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

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.

Temporal Course of Plasma Trimethylamine N-Oxide (TMAO) Levels in ST-Elevation Myocardial Infarction

“…Atherosclerosis hallmarks CHD, and efforts are currently being directed at better understanding the manner through which this inflammatory process contributes to the development of CHD. Trimethylamine N-oxide (TMAO), a gut microbial product derived from L-carnitine and choline-rich foods, has gained substantial attention due to its atherogenic potential and its impact on CHD prognosis and all-cause mortality [ 4 , 5 , 6 , 7 , 8 , 9 ]. Indeed, recent endeavors have suggested that higher admission plasma TMAO values reflect a larger atherosclerotic burden and a higher risk of plaque rupture in patients presenting with ST-segment elevation myocardial infarction (STEMI) prior to undergoing percutaneous coronary intervention (PCI) [ 10 , 11 ].…”

Gut microbiota–derived metabolite trimethylamine-N-oxide and multiple health outcomes: an umbrella review and updated meta-analysis

“…The updated meta-analysis on CVDs included 12 studies ( 4 , 6 , 83 , 91–96 ) with 22,945 participants and showed that high TMAO concentrations were statistically significantly associated with an increased risk of CVD (OR: 1.50; 95% CI: 1.26, 1.79; P = 8.00 × 10 −6 ) ( Figure 2 , Supplemental Figure 8 ). Eight studies from 5 articles ( 11 , 14 , 60 , 72 , 83 ) were used to perform a meta-analysis on CVD mortality. The results revealed that participants with high TMAO concentrations were more likely to die from CVDs than those with low TMAO concentrations (HR: 2.02; 95% CI: 1.74, 2.34; P = 6.01 × 10 −21 ) ( Figure 2 , Supplemental Figure 9 ).…”

“…The results of the updated meta-analyses showed no significant association between TMAO and DBP [14 studies ( 9 , 13–15 , 59 , 67 , 87–89 , 98 , 112–114 ) enrolling 10,085 subjects, WMD: −0.25; 95% CI: −0.95, 0.46; P = 0.495] ( Figure 4 , Supplemental Figure 15 ). Higher circulating TMAO was related to higher SBP [16 studies ( 3 , 9 , 13–15 , 59 , 67 , 87–89 , 98 , 112–115 ) enrolling 17,369 subjects, WMD: 1.92; 95% CI: 1.33, 2.51; P = 1.70 × 10 −10 ] ( Figure 4 , Supplemental Figure 16 ) and BMI [19 studies ( 3 , 9 , 13 , 14 , 53 , 65 , 67 , 84 , 87–90 , 98 , 103 , 113–116 ) enrolling 20,851 subjects, WMD: 0.54; 95% CI: 0.12, 0.97; P = 0.012] ( Figure 4 , Supplemental Figure 17 ). The association between TMAO concentrations and SBP remained significant when the meta-analysis included only cohort studies (WMD: 1.91; 95% CI: 1.39, 2.43; P = 6.85 × 10 −13 ) ( Figure 4 ).…”

“…The umbrella review identified 1 meta-analysis reporting that circulating TMAO was associated with a decrease of GFR (WMD: −12.86; 95% CI: −16.57, −9.15; P = 1.11 × 10 −11 ) ( 47 ). Our updated meta-analysis including 20 studies from 19 articles ( 3 , 9 , 13 , 14 , 48 , 53 , 55 , 59 , 65–67 , 70 , 77 , 80 , 89 , 98 , 113–115 ) enrolling 29,497 subjects found a consistently significant association (WMD: −13.30; 95% CI: −16.73, −9.86; P = 3.14 × 10 −14 ) ( Figure 4 , Supplemental Figure 23 ). The association remained significant in the confined meta-analysis of cohort studies (WMD: −15.38; 95% CI: −19.32, −11.45; P = 1.78 × 10 −14 ) ( Figure 4 ).…”

“…A multitude of studies have discovered that circulating TMAO concentrations are linked to a wide range of health outcomes, including cardiovascular and cerebrovascular diseases ( 4–6 ), type 2 diabetes mellitus (DM) ( 7 ), hypertension ( 8 ), renal dysfunction ( 9 , 10 ), cancer, and mortality ( 11 , 12 ). The relations between elevated plasma TMAO concentrations and health-related traits have also been explored, including glomerular filtration rate (GFR) ( 9 ), blood pressure ( 13 , 14 ), BMI ( 9 , 14 ), and total cholesterol ( 15 ). It has been hypothesized that the intestinal microbiota may alter the risk of disease by inducing TMAO changes in the metabolome profile ( 16 ), and therefore TMAO might be a novel biomarker representing human health conditions related to the gut microbiota ( 17–19 ).…”