An impressively rigorous new study, led by researchers at the Broad Institute of MIT and Harvard, is shedding light on a century-old mystery. The study describes how bacteria in the gut can metabolize cholesterol at levels high enough to improve a person’s cardiac health.
For well over 100 years scientists have known some people seem to have an ability to metabolize cholesterol in the gut more effectively than others. A compound called coprostanol was the big clue, and the general hypothesis has been there must be a type of gut microbe that can turn cholesterol into coprostanol.
“It’s been known for a long time that some gut bacteria could form coprostanol from cholesterol, but we didn’t know which species of bacteria were doing this or how they were doing it,” explains Douglas Kenny, first author on the new study.
One of the starting points for the research came from an old study describing the discovery of microbe in a lagoon filled with hog sewage that was found to effectively metabolize cholesterol into coprostanol. So the researchers set out to sequence the entire genome of this cholesterol-consuming hog bacterium with the goal of finding out which particular enzyme is responsible for converting cholesterol into coprostanol.
“Because the hog sewage lagoon microbe also formed coprostanol we decided to identify the genes responsible for this activity, hoping we might find similar genes in the human gut,” says Emily Balskus, co-senior author on the study.
At the same time, the researchers analyzed a massive human microbiome dataset to try to find particular genes that were only present in subjects excreting high volumes of coprostanol. Cross-referencing these two genetic investigations, the researchers homed in on four particular genes that were both prominent in humans with high levels of excreted coprostanol, and present in the cholesterol-consuming hog bacterium.
Engineering bacteria with each of these four genes to test which one best produced enzymes that convert cholesterol to coprostanol, the researchers eventually landed on one particular gene. They named this gene Intestinal Steroid Metabolism A (IsmA).
“Once we knew this was the gene, we wanted to go back and look at human populations and ask, ‘what’s the difference between someone whose microbiome has this gene and someone whose microbiome lacks it?’” says Kenny.
Subsequent analysis revealed those subjects carrying the IsmA gene in their microbiome had up to 75 percent less cholesterol in their stool than those subjects without the gene. It was also discovered the microbiome IsmA gene correlated with an average of 0.15 mmol/L (2.7 mg/dL) lower blood cholesterol.
Ramnik Xavier, co-senior author on the new study, says this suggests the detection of this gene in a person’s microbiome indicates the presence of gut microbes that are actively metabolizing cholesterol.
“We could now correlate the presence or absence of potential bacteria that have these enzymes with blood cholesterol levels collected from the same individuals,” adds Xavier. “Those who have this enzyme activity basically have lower cholesterol.”
Although this new study offers a clear mechanical pathway illustrating how bacteria in the gut can hypothetically lower cholesterol levels in humans, there are still several questions that need answering before this translates into a clinical therapy.
It is still unclear exactly what human microbiome bacteria is responsible for this cholesterol to coprostanol conversion process. It is also unclear whether excess microbiome production of coprostanol has any negative impact on human health.
“The ultimate long-term goal is that we’d like to get a sense of whether this coprostanol pathway is really directly responsible for lowered cholesterol levels,” concludes Balskus. “If it is, that provides a strong motivation for developing some cholesterol-lowering interventions based around the microbiome.”
The new study was published in the journal Cell Host & Microbe.
Sources: Harvard University, Broad Institute