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Trimethylamine-N-oxide affects cell type-specific pathways and networks in mouse aorta to promote atherosclerotic plaque vulnerability

ABSTRACT: We performed single cell RNA-sequencing (scRNAseq) identify which aortic cell types, differentially expressed genes, and biological pathways are affected by trimethylamine-N-oxide (TMAO). We also modeled cell-cell communications and intracellular gene regulatory networks to identify gene networks perturbed by TMAO feeding. The objective of this study was to characterize the cell type-dependent and independent effects of TMAO on key vascular cell types involved in atherosclerosis progression in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE290376 | GEO | 2025/11/13

REPOSITORIES: GEO

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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

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

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

RNA-seq of mouse brain tissue to investigate the integrity of the blood brain barrier to trimethylamine N-oxide

Project description:In vivo work done to determine how trimethylamine N-oxide (TMAO) affects integrity of the blood-brain barrier. Wild-type male C57Bl/6 mice were injected with saline or TMAO (1.8 mg/kg in saline), and killed 2 h after injection. Mice were transcardially perfused with 0.9% saline at 4 °C to remove circulating blood, and brains were removed and collected into RNAlater. Whole brain total RNA was extracted using a PureLink RNA Mini Kit. RNA samples (n=3 TMAO, n=3 control) were sent to Macrogen Inc. (Republic of Korea) where they were subject to quality checks (RIN analysis), library prep and sequencing [TruSeq Stranded mRNA LT Sample Prep Kit; paired-end (2x 100 nt) sequencing; Illumina HiSeq 4000].

2020-12-19 | E-MTAB-9869 | biostudies-arrayexpress

Gut Microbiota-Derived Trimethylamine-N-Oxide Protects Pulmonary Vascular Barrier Integrity via VAV3-Mediated Cytoskeletal Remodeling in Acute Lung Injury

Project description:Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are characterized by increased pulmonary capillary permeability, but lack effective pharmacotherapies. Emerging evidence implicates gut-lung axis dysregulation contributes to ARDS pathogenesis through microbiome-host interactions, but the effects of the microbiota-derived metabolite, trimethylamine-N-oxide (TMAO) remains unclear. Here, we demonstrate that plasma TMAO levels are significantly elevated in ARDS patients compared to healthy controls, correlating positively with hypersensitive C-reactive protein (hs-CRP). In a murine lipopolysaccharide (LPS)-induced ALI model, TMAO administration reduced lung vascular leakage and neutrophil infiltration, whereas inhibition of gut-microbiome-derived TMAO synthesis worsened injury. Mechanistically, TMAO enhances endothelial barrier integrity by upregulating VAV3, which drives Rac1-dependent cortical actin reorganization. Knockdown of VAV3 abolished TMAO-mediated endothelial barrier protection, confirming its necessity. Our study identifies TMAO as an adaptive mediator involved in gut-lung axis, that mitigates pulmonary vascular hyperpermeability via VAV3-Rac1-cytoskeletal signaling, highlighting its therapeutic potential for ALI/ARDS.

2025-09-23 | GSE308474 | GEO

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

Trimethylamine N-oxide Aggravates Neuro-inflammation via lncRNA Fendrr/miR-145-5p/PXN axis in Vascular Dementia Rats

Project description:Vascular dementia (2VO) is the second-most cause of dementia, and our previous investigation showed that Trimethylamine-N-oxide (TMAO) exacerbates cognitive dysfunction and neuropathological changes in 2VO rats. Therefore, this study is aimed to evaluate the mechanism of TMAO in 2VO. Bilateral common carotid artery (2VO) model was established in rats and TMAO (120 mg/kg) was administered for 8 consecutive weeks, 4 weeks preoperatively and 4 weeks postoperatively. High-throughput sequencing was performed to find out the effects of TMAO treatment on lncRNA expression in rat hippocampus and bioinformatics analysis was conducted to identify potential downstream targets. Learning and spatial memory capacities were measured, as well as inflammatory factors. Nissl staining was used to observe neuronal injury in the CA1 area of the hippocampus. TMAO administration upregulated lncRNA Fendrr expression in the rat hippocampus, while the damaging effects of TMAO were counteracted after knockdown of Fendrr. Fendrr was highly expressed in 2VO rats and sponged miR-145-5p, which targets PXN. Silencing of Fendrr or PXN, or promotion of miR-145-5p improved neurological function injury, reduced neuronal damage, as well as repressed inflammation response. Inhibition of miR-145-5p abrogated up Fendrr knockdown mediated influence on 2VO rats. Taken together, our results showed that TMAO inhibits the miR-145-5p/PXN axis by increasing the Fendrr expression, thus exacerbating the development of 2VO.

2024-10-30 | GSE249873 | 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

Trimethylamine-N-oxide affects cell type-specific pathways and networks in mouse aorta to promote atherosclerotic plaque vulnerability

Project description:Trimethylamine-N-oxide affects cell type-specific pathways and networks in mouse aorta to promote atherosclerotic plaque vulnerability

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Next Generation Sequencing of TMAO (Trimethylamine N-oxide)-treated Cardiac Transcriptomes

Project description:Next Generation Sequencing of TMAO (Trimethylamine N-oxide)-treated Cardiac Transcriptomes

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