Gut flora-dependent metabolite Trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress

Ke, Yilang; Dang, Li; Zhao, Mingming; Liu, Changjie; Liu, Jia; Zeng, Aiping; Shi, Xiaonan; Cheng, Si; Pan, Bing; Zheng, Lemin; Hong, Huashan

doi:10.1016/j.freeradbiomed.2018.01.007

Cited by 194 publications

(171 citation statements)

References 49 publications

Supporting

Mentioning

147

Contrasting

Unclassified

Order By: Relevance

“…Moreover, we had compared the plasma TMAO levels in different aged (1‐, 3‐, 6‐ and 10‐month‐old) SAMR1 and SAMP8 mice by LC/MS/MS in our previous study (Ke et al., 2018). We had found an age‐related increase in TMAO levels in both SAMR1 and SAMP8 mice.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

et al. 2018

Self Cite

View full text Add to dashboard Cite

SummaryGut microbiota can influence the aging process and may modulate aging‐related changes in cognitive function. Trimethylamine‐N‐oxide (TMAO), a metabolite of intestinal flora, has been shown to be closely associated with cardiovascular disease and other diseases. However, the relationship between TMAO and aging, especially brain aging, has not been fully elucidated. To explore the relationship between TMAO and brain aging, we analysed the plasma levels of TMAO in both humans and mice and administered exogenous TMAO to 24‐week‐old senescence‐accelerated prone mouse strain 8 (SAMP8) and age‐matched senescence‐accelerated mouse resistant 1 (SAMR1) mice for 16 weeks. We found that the plasma levels of TMAO increased in both the elderly and the aged mice. Compared with SAMR1‐control mice, SAMP8‐control mice exhibited a brain aging phenotype characterized by more senescent cells in the hippocampal CA3 region and cognitive dysfunction. Surprisingly, TMAO treatment increased the number of senescent cells, which were primarily neurons, and enhanced the mitochondrial impairments and superoxide production. Moreover, we observed that TMAO treatment increased synaptic damage and reduced the expression levels of synaptic plasticity‐related proteins by inhibiting the mTOR signalling pathway, which induces and aggravates aging‐related cognitive dysfunction in SAMR1 and SAMP8 mice, respectively. Our findings suggested that TMAO could induce brain aging and age‐related cognitive dysfunction in SAMR1 mice and aggravate the cerebral aging process of SAMP8 mice, which might provide new insight into the effects of intestinal microbiota on the brain aging process and help to delay senescence by regulating intestinal flora metabolites.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Thus, the TMAO plasma level may be altered during the aging process. In our recently published study, we found that the circulating TMAO level was markedly higher in SAMP8 mice than age‐matched SAMR1 mice (Ke et al., 2018). Compared with age‐matched SAMR1 mice, SAMP8 mice are more prone to aging characteristics (Flood & Morley, 1997).…”

Section: Discussionmentioning

confidence: 99%

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…While the studies show the ability of TMAO to promote atherosclerosis [10,11,17,18,30,31], there are numerous contrasting results [19,[32][33][34][35][36]. Treatment of male Fischer 344 rats by L-carnitine in drinking water for 1 year induced tenfold higher TMAO plasma concentration when compared to the control (2.5 vs. 25.0 μM) [36].…”

Section: Discussion/conclusionmentioning

confidence: 98%

“…Ma et al [18], using human umbilical vein endothelial cells, demonstrated that TMAO up-regulates VCAM-1 expression and promotes monocyte adhesion. In the same human umbilical vein endothelial cells model, TMAO promotes early pathological process of atherosclerosis by accelerating inflammation and triggering oxidative stress [17,30,31].…”

Section: Discussion/conclusionmentioning

confidence: 99%

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

et al. 2018

View full text Add to dashboard Cite

Background: L-carnitine can be metabolized to trimethylamine N-oxide (TMAO), a molecule that promotes atherogenesis through its interaction with macrophages and lipid metabolism. Objective: The aim of the present study was to assess whether L-carnitine supplementation may promote changes in selected serum biomarkers of atherosclerosis. Methods: Before the start, in the mid-point and after completing the 24-weeks supplementation protocol, fasting blood samples were taken from the antecubital vein. Plasma free L-carnitine and TMAO were determined by the UPLC/MS/MS method. Serum proteins were determined by the enzyme immunoassay method using commercially available kits. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglycerides have been determined using standard automatic analyzer. Results: L-carnitine supplementation elevated fasting plasma carnitine in the mid-point of our study and it remained increased until the end of supplementation period. Moreover, it induced tenfold increase in plasma TMAO concentration but did not affect serum C-reactive protein, interleukin-6, tumour necrosis factor-α, L-selectin, P-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 or lipid profile markers. Conclusion: We demonstrated that although oral L-carnitine supplementation significantly increased plasma TMAO concentration, no lipid profile changes or other markers of adverse cardiovascular events were detected in healthy aged women over the period of 24 weeks.

show abstract

“…Moreover, TMAO‐treated human umbilical vein endothelial cells showed an elevation in ROS formation and a decreased SOD activity. This could be attributed to the ability of TMAO to repress SIRT1 expression, which is known to be a suppressor to oxidative stress . Taken these data together, it is plausible that TMAO induces oxidative stress by impairing the expression of SIRT1.…”

Section: Discussionmentioning

confidence: 99%

The interplay between microbiota‐dependent metabolite trimethylamine N‐oxide, Transforming growth factor β/SMAD signaling and inflammasome activation in chronic kidney disease patients: A new mechanistic perspective

El-Deeb

Atef

Hafez

2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

Background Chronic kidney disease (CKD) signifies a frequently life‐threatening condition influencing kidney structure and function. Despite its irrefutable importance, its exact pathogenesis is not completely clarified. However, CKD is known to be associated with accumulated uremic toxins/metabolites, interstitial fibrosis, and systemic inflammation. So we aimed to investigate the role of microbiota‐dependent metabolite trimethylamine N‐oxide (TMAO), transforming growth factor β (TGFβ)/SMAD signaling, and inflammasome activation in CKD pathogenesis through its different stages. Subjects and Methods Eighty patients with CKD of stages 2 to 4 in addition 15 healthy control subjects were enrolled. SMAD3 and nucleotide‐binding oligomerization domain‐, leucine‐rich repeat‐ and pyrin domain‐containing 3 (NLRP3) messenger RNA (mRNA) expressions from whole blood were assessed by quantitative real‐time polymerase chain reaction (RT‐PCR). Serum TGF‐β1 and interleukin‐1β (IL‐1β) levels were estimated by the enzyme‐linked immunosorbent assay. Plasma and urinary TMAO levels were measured. Oxidative stress markers were also assessed. Results SMAD3 and NLRP3 mRNA expressions were significantly upregulated in patients with CKD. Likewise, serum TGF‐β1 and IL‐1β levels were significantly elevated in patients with CKD, with increase in plasma and urinary TMAO levels and altered redox status throughout different CKD stages. Conclusion The study documented that TMAO could be used as a reliable biomarker to evaluate CKD progression; being linked to TGF‐β/SMAD signaling, NLRP3 inflammasome activation as well as being a noninvasive applicable technique.

show abstract

Gut flora-dependent metabolite Trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress

Cited by 194 publications

References 49 publications

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

The interplay between microbiota‐dependent metabolite trimethylamine N‐oxide, Transforming growth factor β/SMAD signaling and inflammasome activation in chronic kidney disease patients: A new mechanistic perspective

Contact Info

Product

Resources

About