Illustration of red blood cells moving through clogged artery to indicate cholesterol build up as a result of homozygous familial hypercholesterolemia and atherosclerosis
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Researchers from the Broad Institute of MIT and Harvard together with Massachusetts General Hospital investigators have identified specific species of bacteria in the gut that consume bacteria to help lower cholesterol and decrease the risk of heart disease. The research, published Tuesday in the journal Cell, adds to the list of diseases influenced by the gut microbiome that includes type 2 diabetes, obesity, and inflammatory bowel disease (IBD).

For this finding, the researchers tapped stool samples from the decades-long Framingham Heart Study which has searched for a variety of risk factors that contribute to cardiovascular disease. Data from more than 1,400 participants were used to analyze their metabolites and microbial genomes, which showed that a bacteria called Oscillibacter take up and metabolize cholesterol from its surroundings and people with a larger population of these bacteria in their but also had lower cholesterol levels.

“Our research integrates findings from human subjects with experimental validation to ensure we achieve actionable mechanistic insight that will serve as starting points to improve cardiovascular health,” said Ramnik Xavier, MD, PhD, a core institute member, director of the immunology program, and co-director of the infectious disease and microbiome program at the Broad.

In addition to identifying the specific bacteria that lowers cholesterol in people, the team also identified that the mechanism the bacteria likely use to break down cholesterol and this finding suggest that in the future, physicians may be able to manipulate the microbiome of people to help control their high cholesterol.

Over the past ten years, researchers have gained some knowledge on the links between cardiovascular disease and the influence of the gut microbiome, such as triglyceride levels and blood sugar levels after a person eats. Despite this knowledge, therapeutic development has not been possible due to a lack of a more detailed understanding of the metabolic pathways in the gut.

In order to get a more complete picture of the activity of microbes in the gut, researchers in the Xavier lab, Broad’s Metabolomics Platform, and collaborators performed shotgun metagenomic sequencing to profile all the microbial DNA in patients stool samples and combined it with metabolomics to identify both known and unknown metabolites.

This method identified more than 16,000 associations between microbes and metabolic traits including one particularly strong signal that showed people with several species of the Oscillibacter bacteria had lower cholesterol levels than those people who lacked these species. The researchers were surprised to find how abundant the different Oscillibacter species were—representing, on average, one in every 100 bacteria identified.

A second gut bacterial species—Eubacterium coprostanoligenes—that contributes to decreased cholesterol was also found. This bacteria has been previously shown to play some role in cholesterol metabolism. In further work to determine the bacterial pathways at work that help lower cholesterol, the team found that the bacteria converts cholesterol into intermediate products that were then broken down further by other gut bacteria and then excreted. The investigators discovered that Eubacterium may have a synergistic effect with Oscillibacter.

The researchers note that while the majority of genes in the gut microbiome remain uncharacterized, their work in identifying these cholesterol-metabolizing bacteria provides a method to discovering additional metabolic pathways that contribute to human health and disease, while also providing new targets that might be addressed therapeutically.

“There are many clinical studies trying to do fecal microbiome transfer studies without much understanding of how the microbes interact with each other and the gut,”  said Chenhao Li, a postdoc researcher in the Xavier lab. “Hopefully stepping back by focusing on one particular bug or gene first, we’ll get a systematic understanding of gut ecology and come up with better therapeutic strategies like targeting one or a few bugs.”

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