Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure

J Intern Med. 2015 Jun;277(6):717-26. doi: 10.1111/joim.12328. Epub 2014 Dec 1.


Objectives: Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF.

Design: Prospective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant-free survival in the patients with HF were explored.

Results: Plasma levels of TMAO (P = 0.01), choline (P < 0.001) and betaine (P < 0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant-free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2 years of follow-up (unadjusted Cox-regression: hazard ratio 2.24, 95% confidence interval 1.28-3.92, P = 0.005).

Conclusions: TMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.

Keywords: gut microbiota; heart failure; nutrition; survival; trimethylamine-N-oxide.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Betaine / blood*
  • Biomarkers / blood
  • Choline / blood*
  • Chronic Disease
  • Female
  • Heart Failure / blood
  • Heart Failure / diagnosis*
  • Heart Failure / metabolism
  • Heart Failure / mortality
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestines / microbiology*
  • Lipotropic Agents / blood*
  • Male
  • Methylamines / blood*
  • Microbiota*
  • Middle Aged
  • Oxidants / blood*
  • Predictive Value of Tests
  • Prognosis
  • Prospective Studies
  • Risk Assessment
  • Risk Factors
  • Sensitivity and Specificity
  • Severity of Illness Index
  • Survival Analysis


  • Biomarkers
  • Lipotropic Agents
  • Methylamines
  • Oxidants
  • Betaine
  • trimethyloxamine
  • Choline