The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease

Tomlinson, James; Wheeler, David C.

doi:10.1016/j.kint.2017.03.053

Cited by 93 publications

(69 citation statements)

References 50 publications

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“…Notably, trimethylamine N-oxide is a gut-derived amine oxide that has been implicated in the etiology of CVD in the normal population 25 and in patients with CKD. 26 Second, intestinal dysbiosis partly accounts for the impaired barrier function of the intestinal epithelium, resulting in the translocation of bacterial fragments through the bowel wall. In the past few years, numerous studies have shown that translocated bacterial fragments play important roles in the pathogenesis of uremic toxicity, inflammation, insulin resistance, protein-energy wasting, and progression of CKD, and are an important nontraditional cardiovascular risk factor in CKD.…”

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confidence: 99%

Circulating Bacterial Fragments as Cardiovascular Risk Factors in CKD

Szeto

McIntyre

2018

JASN

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Cardiovascular disease (CVD) is a major cause of mortality and morbidity in patients with CKD. In the past decade, intestinal dysbiosis and altered gut epithelial barrier function are increasingly recognized in CKD. Uremic patients have slow intestinal transit time, impaired protein assimilation, and decreased consumption of dietary fiber. The use of multiple medications also may contribute to the proliferation of dysbiotic bacteria, which affect the barrier function of intestinal epithelium. In addition, fluid overload and uremic toxins directly reduce the gut barrier function. The major consequence of these alterations, the translocation of bacterial fragments from bowel lumen to systemic circulation, can lead to diverse biologic effects and probably represents an important nontraditional CVD risk factor in CKD. Among all bacterial fragments, endotoxin is the most well studied. Plasma endotoxin levels are markedly elevated in both patients with CKD and those on dialysis, and are associated with the systemic inflammatory state, accelerated atherosclerosis, and clinical CVD in patients on dialysis. Optimization of BP control and the use of ultrapure dialysate can reduce plasma endotoxin levels, with probable metabolic and cardiovascular benefits. The benefit of synbiotic therapy is not confirmed, although results from animal studies are impressive. The biologic effects and clinical relevance of other bacterial fragments, such as bacterial DNA fragments, are less well defined. Further studies are needed to delineate the pathogenic relation between circulating bacterial fragments and CVD, and to define the role of the plasma bacterial fragment level as a prognostic indicator of CKD.

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confidence: 99%

Circulating Bacterial Fragments as Cardiovascular Risk Factors in CKD

Szeto

McIntyre

2018

JASN

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“…TMA is further oxidized by hepatic enzymes flavin monooxygenases 3(FMO3) in the host liver and generates TMAO, which is the end product and cannot be metabolized further (). The majority of TMAO can be excreted unchanged in the urine by the kidney within 24 h (). The remaining TMAO is reduced to TMA by the action of TMAO reductase () (Fig.…”

Section: Production and Metabolism Of Tmaomentioning

confidence: 99%

Gut microbiota in atherosclerosis: focus on trimethylamine N‐oxide

Zhu

Jiang

2020

APMIS

125

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in atherosclerosis: focus on trimethylamine N-oxide. APMIS 2020; 128: 353-366.The increasing prevalence of cardiovascular diseases cannot adequately be explained by traditional risk factors. Recently, accumulating evidence has suggested that gut microbiota-derived numerous metabolites are contributors to atherosclerotic events. Among them, the role of trimethylamine N-oxide (TMAO) in promoting atherosclerosis has gained attention. TMAO is reported to exert the proatherogenic effects by impacting on the traditional risk factors of atherosclerosis and is associated with high risk of cardiovascular events. Besides that, TMAO is involved in the complex pathological processes of atherosclerotic lesion formation, such as endothelial dysfunction, platelet activation and thrombus generation. In light of these promising findings, TMAO may serve as a potential target for atherosclerosis prevention and treatment, which is conceptually novel, when compared with existing traditional treatments. It is likely that regulating TMAO production and associated gut microbiota may become a promising strategy for the anti-atherosclerosis therapy.

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“…Therefore, an imbalance in gut microbiota could increase plasma TMAO levels in patients with CKD and aggravated renal function impairment [5]. Furthermore, studies have shown that safe and well-tolerated therapeutic interventions, such as the use of probiotics to improve the gut microbiota, can reduce TMAO levels in the body and mitigate its cardiovascular and renal damage [6][7][8]. Accordingly, investigating methods to reduce TMAO levels in the body will be of great significance in delaying the development of cardiovascular and renal diseases [1,2].…”

Section: Ivyspringmentioning

confidence: 99%

Ranitidine and finasteride inhibit the synthesis and release of trimethylamine N-oxide and mitigates its cardiovascular and renal damage through modulating gut microbiota

Liu¹,

Lai²,

Lin³

et al. 2020

Int. J. Biol. Sci.

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Trimethylamine N-oxide (TMAO) leads to the development of cardiovascular and chronic kidney diseases, but there are currently no potent drugs that inhibit the production or toxicity of TMAO. In this study, high-fat diet-fed ApoE-/-mice were treated with finasteride, ranitidine, and andrioe. Subsequently, the distribution and quantity of gut microbiota in the faeces of the mice in each group were analysed using 16S rRNA sequencing of the V3+V4 regions. Pathological examination confirmed that both ranitidine and finasteride reduced atherosclerosis and renal damage in mice. HPLC analysis also indicated that ranitidine and finasteride significantly reduced the synthesis of TMAO and the TMAO precursor delta-Valerobetaine in their livers. The 16S rRNA sequencing showed that all 3 drugs significantly increased the richness and diversity of gut microbiota in the model mice. Bioinformatic analysis revealed that the faeces of mice treated with ranitidine and finasteride, had significant increases in the number of microbes in the families g_Helicobacter, f_Desulfovibrionaceae, Mucispirillum_schaedleri_ASF457, and g_Blautia, whereas the relative abundances of microbes in the families Enterobacter_sp._IPC1-8 and g_Bacteroides were significantly reduced. The microbiota metabolic pathways, such as nucleotide and cofactor and vitamin metabolism were also significantly increased, whereas the activities of metabolic signalling pathways related to glycan biosynthesis and metabolism and cardiovascular diseases were significantly reduced. Therefore, our study indicates that in addition to their known pharmacological effects, ranitidine and finasteride also exhibit potential cardiovascular and renal protective effects. They inhibit the synthesis and metabolism of TMAO and delay the deposition of lipids and endotoxins through improving the composition of the gut microbiota.

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The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease

Cited by 93 publications

References 50 publications

Circulating Bacterial Fragments as Cardiovascular Risk Factors in CKD

Circulating Bacterial Fragments as Cardiovascular Risk Factors in CKD

Gut microbiota in atherosclerosis: focus on trimethylamine N‐oxide

Ranitidine and finasteride inhibit the synthesis and release of trimethylamine N-oxide and mitigates its cardiovascular and renal damage through modulating gut microbiota

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