Elevated serum trimethylamine oxide levels as potential biomarker for diabetic kidney disease

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Abstract

Background

Diabetic kidney disease (DKD) has become a major cause of chronic kidney disease. However, early diagnosis of DKD is challenging. Trimethylamine oxide (TMAO) is an intestinal microbial metabolite which might be associated with diabetes complications. The aim of this study was to investigate the correlation between TMAO and DKD.

Methods

A cross-sectional study was conducted. A total of 108 T2DM patients and 33 healthy subjects were enrolled in this study. Multiple logistic regression analyses and area under receiver operating characteristic curves (AUROC) were performed to evaluate the correlation between serum TMAO and DKD.

Results

Serum TMAO levels were significantly higher in DKD patients than healthy control group and the NDKD (T2DM without combined DKD) group ( P < 0.05). TMAO levels were negatively correlated with eGFR and positively correlated with urea nitrogen, ACR and DKD ( P < 0.05). Logistic regression analysis indicated that serum TMAO was one of the independent risk factors for DKD patients ( P < 0.05). In the diagnostic model, the AUROC of TMAO for the diagnosis of DKD was 0.691.

Conclusion

Elevated levels of serum TMAO levels were positively associated with the risk of DKD in T2DM patients, which might be a potential biomarker for DKD.

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Most cited references 21

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Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk

W.H. Tang, Zeneng Wang, Bruce S. Levison … (2013)

Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans. We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography. Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups. The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.).

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Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease.

W.H. Tang, Zeneng Wang, David J Kennedy … (2015)

Trimethylamine-N-oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and l-carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis.

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Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway

Ming‐liang Chen, Xiao‐hui Zhu, Li Ran … (2017)

Background Trimethylamine‐N‐oxide (TMAO) has recently been identified as a novel and independent risk factor for promoting atherosclerosis through inducing vascular inflammation. However, the exact mechanism is currently unclear. Studies have established a central role of nucleotide‐binding oligomerization domain–like receptor family pyrin domain–containing 3 (NLRP3) inflammasome in the pathogenesis of vascular inflammation. Here, we examined the potential role of the NLRP3 inflammasome in TMAO‐induced vascular inflammation in vitro and in vivo and the underlying mechanisms. Methods and Results Experiments using liquid chromatography‐tandem mass spectrometry, Western blot, and fluorescent probes showed that TMAO‐induced inflammation in human umbilical vein endothelial cells (HUVECs) and aortas from ApoE−/− mice. Moreover, TMAO promoted NLRP3 and activated caspase‐1 p20 expression and caspase‐1 activity in vitro and in vivo. Notably, a caspase‐1 inhibitor (YVAD), an NLRP3 inhibitor (MCC950), as well as NLRP3 short interfering RNA attenuated TMAO‐induced activation of the NLRP3 inflammasome, subsequently leading to suppression of inflammation in HUVECs. TMAO additionally stimulated reactive oxygen species (ROS) generation, in particular, mitochondrial ROS, while inhibiting manganese superoxide dismutase 2 (SOD2) activation and sirtuin 3 (SIRT3) expression in HUVECs and aortas from ApoE−/− mice. TMAO‐induced endothelial NLRP3 inflammasome activation was ameliorated by the mitochondrial ROS scavenger Mito‐TEMPO, or SIRT3 overexpression in HUVECs. Conversely, TMAO failed to further inhibit magnesium SOD2 and activate the NLRP3 inflammasome or induce inflammation in SIRT3 short interfering RNA–treated HUVECs and aortas from SIRT3−/− mice. Conclusions TMAO promoted vascular inflammation by activating the NLRP3 inflammasome, and the NLRP3 inflammasome activation in part was mediated through inhibition of the SIRT3‐SOD2–mitochondrial ROS signaling pathway.

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Author and article information

Journal

Journal ID (nlm-ta): Endocr Connect

Journal ID (iso-abbrev): Endocr Connect

Journal ID (hwp): EC

Title: Endocrine Connections

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Electronic): 2049-3614

Publication date (Electronic): 15 May 2023

Publication date (Electronic preprint): 15 May 2023

Publication date Collection: 01 August 2023

Volume: 12

Issue: 8

Electronic Location Identifier: e220542

Affiliations

[1 ]Department of Endocrinology , the Second Affiliated Hospital of Fujian Medical University, Quanzhou, China

[2 ]Department of Endocrinology , Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China

Author notes

Correspondence should be addressed to J Zhou: zhoujx88@ 123456fjmu.edu.cn

^*(Y Huang and Z Zhu contributed equally to this work)

Author information

Yinqiong Huang http://orcid.org/0000-0001-9186-3896

Jingxiong Zhou http://orcid.org/0000-0002-1464-0899

Article

Publisher ID: EC-22-0542

DOI: 10.1530/EC-22-0542

PMC ID: 10388659

PubMed ID: 37183928

SO-VID: fbe6c905-1371-422b-8262-c2ca13a8b83a

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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Elevated serum trimethylamine oxide levels as potential biomarker for diabetic kidney disease

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Most cited references 21

Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk

Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease.

Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway

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