It is well known that we have to be careful with what foods we eat, remembering to stay healthy and eat our fruits and vegetables. Diets high in fat can create serious health issues such as obesity, high cholesterol, and possibly Type 2 diabetes. Also on that list of related health problems is cardiovascular disease, which is characterized by blood clots, due to fat and plaque build-up in blood vessels, and can lead to a heart attack or stroke. Previous research has implied a connection between the microbiome and cardiovascular disease, due to the microbiome’s effect on production of a molecule called trimethylamine N-oxide (TMAO). As of yet, no research has been done to track the association between the microbiome and lipid (fat) build-up, so this is precisely what researchers published in Circulation Research set out to do.

The scientists located in The Netherlands, Poland, and Massachusetts, collected blood cholesterol measurements from 1500 LifeLines-DEEP subjects. LifeLines-DEEP is a collection of subjects used for assessing various health issues. Ethnic outliers and genetically related participants were removed from the study. Fecal samples were collected from 1180 participants, and sequenced. By the end of the data collection, 99 participants were excluded for reasons such as antibiotic use, or use of potentially microbiome-altering medications. In total there was a final number of 893 participants (380 men and 513 women) for which cholesterol samples, microbiome samples, and genotypic information was obtained. The participants included a wide range of age, BMI, and blood lipid levels.

The researchers found that gut microbiome species richness was significantly higher in women, and increased with age. Microbial richness was positively correlated with high density lipoproteins (HDL, the 'good cholesterol'), not correlated with low density lipoproteins (LDL, the bad cholesterol), and negatively correlated with body mass index (BMI). For example, the study confirmed that lower abundances of kingdom Archaea, families Christensenellaceae and Rikenellaceae, class Mollicutes, and genus Dehalobacterium are associated with high BMI. It was estimated that the microbiome could explain 4.57% to 65 of variation in BMI, triglyceride and HDL. No link was found between the gut microbiome and genetic predisposition to obesity of high blood lipid levels.

One hypothesis raised by the researchers is that bacteria potentially try to correct lipid imbalances, thereby helping to prevent cardiovascular disease. The strong associated between the gut microbiome and BMI and blood lipid levels – regardless of age, sex, and genetics – suggests that the microbiome does indeed play a role, if indirectly, in cardiovascular disease and other fat-related issues. 34 gut bacteria were found to be associated with BMI and blood lipids. There is a real potential for the utilization of this information in health therapies, such as blood clot and stroke prevention.

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.

Associations between the microbiome and blood lipids

Red meat, atherosclerosis, and the microbiome