Circulating Trimethylamine N-Oxide Is Associated with Increased Risk of Cardiovascular Mortality in Type-2 Diabetes: Results from a Dutch Diabetes Cohort (ZODIAC-59).

Gerjan Navis,Jose L Flores-Guerrero,Erwin Garcia,Henk J G Bilo,Stephan J L Bakker,Margery A Connelly,Peter R Van Dijk,Robin P F Dullaart

doi:10.3390/jcm10112269

Abstract

Trimethylamine N-oxide (TMAO), a novel cardiovascular (CV) disease and mortality risk marker, is a gut microbiota-derived metabolite as well. Recently, plasma concentrations of branched-chain amino acids (BCAA) have been reported to be affected by microbiota. The association of plasma TMAO with CV mortality in Type 2 Diabetes (T2D) and its determinants are still incompletely described. We evaluated the association between plasma BCAA and TMAO, and the association of TMAO with CV mortality in T2D individuals. We used data of 595 participants (mean age 69.5 years) from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort were analyzed. Plasma TMAO and BCAA were measured with nuclear magnetic resonance spectroscopy. CV mortality risk was estimated using multivariable-adjusted Cox regression models. Cross-sectionally, TMAO was independently associated with BCAA standardized (Std) β = 0.18 (95% Confidence Interval (CI) 0.09; 0.27), p <0.001. During a median follow-up of 10 years, 113 CV deaths were recorded. In Cox regression analyses, adjusted for multiple clinical and laboratory variables including BCAA, TMAO was independently associated with CV mortality: adjusted hazard ratio (adjHR) 1.93 (95% CI 1.11; 3.34), p = 0.02 (for the highest vs. the lowest tertile of the TMAO distribution). The same was true for analyses with TMAO as continuous variable: adjHR 1.32 (95% CI 1.07; 1.63), p = 0.01 (per 1 SD increase). In contrast, BCAAs were not associated with increased CV mortality. In conclusion, higher plasma TMAO but not BCAA concentrations are associated with an increased risk of CV mortality in individuals with T2D, independent of clinical and biochemical risk markers.

Highlights

Licensee MDPI, Basel, Switzerland.Trimethylamine-N-oxide (TMAO) is a microbiota-derived metabolite [1,2] that recently has gained attention as a consequence of its potential role in the progress of ischemic heart disease [3,4] kidney disease [5,6,7], complications in the setting of Type 2 Diabetes (T2D) [8,9]and premature mortality in the general population [10]
Trimethylamine (TMA) is a byproduct of a microbial fermentation, in which the gut microbiota metabolizes dietary components such as phosphatidylcholine, choline, and L-carnitine to be used as carbon fuel
The conversion of TMA to Trimethylamine N-oxide (TMAO) occurs in the host liver by the flavin monooxygenase 3, after which it is cleared by the kidneys [11]

Summary

Introduction

Licensee MDPI, Basel, Switzerland.Trimethylamine-N-oxide (TMAO) is a microbiota-derived metabolite [1,2] that recently has gained attention as a consequence of its potential role in the progress of ischemic heart disease [3,4] kidney disease [5,6,7], complications in the setting of Type 2 Diabetes (T2D) [8,9]and premature mortality in the general population [10]. Trimethylamine-N-oxide (TMAO) is a microbiota-derived metabolite [1,2] that recently has gained attention as a consequence of its potential role in the progress of ischemic heart disease [3,4] kidney disease [5,6,7], complications in the setting of Type 2 Diabetes (T2D) [8,9]. Trimethylamine (TMA) is a byproduct of a microbial fermentation, in which the gut microbiota metabolizes dietary components such as phosphatidylcholine, choline, and L-carnitine to be used as carbon fuel. The association of TMAO with CV mortality in individuals with T2D has recently been identified to be present in high-risk individuals [12]

Objectives

Methods

Results