Researchers from the Broad Institute of MIT and Harvard, in collaboration with Massachusetts General Hospital, have made a breakthrough discovery regarding the impact of gut bacteria on cholesterol levels and heart disease risk. The study, published in the journal Cell and conducted as part of the Framingham Heart Study involving over 1,400 participants, identified specific bacteria called Oscillibacter that metabolize cholesterol and may potentially pave the way for microbiome-based interventions to decrease cholesterol levels in humans.

The research team, consisting of members from the Broad's Metabolomics Platform and Ramnik Xavier's lab, along with collaborators, analyzed metabolites and microbial genomes from the participants in the Framingham Heart Study. They found that individuals with higher levels of Oscillibacter bacteria in their gut had lower levels of cholesterol. The team also identified the mechanism by which these bacteria break down cholesterol, shedding light on potential interventions to manipulate the microbiome and reduce cholesterol in people.

The link between alterations in the gut microbiome and various diseases, including type 2 diabetes, obesity, and inflammatory bowel disease, is well-known. However, this study reveals a new connection between gut bacteria and cardiovascular disease. Previous research has shown associations between the composition of the gut microbiome and elements of cardiovascular disease, but researchers have lacked a comprehensive understanding of the metabolic pathways involved, limiting the development of targeted therapies.

To gain a more detailed understanding, the researchers combined shotgun metagenomic sequencing and metabolomics, which measures the levels of metabolites, to study stool samples from the Framingham Heart Study. The approach revealed over 16,000 associations between gut microbes and metabolic traits, with one association standing out—individuals with several species of bacteria from the Oscillibacter genus had lower cholesterol levels compared to those lacking these bacteria. Surprisingly, Oscillibacter species were found to be abundant in the gut, representing approximately 1 in every 100 bacteria.

In order to further investigate the biochemical pathways utilized by Oscillibacter to break down cholesterol, the researchers grew the bacteria in the lab. Using mass spectrometry, they identified the byproducts of cholesterol metabolism in the bacteria, allowing them to determine the pathways involved. The team employed machine-learning models to identify the candidate enzymes responsible for this conversion and successfully detected those enzymes and cholesterol breakdown products in specific Oscillibacter species.

Additionally, the team discovered another gut bacterial species, Eubacterium coprostanoligenes, which also contributes to decreased cholesterol levels. This species carries a gene previously shown to be involved in cholesterol metabolism, and its synergistic effect with Oscillibacter suggests that studying combinations of bacterial species could yield further insights into how different microbial communities impact human health.

Despite the majority of genes in the human gut microbiome remaining uncharacterized, the researchers are confident that their success in identifying cholesterol-metabolizing enzymes will lead to the discovery of other similar metabolic pathways influenced by gut bacteria. This, in turn, may enable the development of targeted therapeutic strategies.

The findings of this study lay the groundwork for future investigations into the microbiome's role in health and disease. By understanding the complex interactions between gut microbes and the host, researchers hope to develop more effective interventions to improve cardiovascular health and potentially address other metabolic conditions.

As the lead author of the study, Chenhao Li expressed the importance of expanding our knowledge of gut ecology systematically, focusing on individual bacteria or genes before proceeding to more complex studies. This approach may provide a broader understanding of the gut microbiome and lead to the development of more precise therapeutic strategies.

Overall, this groundbreaking research highlights the significant role that gut bacteria play in cholesterol metabolism and heart disease risk, offering hope for the development of novel interventions to combat cardiovascular conditions in the future.

Reference:
Li, C., Stražar, M., Mohamed, A. M., Pacheco, J. A., Walker, R. L., Lebar, T., ... Xavier, R. J. (2024). Gut microbiome and metabolome profiling in Framingham Heart Study reveals cholesterol-metabolizing bacteria. Cell.