Physicians' Academy for Cardiovascular Education

Gut microbiota appear novel but modifiable CV risk factor

Literature - Tang WHW, Wang Z, Levison BS, et al. - N Engl J Med 2013; 368:1575-1584 April 25, 2013 DOI: 10.1056/NEJMoa1109400


Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk

 
Tang WHW,  Wang Z, Levison BS, et al.
N Engl J Med 2013; 368:1575-1584 April 25, 2013 DOI: 10.1056/NEJMoa1109400
 

Background

Choline is involved in lipid metabolism and cell membrane structure, and is a precursor of the neurotransmitter acetylcholine, among other functions. The phospholipid phosphatidylcholine (lecithin) is the major dietary source of choline [1,2].
The authors recently described the potential role of a phosphatidylcholine-choline metabolic pathway involving gut microbiota in atherogenesis in animal models [3]. Furthermore, they found an association between a history of cardiovascular disease (CVD) and elevated fasting plasma levels of TMAO (trimethylamine-N-oxide), which is an intestinal microbiota-dependent metabolite of choline [3-8].
The current study explored the relationship between oral intake of phosphatidylcholine and the involvement of the intestinal microbial organisms in TMAO production in humans. Furthermore, fasting TMAO plasma levels were related to long-term risk of incident major adverse events (MACE).
In the first study, 40 healthy adults were subjected to a dietary phosphatidylcholine challenge at the start of the study. They subsequently took broad-spectrum antibiotics for one week, after which the phosphatidylcholine challenge was repeated, as well as a final time >1 month after antibiotics withdrawal. In a clinical outcomes study, 4007 adults who underwent elective diagnostic cardiac catheterization were enrolled and followed for 3 years. Participants had no evidence of acute coronary syndrome (ACS).
 

Main results

  • The phosphatidylcholine challenge resulted in time-dependent increases of TMAO and choline. Suppression of intestinal microbiota with antibiotics almost completely abolished TMAO concentrations after the second challenge. After reacquisition of gut flora, TMAO was again readily detectable.
  • In the clinical outcomes study, elevated plasma levels of TMAO were a significant predictor of the risk of MACE, after adjustment for traditional risk factors.
    When comparing the highest quartile of TMAO levels with the lowest quartile of TMAO levels, high TMAO was associated with an increased risk of death (HR: 3.37, 95%CI: 2.39-4.75, P<0.001) and nonfatal myocardial infarction or stroke (HR: 2.13, 95%CI: 1.48-3.05, P<0.001).
    Inclusion of TMAO as a covariate resulted in a significant improvement (8.6%, P<0.001) of risk estimation over traditional risk factors. The prognostic value of plasma TMAO levels for CV risk was maintained in various subgroups with lower risk of MACE.
 

Conclusion

This study provides evidence for the generation of the proatherogenic metabolite TMAO from dietary phosphatidylcholine, and the involvement of intestinal microbiota therein. Fasting plasma TMAO levels predict the risk of incident MACE, independently of traditional cardiovascular risk factors, even in low-risk cohorts. Modulating intestinal microbiota could prove interesting for therapeutic purposes in relation to the TMAO pathway.
 

Editorial comment [9]:

This study describes a biochemical pathway that links the host metabolism and its microbial residents in the gut, to atherogenesis. These observations point to a truly novel and potentially modifiable risk factor for atherothrombotic vascular disease. However, much remains unknown about the multiple biochemical actions of TMAO. Therefore, the precise role of TMAO in atherothrombogenesis needs to be specified, whether it has a direct effect on pathogenesis, is an epiphenomenal biomarker, or is a precursor to a more direct effector.


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References

1. Patterson KY, Bhagwat SA, Williams JR, et al. USDA database for the choline content of common foods:
release two. January 2008 (http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/Choline/Choln02.pdf).
2. Zhang AQ, Mitchell SC, Smith RL. Dietary precursors of trimethylamine in man: a pilot study. Food Chem Toxicol 1999;37:515-20.
3. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472:57-63.
4. de la Huerga J, Popper H. Urinary excretion of choline metabolites following choline administration in normals and patients with hepatobiliary diseases. J Clin Invest 1951;30:463-70.
5. Simenhoff ML, Saukkonen JJ, Burke JF, Wesson LG, Schaedler RW. Amine metabolism and the small bowel in uraemia. Lancet 1976;2:818-21.
6. Ihle BU, Cox RW, Dunn SR, Simenhoff ML. Determination of body burden of uremic toxins. Clin Nephrol 1984;22:82-9.
7. Bain MA, Fornasini G, Evans AM. Trimethylamine: metabolic, pharmacokinetic and safety aspects. Curr Drug Metab 2005;6:227-40.
8. Erdmann CC. On the alleged occurrence of trimethylamine in the urine. J Biol Chem 1910;8:57-60.
9. Loscalzo J. Gut Microbiota, the Genome, and Diet in Atherogenesis. NEJM 2013;368;1647-1649
 
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