Gut Microbiota–Dependent Trimethylamine N -Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes

Abstract

Objective- Gut microbiota-dependent metabolites, in particular trimethylamine N-oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied. Approach and Results- In a first study (n=78), higher TMAO plasma levels were linked with an increased risk of incident cardiovascular events including myocardial infarction, recurrent stroke, and cardiovascular death (fourth quartile versus first quartile; hazard ratio, 2.31; 95% CI, 1.25-4.23; P<0.01). In the second independent validation cohort (n=593), high TMAO levels again heralded marked increased risk of adverse cardiovascular events (fourth quartile versus first quartile; hazard ratio, 5.0; 95% CI, 1.7-14.8; P<0.01), and also after adjustments for cardiovascular risk factors including hypertension, diabetes mellitus, LDL (low-density lipoprotein) cholesterol, and estimated glomerular filtration rate (hazard ratio, 3.3; 95% CI, 1.2-10.9; P=0.04). A significant correlation was also found between TMAO levels and percentage of proinflammatory intermediate CD14CD16 monocytes ( r=0.70; P<0.01). Moreover, in mice fed a diet enriched with choline to increase TMAO synthesis, levels of proinflammatory murine Ly6C monocytes were higher than in the chow-fed control group (choline: 9.2±0.5×10 per mL versus control: 6.5±0.5×10 per mL; P<0.01). This increase was abolished in mice with depleted gut microbiota (choline+antibiotics: 5.4±0.7×10 per mL; P<0.001 versus choline). Conclusions- The present study demonstrates for the first time a graded relation between TMAO levels and the risk of subsequent cardiovascular events in patients with recent prior ischemic stroke. Our data support the notion that TMAO-related increase of proinflammatory monocytes may add to elevated cardiovascular risk of patients with increased TMAO levels.

Gut microbiota‐derived metabolite trimethylamine N‐oxide (TMAO) potentially increases the risk of obesity in adults: An exploratory systematic review and dose‐response meta‐ analysis

“…In a cross‐sectional study among 1286 Canadians, the highest quintile of serum TMAO was associated with increased prevalent CVD after adjustment for potential confounders (OR, 9.33; CI, 1.88‐46.37; P = .006). Increased carotid intima‐media thickness in higher TMAO concentrations was also reported by Randrianarisoa et al Several other studies also reported an association between TMAO and stroke in hypertensive adults, an association with vulnerable plaque characteristics in coronary artery disease (CAD) patients, and a higher mortality risk among patients with type 2 diabetes mellitus (T 2 DM) independent of glycemic status . Most of these studies focused on the association between TMAO and CVD, diabetes, or major advanced cardiac events (MACE) and obesity or body mass index (BMI) were investigated as secondary or even tertiary outcomes in these studies.…”

“…TMAO substrate metabolites are abundant in foods rich in carnitine, choline, and lecithin, including egg yolks, milk, dairy products, organ and muscle meats, and seafood such as mollusks, crustaceans, and fish . Recently, several studies have found a possible role for TMAO in chronic disease including CVD and mortality diabetes, chronic kidney disease and metabolic syndrome . In a cross‐sectional study among 1286 Canadians, the highest quintile of serum TMAO was associated with increased prevalent CVD after adjustment for potential confounders (OR, 9.33; CI, 1.88‐46.37; P = .006).…”

The role of intestinal microbiota in cardiovascular disease

“…41 Other studies have also highlighted the participation of TMAO in the development of CVD in a variety of patient cohorts. [42][43][44] Collectively, mounting evidence suggests that TMAO is part of an important mechanism by which the intestinal microflora influence CVD.…”

Derivatization‐free determination of short‐chain volatile amines in human plasma and urine by headspace gas chromatography‐mass spectrometry

“…In recent years, the non‐odorous and non‐volatile oxidation product of TMA—trimethylamine‐N‐oxide (TMAO)—attracted the attention of physicians and clinical chemists worldwide . TMAO is suspected to be of diagnostic or prognostic value, respectively, in cardio vascular events and pneumological diseases like community acquired pneumonia . Oxidation of TMA to TMAO is catalyzed by flavin‐monooxygenases (FMO) in liver microsomes .…”

“…[5][6][7][8] TMAO is suspected to be of diagnostic or prognostic value, respectively, in cardio vascular events and pneumological diseases like community acquired pneumonia. 9,10 Oxidation of TMA to TMAO is catalyzed by flavin-monooxygenases (FMO) in liver microsomes. 11 Genetic mutations and liver damage can lead to a loss in FMO activity and result in trimethylaminuria, also known as fish odor syndrome.…”