Alterations in the gut microbiota are thought to be involved in a variety of diseases, including type 2 diabetes, obesity, and inflammatory bowel disease. Now, a team of researchers from the Broad Institute of MIT and Harvard University and Massachusetts General Hospital has discovered that the microbes in your gut can also influence cardiovascular disease.in Research published in cellThe research team has identified a specific species of bacteria that consumes cholesterol in the intestines and may lower people’s cholesterol and risk of heart disease.

Members and collaborators in the Ramnik-Xavier lab, the Broad’s metabolomics platform, analyzed metabolites in more than 1,400 participants in the Framingham Heart Study, a decades-long project focused on risk factors for cardiovascular disease. and analyzed the microbial genome.The research team found that bacteria Oscilibacter It has been shown that the body takes in and metabolizes cholesterol from its surroundings, and that people with higher levels of microorganisms in their gut have lower cholesterol levels. They also identified a mechanism that bacteria may use to break down cholesterol. The results suggest that interventions that manipulate the microbiome in specific ways could one day help people reduce cholesterol. The findings also provide the basis for more targeted investigations into how changes in the microbiome affect health and disease.

“Our study integrates findings from human subjects with experimental validation to ensure we achieve actionable mechanistic insights that serve as a starting point for improving cardiovascular health.” said Xavier, who is a core member of the Institute and director and co-director of the immunology program. of a wide range of infectious disease and microbiome programs. He is also a professor at Harvard Medical School and Massachusetts General Hospital.

Chenghao Li, a postdoctoral researcher in the Xavier lab, and Martin Strassard, a research scientist, were co-lead authors of the study.

Cholesterol cues

Over the past decade, other researchers have uncovered links between the composition of the gut microbiome and factors in cardiovascular disease, such as a person’s triglycerides and postprandial blood sugar levels. But scientists have been unable to target these therapeutic implications, in part because they lack a complete understanding of the metabolic pathways in the gut.

In a new study, the Broad team has developed a more complete and detailed picture of how gut microbes influence metabolism. They combined shotgun metagenomic sequencing, which profiles all the microbial DNA in a sample, with metabolomics, which measures the levels of hundreds of known and thousands of unknown metabolites. They used these tools to study stool samples from the Framingham Heart Study.

“The results of the project highlight the importance of high-quality, well-curated patient data,” Strassard said. “This allowed us to focus on very subtle and difficult-to-measure effects and track them directly.”

This approach revealed more than 16,000 associations between microorganisms and metabolic traits. Among them were some particularly strong associations. Oscilibacter Bacteria from this genus had lower cholesterol levels than those lacking the bacterium.Researchers found that the species Oscilibacter This genus is surprisingly abundant in the gut, with an average of one in every 100 bacteria.

So the researchers wanted to understand the biochemical pathway that microbes use to break down cholesterol. To do this, they first needed to grow microorganisms in the laboratory. Fortunately, this lab has spent years collecting bacteria from stool samples and creating its own library, which includes: Oscilibacter.

After successfully growing the bacteria, the research team used mass spectrometry to identify the most likely byproducts of cholesterol metabolism within the bacteria. This allowed them to determine the pathway the bacteria use to lower cholesterol levels. They discovered that bacteria convert cholesterol into intermediate products that are then broken down by other bacteria and excreted from the body. The team then used machine learning models to identify candidate enzymes involved in this biochemical transformation and specifically detected those enzymes and cholesterol breakdown products in certain cells. Oscilibacter At the Institute.

The research team discovered another species of gut bacteria. Eubacterium coprostanorigenes, It also contributes to lowering cholesterol levels. This species has a gene that scientists have previously shown to be involved in cholesterol metabolism. In new work, the team discovered: eubacteria There may be a synergistic effect with Oscilibacter About cholesterol levels, This suggests that new experiments studying combinations of bacterial species could help elucidate how different microbial communities interact to influence human health. .

Microbial message

Although the majority of the genes in the human gut microbiome are still uncharacterized, the research team’s success in identifying cholesterol-metabolizing enzymes points to other similar gut microbiome-influenced enzymes that could serve as therapeutic targets. We are confident that this will pave the way for the discovery of metabolic pathways for

“There are a number of clinical studies attempting to study fecal microbiome transfer without much understanding of how microorganisms interact with each other and in the gut,” Lee said. “Hopefully, [by] By focusing on one specific bug or gene first, we can step back, systematically understand the biology of the gut, and come up with better treatment strategies, such as targeting one or a few bugs. Masu. ”

“The gut microbiome contains many genes with unknown functions, so there are gaps in our ability to predict metabolic function,” Lee added. “Our study highlights the possibility that additional sterol metabolic pathways are modified by gut microbes. new discoveries may be made.”

– This press release was originally published by Broad Institute website Edited for style and clarity