Gut bacteria break down cholesterol — hinting at probiotic treatments
Species in the human microbiome have enzymes that can metabolize a potentially dangerous lipid
Scientists have pinpointed human gut bacteria that have a useful tool: an enzyme that can convert artery-clogging cholesterol into a more harmless form that is not absorbed by the body. The finding points towards possible treatments for high cholesterol levels.
Although the newly described bacterial species can metabolize cholesterol in the laboratory, whether they can cause changes in their hosts’ blood cholesterol levels has yet to be confirmed in animal models or clinical trials.
“It’s very exciting to further explore,” says bioinformatician Daoming Wang at the University of Groningen in the Netherlands, who was not involved in the research.
Wang adds that the methods in the study, published on 2 April in Cell1, address thorny challenges in human microbiome research. The research is “really outstanding”, agrees bioinformatician Alexander Kurilshikov at the University of Groningen, who also was not involved in the work.
Missing link
It has been established that the human gut microbiome affects cholesterol levels, and previous research has pointed to microbial enzymes that might be involved. A 2020 study2 identified a bacterial enzyme called ismA that can convert cholesterol into coprostanol, a lipid that is excreted instead of absorbed by the body. People whose gut bacteria made this enzyme had lower cholesterol levels in their blood than did those who did not. This study was published by the same research group — led by gastroenterologist and microbiologist Ramnik Xavier at the Massachusetts General Hospital in Boston — that is responsible for the new finding. Until now, it was not clear which bacteria produced enzymes that metabolize cholesterol.
For the current study, the researchers analysed microbial genomes in stool samples from 1,429 participants in a long-term study of risk factors for cardiovascular disease. The team found many gut-bacteria species, including those in the genus Oscillibacter, that were correlated with lower cholesterol levels. The researchers confirmed their results in participants in two independent studies.
Dark matter of the gut
Next, the team searched two Oscillibacter species and one other bacterial species for genes similar to those known to affect cholesterol metabolism. To do so, the scientists used a deep-learning algorithm that they call a ‘protein language model’. The model assesses not only the features of a gene itself, but also predictions of how the protein encoded by the gene will fold into a 3D structure. The extra information makes the algorithm more sensitive than those that rely on only information about the gene.
They found that the three species have genes encoding proteins that are structurally similar to ismA and other enzymes involved in cholesterol metabolism.
This technique is “innovative and significant”, says Wang, because it provides a method for getting at the ‘dark matter’ of the microbiome: the large number of bacterial genes that aren’t similar enough to any known genes to give clues about their function.
The authors also showed in lab experiments that these three species can metabolize cholesterol. Xavier suspects, on the basis of their data, that there are “many more” Oscillibacter species to be discovered than the 25 identified in the study.
Treatment barriers
If the bacterial species or enzymes could be delivered to the right place in the gut, it might be possible to lower the necessary dose of drugs such as statins to reduce or manage cholesterol levels.
But there are hurdles facing development of such a treatment. Delivering beneficial bacteria has worked very well in treating infections with the common pathogen Clostridium difficile, says Xavier, but C. difficile’s toxin kills off a lot of bacteria, creating space for helpful bacteria. Individuals receiving treatment for high cholesterol would still have their usual gut microbiome community, he says, which could squeeze out the beneficial bacteria.
“It's a long way off,” says Xavier. But “maybe in patients at risk, we could lower that risk at a much earlier stage”, he says.
doi: https://doi.org/10.1038/d41586-024-00955-3
This story originally appeared on: Nature - Author:Julian Nowogrodzki
