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.  

New study suggests gut microbiome directly influences BMI, triglyceride, and HDL levels

Molecular structure of cholesterol

The microbiome has long been associated with cardiovascular disease, especially after studies showing differences between the gut microbiomes of obese and slim individuals.  The mechanisms by which the microbiome may be influencing heart disease are still unknown, but there are a few mechanisms that have been identified.  For example, as has been previously discussed on this blog, trimethylamine N-oxide (TMAO) in the blood is an independent risk factor for atherosclerosis, and is produced by gut bacteria from choline and carnitine.  In addition, systemic, chronic inflammation is associated with heart disease, and our avid readers will know that the microbiome can cause chronic inflammation in the vagina, gut, and mouth.  Overall though, a direct relationship between specific bacteria and heart disease has not been shown.  A recent epidemiological study though, did just that.  The researchers, mostly from the Netherlands, were able to identify specific species that were associated with higher BMIs, as well as those that were directly correlated with HDL cholesterol levels.  They published their results in the journal Circulation Research.

The scientists measured the genomes, microbiomes, BMI, and blood lipids of 1500 adults.  Their results showed that higher overall diversity and richness of the gut microbiome was associated with a lower a lower BMI (healthier state), lower triglycerides (healthier state), and higher level of HDL cholesterol (healthier state).  The diversity was not, however, associated with total cholesterol nor LDL levels.  The researchers then identified specific bacteria associated with these health indicators.  There are too many to list in this blog, so we encourage interested readers to take a look at the article.  Some examples though: Akkermansia, Christensenellaceae, and Tenericutes were each associated with low BMI, low triglycerides, and high HDL (all healthy states), while Eggerthella was associated with high BMI and high triglycerides, and Butyricimonas was associated with high BMI, high triglycerides, and low HDL (all unhealthy states).  Finally, the researchers sought to determine just how important the microbiome was to overall BMI, triglyceride levels, and HDL levels by incorporating the host genetics, age, and gender into their calculations.  They showed the 4.5% of the variance in BMI, 6% of the variance in triglycerides, and 4% of the variance in HDL is directly attributable to the microbiome.

These study results reaffirm the importance of the microbiome to our overall health, and even quantitatively show its influence on specific health indicators.  The authors do not attempt to explain why specific bacteria would cause variation in these metrics, although as previously mentioned some mechanisms have already been demonstrated.  To check to see which other diseases these bacteria have been associated with, use the search tool, or click the tags below to see all the blog articles that mention them.

Microbiome metabolite, TMAO, associated with increased risk of chronic kidney disease and atherosclerosis

Our microbiome is responsible for producing many of the molecules and metabolites that end up in our bloodstream.  Here, these molecules can serve many important therapeutic functions, like in the case of short chained fatty acids (SCFAs).  However, some of these metabolites are beginning to be linked to various diseases.  The best known example of this is microbiome mediated production of trimethylamine-(N)-oxide (TMAO).  TMAO is produced by the microbiome from molecules called carnitine and choline, which come from foods like red meat and eggs.  A lot of literature is now being published that is establishing a connection between TMAO and atherosclerosis, and more recently between TMAO and chronic kidney disease (CKD).  In a new study published last week in the Journal of the American Society of Nephrology, researchers from the University of Kansas assessed the connection between each of these things, TMAO, atherosclerosis, and CKD.

The researchers hypothesized that patients with chronic kidney disease would show increased levels of atherosclerosis because circulating TMAO cannot be cleared from the blood by their injured kidneys.  They measured the degree of CKD and plasma TMAO levels in over 100 patients and confirmed their hypothesis: they noticed a direct relationship between severity of their CKD and circulating TMAO levels.  In addition, the researchers noticed that those people who received kidney transplants had improved TMAO levels, showing that the relationship between CKD and TMAO was most likely due to loss of kidney function.  Finally, the researchers measured biomarkers for atherosclerosis in these patients and correlated the amount of TMAO with the amount of atherosclerosis, even showing that the long term survival of these patients was related to the amount of circulating TMAO levels.

This paper is one of the first to make a connection between circulating TMAO levels and kidney function, which itself is related to atherosclerosis and mortality.  The microbiome is ultimately responsible for the creation of TMAO in the blood, by breaking down things like meats, eggs, and nuts.  It appears that a dietary shift, or a modulation of the microbiome that decreases its ability to perform this transformation should be considered for patients with CKD who are at risk for atherosclerosis.

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.