Drugging the microbiome to decrease atherslcerosis

TMAO is sometimes found in fish.

Trimethylamine N-oxide is a metabolite produced by the microbiome from foods such as red meat and fish.  This metabolite has been independently linked to atherosclerosis, among a host of other diseases.  Researchers at the Cleveland Clinic have been investigating the relationship between the microbiome and this molecule for many years, and we have written about a few of their publications previously.  (Click the TMAO tag below to learn more.)  Most recently, they have researched various compounds that could possibly decrease the production of TMAO by the microbiome.  Last week they published the results of this study in the journal Cell.

The researchers identified a molecule, 3,3-dimethyl-1-butanol (DMB), which inhibited the production of TMAO by gut bacteria.  DMB is a natural product that is commonly found in balsamic vinegar and olive oil.  This molecule was able to shift the microbiome towards bacteria that did not produce TMAO, and importantly, it did not strictly act as an antibiotic and broadly decrease the abundance of microbiome bacteria.  The scientists tested this molecule in mice and showed that it decreased the plasma levels of TMAO in mice that ingested choline.  Moreover, the mice that received DMB had less arterial plaque (i.e. less atherosclerosis).  In addition, the DMB did not appear to have any toxic effects on the mice. 

These researchers hope that the DMB or other agents that lower TMAO levels could possibly be used as therapeutics.   Beyond atherosclerosis, TMAO has been implicated in a number of diseases, ranging from certain cancers to inflammatory diseases.  These diseases are complex though, and their etiologies are not completely understood, so it remains to be seen if this microbiome approach will be successful.  In the mean time, a little less red meat and a little more balsamic vinegar probably won’t hurt.  

Red meat, atherosclerosis, and the microbiome

Atherosclerosis is a disease in which plaque accumulates in your blood vessels.  This can lead to heart attack, stroke, and sometimes death.  One of the major risk factors for atherosclerosis is high levels of a molecule called trimethylamine-N-oxide (TMAO).  TMAO is known to interfere with how the body handles cholesterol, and has long been associated with heart disease.  Researchers from the Cleveland Clinic recently published their discovery of the main pathway by which TMAO is formed in the body.  In the article they describe how TMAO is formed after the microbiome breaks down a molecule found in red meat, which is then converted by the liver to TMAO

Red meat is rich in a molecule called L-carnitine.  The researchers fed this molecule to germ free mice, mice on antibiotics, and control mice and discovered that those with a healthy microbiome produced high levels of TMAO.  They proved a new pathway for this conversion, via an intermediate molecule called γ-Butyrobetaine, by detecting genes for its production.  They then proved that γ-Butyrobetaine alone could be converted to trymethyl-amine (TMA) by the microbiome. (TMA is the precursor to TMAO before being acted on by the liver.)  Next, they discovered that a diet consisting of L-carnitine or γ-Butyrobetaine shifted the microbiome to be enriched in bacteria that could efficiently break them down to convert them to TMAO.  Finally, they gave two groups of mice a diet high in γ-Butyrobetaine to demonstrate the microbiome’s importance in atherosclerosis. One group of mice was given antibiotics to disrupt their microbiomes and the other was not.  The group given the antibiotics had less levels of TMAO and less symptoms of atherosclerosis, including plaque build-up, than those mice that had the normal gut microbiome capable of converting γ-Butyrobetaine to TMA.

This paper provides a definitive link between the actions of the microbiome and atherosclerosis.  Interestingly, some people that eat diets high L-carnitine do not produce high levels of TMAO, and are thus at less risk for atherosclerosis.  The paper hypothesizes that these people do not have the bacteria capable of converting L-carnitine to TMA.  The paper also discusses how γ-Butyrobetaine, which is now shown to be a major precursor source of TMAO, can be purchased at nutrition stores as a dietary supplement to help in building muscle.  These supplements are not regulated by the FDA, and no long term studies have been performed on γ-Butyrobetaine as a supplement to humans.  Anyone taking it should be warned that they may be at a much higher risk for heart disease.  There are clearly dangers in taking unregulated supplements, and we encourage all of our readers to be prudent with what they put in their bodies.