). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation.
Topics: Acetates; Animals; Brain; Fatty Acids, Volatile; Immune System; Mice; Microbiota
PubMed: 34731656
DOI: 10.1016/j.cmet.2021.10.010 -
Nature Communications Feb 2023Pathogenic viral infections represent a major challenge to human health. Host immune responses to respiratory viruses are closely associated with microbiome and...
Pathogenic viral infections represent a major challenge to human health. Host immune responses to respiratory viruses are closely associated with microbiome and metabolism via the gut-lung axis. It has been known that host defense against influenza A virus (IAV) involves activation of the NLRP3 inflammasome, however, mechanisms behind the protective function of NLRP3 are not fully known. Here we show that an isolated bacterial strain, Bifidobacterium pseudolongum NjM1, enriched in the gut microbiota of Nlrp3 mice, protects wild-type but not Nlrp3 deficient mice against IAV infection. This effect depends on the enhanced production of type I interferon (IFN-I) mediated by NjM1-derived acetate. Application of exogenous acetate reproduces the protective effect of NjM1. Mechanistically, NLRP3 bridges GPR43 and MAVS, and promotes the oligomerization and signalling of MAVS; while acetate enhances MAVS aggregation upon GPR43 engagement, leading to elevated IFN-I production. Thus, our data support a model of NLRP3 mediating enhanced induction of IFN-I via acetate-producing bacterium and suggest that the acetate-GPR43-NLRP3-MAVS-IFN-I signalling axis is a potential therapeutic target against respiratory viral infections.
Topics: Humans; Animals; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Influenza A virus; Microbiota; Acetates; Antiviral Agents
PubMed: 36746963
DOI: 10.1038/s41467-023-36323-4 -
Microbiome Jun 2021Modification of the gut microbiota has been reported to reduce the incidence of type 1 diabetes mellitus (T1D). We hypothesized that the gut microbiota shifts might also...
BACKGROUND
Modification of the gut microbiota has been reported to reduce the incidence of type 1 diabetes mellitus (T1D). We hypothesized that the gut microbiota shifts might also have an effect on cognitive functions in T1D. Herein we used a non-absorbable antibiotic vancomycin to modify the gut microbiota in streptozotocin (STZ)-induced T1D mice and studied the impact of microbial changes on cognitive performances in T1D mice and its potential gut-brain neural mechanism.
RESULTS
We found that vancomycin exposure disrupted the gut microbiome, altered host metabolic phenotypes, and facilitated cognitive impairment in T1D mice. Long-term acetate deficiency due to depletion of acetate-producing bacteria resulted in the reduction of synaptophysin (SYP) in the hippocampus as well as learning and memory impairments. Exogenous acetate supplement or fecal microbiota transplant recovered hippocampal SYP level in vancomycin-treated T1D mice, and this effect was attenuated by vagal inhibition or vagotomy.
CONCLUSIONS
Our results demonstrate the protective role of microbiota metabolite acetate in cognitive functions and suggest long-term acetate deficiency as a risk factor of cognitive decline. Video Abstract.
Topics: Acetates; Animals; Bacteria; Brain; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Gastrointestinal Microbiome; Mice
PubMed: 34172092
DOI: 10.1186/s40168-021-01088-9 -
Circulation Research Jan 2024T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of...
BACKGROUND
T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear.
METHODS
Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell-specific LGMN-knockout) mice (Lgmn/CD4), regulatory T cell (Treg)-specific LGMN-knockout mice (Lgmn/Foxp3), and RR-11a (LGMN inhibitor)-treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development.
RESULTS
LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II-induced or deoxycorticosterone acetate/salt-induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II-induced or deoxycorticosterone acetate/salt-induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II-induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II-induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor-associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II-induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects.
CONCLUSIONS
LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.
Topics: Animals; Humans; Mice; Acetates; Angiotensin II; CD4-Positive T-Lymphocytes; Desoxycorticosterone; Hypertension; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory; TNF Receptor-Associated Factor 6
PubMed: 38047378
DOI: 10.1161/CIRCRESAHA.123.322835 -
Biomolecules Jul 2020Ingestion of alcohol is associated with numerous changes in human energy metabolism, especially that of plasma lipids and lipoproteins. Regular moderate alcohol... (Review)
Review
Ingestion of alcohol is associated with numerous changes in human energy metabolism, especially that of plasma lipids and lipoproteins. Regular moderate alcohol consumption is associated with reduced atherosclerotic cardiovascular disease (ASCVD), an effect that has been attributed to the concurrent elevations of plasma high-density lipoprotein-cholesterol (HDL-C) concentrations. More recent evidence has accrued against the hypothesis that raising plasma HDL concentrations prevents ASCVD so that other metabolic processes associated with alcohol consumption have been considered. This review explored the roles of other metabolites induced by alcohol consumption-triglyceride-rich lipoproteins, non-esterified free fatty acids, and acetate, the terminal alcohol metabolite in athero-protection: Current evidence suggests that acetate has a key role in athero-protection but additional studies are needed.
Topics: Acetates; Alcohol Drinking; Atherosclerosis; Energy Metabolism; Humans; Lipoproteins, HDL
PubMed: 32630283
DOI: 10.3390/biom10070987 -
Proceedings of the National Academy of... Dec 2023Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the...
Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. However, the factors and mechanisms involved remain to be elucidated. Here, we propose that DR-induced optimization of immunological memory requires a complex cascade of events involving memory T cells, the intestinal microbiota, and myeloid cells. Our findings suggest that DR enhances the ability of memory T cells to recruit and activate myeloid cells in the context of a secondary infection. Concomitantly, DR promotes the expansion of commensal Bifidobacteria within the large intestine, which produce the short-chain fatty acid acetate. Acetate conditioning of the myeloid compartment during DR enhances the capacity of these cells to kill pathogens. Enhanced host protection during DR is compromised when Bifidobacteria expansion is prevented, indicating that microbiota configuration and function play an important role in determining immune responsiveness to this dietary intervention. Altogether, our study supports the idea that DR induces both memory T cells and the gut microbiota to produce distinct factors that converge on myeloid cells to promote optimal pathogen control. These findings suggest that nutritional cues can promote adaptation and co-operation between multiple immune cells and the gut microbiota, which synergize to optimize immunity and protect the collective metaorganism.
Topics: Microbiota; Gastrointestinal Microbiome; Fatty Acids, Volatile; Acetates
PubMed: 38011570
DOI: 10.1073/pnas.2304905120 -
Nature Cell Biology Apr 2024The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic...
The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.
Topics: Animals; Mice; Cancer-Associated Fibroblasts; Cell Line, Tumor; Acetates; Pancreatic Neoplasms; Polyamines; Tumor Microenvironment
PubMed: 38429478
DOI: 10.1038/s41556-024-01372-4 -
Biomedicine & Pharmacotherapy =... Jul 2023Gut microbiota can interact with the immune system through its metabolites. Short-chain fatty acids (SCFAs), as one of the most abundant metabolites of the resident gut... (Review)
Review
Gut microbiota can interact with the immune system through its metabolites. Short-chain fatty acids (SCFAs), as one of the most abundant metabolites of the resident gut microbiota play an important role in this crosstalk. SCFAs (acetate, propionate, and butyrate) regulate nearly every type of immune cell in the gut's immune cell repertoire regarding their development and function. SCFAs work through several pathways to impose protection towards colonic health and against local or systemic inflammation. Additionally, SCFAs play a role in the regulation of immune or non-immune pathways that can slow the development of autoimmunity either systematically or in situ. The present study aims to summarize the current knowledge on the immunomodulatory roles of SCFAs and the association between the SCFAs and autoimmune disorders such as celiac disease (CD), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), type 1 diabetes (T1D) and other immune-mediated diseases, uncovering a brand-new therapeutic possibility to prevent or treat autoimmunity.
Topics: Humans; Fatty Acids, Volatile; Autoimmune Diseases; Butyrates; Propionates; Acetates
PubMed: 37105078
DOI: 10.1016/j.biopha.2023.114763 -
The Journal of Nutrition Nov 2021In the last few years, there has been a growing interest in the role of gut microbiota in the development of obesity and its complications. (Clinical Trial)
Clinical Trial
BACKGROUND
In the last few years, there has been a growing interest in the role of gut microbiota in the development of obesity and its complications.
OBJECTIVES
In this study, we tested the following hypotheses: 1) lean youth and youth with obesity experience a different capability of their gut microbiota to ferment carbohydrates and produce acetate; and 2) colonic acetate may serve as a substrate for hepatic de novo lipogenesis (DNL).
METHODS
Nineteen lean youth [mean ± SE BMI (in kg/m2): 21.8 ± 0.521] and 19 youth with obesity (BMI: 35.7 ± 1.66), ages 15-21 y, frequency-matched by age and sex, underwent a fasting 10-h sodium [d3]-acetate intravenous infusion to determine the rate of appearance of acetate (Raacet) into the peripheral circulation before and after an oral dose of 20 g of lactulose. Pre- and post-lactulose Raacet values were determined at a quasi-steady state and changes between groups were compared using a quantile regression model. Acetate-derived hepatic DNL was measured in 11 subjects (6 youth with obesity) and its association with Raacet was assessed using Spearman correlation.
RESULTS
Mean ± SE Raacet was not different before lactulose ingestion between the 2 groups (7.69 ± 1.02 μmol · kg-1 · min-1 in lean youth and 7.40 ± 1.73 μmol · kg-1 · min-1 in youth with obesity, P = 0.343). The increase in mean ± SE Raacet after lactulose ingestion was greater in lean youth than in youth with obesity (14.7 ± 2.33 μmol · kg-1 · min-1 and 9.29 ± 1.44 μmol · kg-1 · min-1, respectively, P = 0.001). DNL correlated with Raacet, calculated as changes from the pre- to the post-lactulose steady state (ρ = 0.621; P = 0.046).
CONCLUSIONS
These data suggest that youth with obesity ferment lactulose to a lesser degree than youth without obesity and that colonic acetate serves as a substrate for hepatic DNL.This trial was registered at clinicaltrials.gov as NCT03454828.
Topics: Acetates; Adolescent; Colon; Female; Fermentation; Gastrointestinal Microbiome; Humans; Male; Obesity; Young Adult
PubMed: 34494088
DOI: 10.1093/jn/nxab277 -
Trends in Cell Biology Sep 2019Acetate and the related metabolism of acetyl-coenzyme A (acetyl-CoA) confer numerous metabolic functions, including energy production, lipid synthesis, and protein... (Review)
Review
Acetate and the related metabolism of acetyl-coenzyme A (acetyl-CoA) confer numerous metabolic functions, including energy production, lipid synthesis, and protein acetylation. Despite its importance as a nutrient for cellular metabolism, its source has been unclear. Recent studies have provided evidence to support the existence of a de novo pathway for acetate production derived from pyruvate, the end product of glycolysis. This mechanism of pyruvate-derived acetate generation could have far-reaching implications for the regulation of central carbon metabolism. In this Opinion, we discuss our current understanding of acetate metabolism in the context of cell-autonomous metabolic regulation, cell-cell interactions, and systemic physiology. Applications relevant to health and disease, particularly cancer, are emphasized.
Topics: Acetates; Acetyl Coenzyme A; Acetylation; Glucose; Glycolysis; Humans; Lipogenesis; Mitochondria; Neoplasms
PubMed: 31160120
DOI: 10.1016/j.tcb.2019.05.005