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Gut-Derived Metabolite Trimethylamine N-Oxide Promotes Inflammation and Fibrosis Following Ischemia/Reperfusion through CCR2-Mediated Macrophage Infiltration

ABSTRACT: Gut-Derived Metabolite Trimethylamine N-Oxide Promotes Inflammation and Fibrosis Following Ischemia/Reperfusion through CCR2-Mediated Macrophage Infiltration

PROVIDER: PRJNA1025306 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26319146_1.fastq.gz	Fastqsanger.gz
	SRR26319146_2.fastq.gz	Fastqsanger.gz
	SRR26319147_1.fastq.gz	Fastqsanger.gz
	SRR26319147_2.fastq.gz	Fastqsanger.gz
	SRR26319148_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Gut-Derived Metabolite Trimethylamine N-Oxide Promotes Inflammation and Fibrosis Following Ischemia/Reperfusion through CCR2-Mediated Macrophage Infiltration

Project description:Inflammation plays a crucial role in the development of acute kidney injury (AKI) and subsequent chronic kidney disease (CKD) following renal ischemia-reperfusion (IR). It has been demonstrated that metabolites from the gut microbiota can trigger inflammatory responses and modulate renal damage induced by IR. However, the exact driving factors and underlying mechanisms of this process remain unclear. Trimethylamine N-oxide (TMAO), a choline metabolite derived from the gut, has been observed to increase in AKI and CKD patients. Our study reveals that glycyrrhizic acid (GA) exacerbates IR-induced AKI and subsequent CKD through TMAO. To delve into the underlying mechanisms, we employed single-cell sequencing to construct a molecular map of kidney cells.

2024-09-09 | GSE244890 | GEO

Gut microbial metabolite trimethylamine N-oxide aggravates pulmonary hypertension

Project description:Gut microbial metabolite trimethylamine N-oxide aggravates pulmonary hypertension

| PRJNA786337 | ENA

Gut microbial metabolite trimethylamine N-oxide aggravates pulmonary hypertension

Project description:Trimethylamine N-oxide (TMAO), a metabolite derived from intestine microbial flora, enhances vascular inflammation in a variety of cardiovascular disease, and the bacterial communities associated with trimethylamine N-oxide (TMAO) metabolism is higher in pulmonary hypertension (PH) patients. The effects of TMAO on PH, however, has not been elucidated. In the present study, we found that circulating TMAO is elevated in intermediate to high-risk PH patients when compared to healthy control or low-risk PH patients. In monocrotaline-induced rat PH models, circulating TMAO is elevated; and reduction of TMAO using 3,3-dimethyl-1-butanol (DMB) significantly decreased right ventricle systolic pressure, pulmonary vascular muscularization in both monocrotaline-induced rat PH and hypoxia induced mice PH models. RNA sequencing of rat lungs on DMB revealed significant suppression of pathways involved in cytokine-cytokine receptor interaction, and cytokine and chemokine signaling. Protein-protein interaction analysis of the differentially expressed transcripts regulated by DMB showed 5 hub genes with a strong connectivity of proinflammatory cytokines and chemokines including Kng1, Cxcl1, Cxcl2, CxcL6 and Il6. In vivo, TMAO significantly increased the expression of Kng1, Cxcl1, Cxcl2, CxcL6 and Il6 in bone marrow derived macrophage. And TMAO-treated conditioned medium from macrophage increased the proliferation and migration of pulmonary artery smooth muscle cells; but TMAO treatment did not change the proliferation or migration of pulmonary artery smooth muscle cells. In conclusion, our study demonstrates that TMAO is increased in severe PH, and the reduction of TMAO using DMB reduces pulmonary vascular muscularization and alleviates PH via suppressing the macrophage production of chemokines and cytokines.

2022-06-07 | GSE190203 | GEO

Time-dependent specific molecular signatures of inflammation and remodelling are associated with Trimethylamine-N-oxide (TMAO)-induced endothelial cell dysfunction

Project description:Cardiovascular diseases (CVDs) are leading causes of death worldwide. Endothelial dysfunction is a critical initiating factor contributing to CVDs, which progression involves the gut microbiome-derived metabolite Trimethylamine N-oxide (TMAO). Here, we aim to clarify the time-dependent pathways by which TMAO mediates endothelial dysfunction.

2023-11-23 | GSE235204 | GEO

Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the pro-atherogenic metabolite trimethylamine-N-oxide

Project description:Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine N-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice, and positively correlates with the severity of this disease in human. However, which microbes contribute to TMA production in the human gut; the extent to which host factors, e.g., genotype and diet, affect TMA production and colonization of these microbes; as well as the effects TMA-producing microbes have on bioavailability of dietary choline remain largely unknown. We screened a collection of 78 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified eight strains capable of producing TMA from choline in vitro. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro. Remarkably, low levels of colonization of TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest the TMA producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans.

2015-04-02 | GSE63461 | GEO

The Gut Microbe-Derived Metabolite Trimethylamine is a Biomarker of and Therapeutic Target in Alcohol-Associated Liver Disease

Project description:BACKGROUND & AIMS: There is mounting evidence that microbes resident in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcoholic hepatitis (AH). However, mechanisms by which gut microbiota synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. METHODS: We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, and identified the metabolite trimethylamine (TMA) as a gut microbe-derived biomarker of AH. In subsequent studies, we treated mice with non-lethal mechanism-based bacterial choline TMA lyase inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. RESULTS: We show the gut microbial choline metabolite trimethylamine (TMA) is elevated in AH patients, which is correlated with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial choline TMA lyase activity protects mice from ethanol-induced liver injury. TMA lyase inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome community and host liver transcriptome. CONCLUSIONS: The microbial metabolite TMA is a biomarker of AH, and blocking TMA production from gut microbes can blunt ALD in mice.

2021-03-31 | GSE157681 | GEO

CCR2+ vs. CCR2- murine hematopoietic stem cells

Project description:Comparative analysis of FACS-sorted CCR2- and CCR2+ HSC in the steady state. CCR2+ HSC have fourfold higher proliferative rates than CCR2- HSC, are are biased towards the myeloid lineage and dominate the migratory HSC population. Comparison of pooled CCR2- and CCR2+ HSC (bone marrow from 20 mice pooled for each sample), three biological replicates each.

2015-05-01 | E-GEOD-53827 | biostudies-arrayexpress

Trimethylamine N-oxide impairs β-cell function and glucose tolerance

Project description:β-Cell dysfunction, manifested as impaired glucose-stimulated insulin secretion (GSIS), and β-cell loss, which presents as dedifferentiation, inhibited transcriptional identity and death, are the hallmarks of type 2 diabetes. Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, has been shown to play a role in cardiovascular disease. Here, we found that plasma TMAO levels are elevated in both diabetic mice and human subjects and that TMAO at a similar concentration to that found in diabetes could directly decrease β-cell GSIS in both MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels through choline diet feeding impairs GSIS, the β-cell proportion, and glucose tolerance. TMAO inhibits calcium transients through NLRP3 inflammasome-related inflammatory cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production through either genetic knockdown or antisense oligomers of Fmo3, the TMAO-producing enzyme, improves β-cell GSIS, the β-cell proportion, and glucose tolerance in both db/db and choline diet-fed mice. These observations elucidate a novel role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be a new approach for the treatment of type 2 diabetes.

2024-02-23 | GSE243083 | GEO

CCR2+ vs. CCR2- murine hematopoietic stem cells

2015-05-01 | GSE53827 | GEO

RNA Sequencing of Wild Type and CCR2-/- mouse esophageal tumor transcriptomes

Project description:Wild type and CCR2-/- C57 mice were gavaged with carboxyl methyl cellulose (1%) or N-nitrosomethylbenzylamine(NMBA) 0.25 mg/kg body weight (BW) twice per week for 5 weeks. At the end of Week 25, the forestomach were harvested to carry out RNA resequencing. We found that CCR2 mediated monocyte infiltration promoted tumor evasion through activating PD-1 signaling pahtway.

2019-09-10 | GSE134067 | GEO

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