Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N‐oxide‐generating pathway, modulates platelet responsiveness and thrombosis risk

Zhu, Weifei; Buffa, Jennifer A.; Wang, Zeneng; Warrier, Manya; Schugar, Rebecca C.; Shih, Diana M.; Gupta, Nilaksh; Gregory, Jill C.; Org, Elin; Fu, Xudong; Li, L.; DiDonato, Joseph A.; Lusis, Aldons J.; Brown, J. Mark; Hazen, Stanley A

doi:10.1111/jth.14234

Cited by 118 publications

(86 citation statements)

References 51 publications

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“…31 Further study showed that host hepatic flavin monooxygenase 3 participates in gut microbiota-dependent changes in platelet responsiveness in vivo. 32 Consistent to previous findings, a recent study found that the increase in platelet count was related to the decrease in intestinal microbial diversity and beneficial intestinal bacterial abundance. 33 Substantial evidence supports that platelet activation is highly relevant to cognitive decline.…”

Section: Discussionsupporting

confidence: 87%

C‐type lectin‐like receptor 2 and zonulin are associated with mild cognitive impairment and Alzheimer's disease

et al. 2019

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Objective: Increased permeability and changes in gut microbiota contributed to the pathogenesis of Alzheimer's disease (AD). Zonulin is a key modulator that regulates intestinal barrier function. Peripheral platelet alterations have been involved in AD pathology. C-type lectin-like receptor 2 (CLEC-2) is a receptor on the platelet surface for activation. The purpose of this study was to determine zonulin and CLEC-2 levels in mild cognitive impairment (MCI) and AD, and investigate the relationship between zonulin and CLEC-2. Methods:In this study, CLEC-2 and zonulin levels were measured using ELISA assay in 110 AD patients, 110 MCI patients, and 110 non-demented control subjects.Results: Increased CLEC-2 and zonulin levels were observed in MCI and AD patients. Furthermore, AD patients had higher CLEC-2 and zonulin levels compared with MCI patients. In addition, CLEC-2 levels were positively correlated with zonulin levels, after adjusting confounding factors (r = .592, P < .001). Multivariate analysis revealed that increased CLEC-2 and zonulin levels were significantly associated with reduced Mini-Mental State Examination (MMSE) score.Conclusions: C-type lectin-like receptor 2 is correlated with zonulin after adjusting confounding covariates. Moreover, increased CLEC-2 and zonulin are the significant factors for reduced MMSE score in MCI and AD. Further studies are needed. K E Y W O R D SAlzheimer's disease, C-type lectin-like receptor 2, mild cognitive impairment, zonulin

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Section: Discussionsupporting

confidence: 87%

C‐type lectin‐like receptor 2 and zonulin are associated with mild cognitive impairment and Alzheimer's disease

et al. 2019

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“…Table 2 The hydrogen and methane production at the end of rumen in vitro fermentation with or without the addition of TMA and NG 2 TMA, trimethylamine. 3 TMA was provided 0.69 mg/mL before fermentation. 4 ND, not detectable.…”

Section: Resultsmentioning

confidence: 99%

“…Table 3 The abundance of the 16S rRNA gene of archaea and Mmc, and CutC genes at the end of rumen in vitro fermentation with or without the addition of Choline and NG 2 Choline chloride concentration was 1.0 g/L at the beginning of fermentation. 3 CutC gene, coding choline trimethylamine lyase. Community composition of methanogens at the end of the rumen in vitro fermentation with or without the addition of TMA and NG.…”

Section: Resultsmentioning

confidence: 99%

“…PC is rst converted to choline, after which the choline is degraded to TMA by the gut microbiota. Subsequently, TMA is absorbed into the blood from the gut lumen and thereafter converted to TMAO by avin-containing monooxygenases (FMOs) in the liver [3]. Therefore, it is crucial to reduce the amount of TMA entering the blood circulation of the host.…”

Section: Introductionmentioning

confidence: 99%

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New Insight Into Rumen Methanogen Function: a Barrier Blocking Trimethylamine From Entering the Host Body

Ying-heng¹,

Wei²,

Xie³

et al. 2020

Preprint

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Background: Trimethylamine (TMA) is the precursor of trimethylamine N-oxide (TMAO), which has been known to promote human cardiovascular disease. Methanomassiliicoccales (Mmc), TMA-utilizing methanogens, may function as a TMA barrier for the host in the rumen. This study aimed to investigate the role of Mmc in rumen TMA elimination and the effect of choline addition in the diet on the rumen TMA and TMAO concentrations in the plasma and milk of dairy cows.Results: Three experiments, 2 rumen in vitro fermentation trials and 1 dairy cow in vivo trial, were conducted. Four groups were set in Experiment 1: control, nitroglycerin (NG, a methanogen inhibitor), TMA (0.69 mg/mL), and TMA + NG. The methanogenic activity was completely inhibited in the NG group, and no methane production was observed in the NG and TMA + NG groups. The TMA content hardly reduced in the TMA + NG group (0.66 mg/mL) after 2 d of incubation; in contrast, it reduced by 47.2% in the TMA group. Methanogen 16S rRNA gene sequencing showed that the relative abundance of Mmc increased in the TMA group (P = 0.005), which was confirmed by real-time polymerase chain reaction testing. Two taxa (Group 9 sp. ISO4-G1 and Group 10 sp.) at the species level mainly contributed to the increase in the relative abundance of Mmc. Four groups were set in Experiment 2: control, NG, choline (choline chloride, 1.0 mg/mL), and choline + NG. Choline was completely degraded in 24 h, and the TMA content reached the peak point in the fermentation culture. The TMA content in the choline + NG group did not reduce after the occurrence of the peak point. In contrast, the TMA content in the choline group started to decrease after 24 h, corresponding to the rapid increase in methane production. Eight mid-lactating, rumen-fistulated Holstein cows were randomly assigned to the control (n = 4) or choline (n = 4) group in Experiment 3: In the choline group, the cows were gradually supplemented with 100–250 g/(cow·d) of choline chloride over 4 weeks. In the choline group, TMA accumulated in the rumen fluid, and the abundance of Mmc 16S rRNA gene and choline-degrading bacterial cutC gene increased in the rumen content (P < 0.050). The TMAO content in the plasma and milk of the dairy cows was approximately 10 times higher in the choline group than in the control at day 28.Conclusion: Rumen Mmc functioned as a TMA barrier for the host. The increase in dietary choline caused more TMA to enter the host body, resulting in higher TMAO deposition in the milk of the dairy cows. It should be noted that TMAO-rich milk might degrade food safety. Moreover, it should be discreet to mitigate rumen methane emission by inhibiting the rumen methanogen activities, which might destroy the rumen TMA barrier.

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“…The present study first identified the critical roles of Fmo3 and Mmp19 in regulating DVT. Zhu et al (38) demonstrated that the microbe-dependent production of trimethylamine N-oxide (TMAO) contributes to the risk of thrombosis. Thus, a murine Fecl 3 -induced carotid artery injury model was established to confirm the impact of FMO3 suppression [via antisense oligonucleotide (ASO) targeting] and overexpression (as a transgene), which was examined by the plasma TMAO levels, platelet responsiveness and thrombosis potential.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of Klf15‑mediated inhibitory functions in a mouse deep venous thrombosis model

et al. 2020

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Krüppel-like family (KLF) members are important regulators of proinflammatory activation in the vasculature. A transcriptome study involving RNA sequencing (RNA-seq) and quantitative PCR (qPCR) was performed to investigate Klf15 and Klf15-regulated gene levels in C57BL/6 mice with inferior vena cava thrombi and in control (Blank) mice. A total of 2,206 differentially expressed genes (DEGs), including 1,330 upregulated and 876 downregulated genes, were identified between the deep venous thrombosis (DVT) group and the Blank group. Additionally, 1,041 DEGs (235 upregulated and 806 downregulated) were identified between the Klf15-small interfering RNA (siRNA) and Klf15-negative control (NC) groups. The DEGs were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and qPCR was conducted to validate the results. A total of seven significant DEGs were selected from the RNA-seq results. Matrix metalloproteinases (Mmp)12, Mmp13, Mmp19, Arg1, Ccl2, heme oxygenase-1 and Fmo3 levels were significantly higher, while Klf15 levels were lower, in the DVT group than in the Blank group. Fmo3 and Mmp19 have not been previously identified as DVT-associated DEGs. Klf15, Mmp12 and Mmp13 levels were compared between the Klf15-siRNA and Klf15-NC groups. Mmp12 and Mmp13 expression was significantly higher, while that of Klf15 was lower, in the Klf15-siRNA group than in the Klf15-NC group. Critical roles of Klf15, Mmp12 and Mmp13 have been identified, which have not previously been shown to help regulate DVT initiation and progression. Moreover, Klf15-mediated regulation of DVT may be modulated by downregulation of various genes, such as Mmp12 and Mmp13, potentially providing a theoretical foundation and diagnostic criteria for DVT treatment.

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Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N‐oxide‐generating pathway, modulates platelet responsiveness and thrombosis risk

Cited by 118 publications

References 51 publications

C‐type lectin‐like receptor 2 and zonulin are associated with mild cognitive impairment and Alzheimer's disease

C‐type lectin‐like receptor 2 and zonulin are associated with mild cognitive impairment and Alzheimer's disease

New Insight Into Rumen Methanogen Function: a Barrier Blocking Trimethylamine From Entering the Host Body

Transcriptome analysis of Klf15‑mediated inhibitory functions in a mouse deep venous thrombosis model

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