The new study, published in 'Cell Host and Microbe', has linked a specific group of bacteria in the intestines to lower cholesterol levels in their blood.
The discovery suggests a possible reason why some people can consume more cholesterol in their diet with minimal effect on their blood cholesterol levels. It also hints that boosting populations of these bacteria, through diet, probiotics, or another kind of treatment, may one day be an effective way to help lower cholesterol levels.
"This study provides a roadmap for how we can use microbial genes and enzymes to manipulate metabolism and impact human health," said Ramnik Xavier, co-senior author of the study, director of Broad's Immunology Program, co-director of the institute's Infectious Disease and Microbiome Program, and co-director of the Center for Microbiome Informatics and Therapeutics at MIT.
The idea that bacteria can metabolise cholesterol isn't a new one; in the early 1900's, scientists reported the existence of bacteria that could chemically transform cholesterol into a compound called coprostanol. Coprostanol-generating bacteria have been found in the guts of rats, baboons, pigs, and even humans, but the biology of these bacteria was poorly understood.
"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," said Douglas Kenny, first author of the new paper and a Broad and Harvard graduate student.
The researchers wanted to know whether there was a link between these bacteria and blood cholesterol levels. But isolating cholesterol-metabolizing bacteria and growing them in the lab proved to be difficult—many species found in the human microbiome are hard to culture in the lab.
Instead, the team turned to large microbiome datasets to unearth genes that might be involved in cholesterol metabolism. The researchers analysed gut microbiomes from 3,097 people across the United States and sequenced nearly 6 million microbial genes found in those microbiomes. Of the microbiome samples, 625 also included information on levels of coprostanol found in the faeces.
They looked for bacterial genes that were present only in people who excreted coprostanol and also resembled those encoding enzymes that perform similar functions to cholesterol metabolism. That led the scientists to just four genes that might be involved in breaking down cholesterol.
From there, the researchers genetically engineered bacteria in the lab to produce each of the four enzymes of interest. They homed in on one gene, which they named Intestinal Stool Metabolism A (IsmA), that could metabolise cholesterol. The gene, they showed in their genetic data, is found in a small number of microbiome-associated bacteria.
"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?'" said Kenny.
The group discovered that people with the IsmA gene in their microbiome excreted 55-75% less cholesterol in their faeces than people who don't carry that bacterial gene. Moreover, people with the IsmA gene had, on average, cholesterol levels in the blood that were 0.15 mmol/L (2.7 mg/dL) lower than those without any copies of the IsmA genes in their microbiomes.
This is a larger average effect on blood cholesterol than human genes such as HMGCR and PCSK9, which are known to alter a person's risk of high cholesterol levels and are targeted by some FDA-approved cholesterol drugs.
"To see how well the particular genes and organisms we found correlated with metabolism and cholesterol levels in people was really exciting and gratifying," said Emily Balskus, Professor of Chemistry and Chemical Biology at Harvard and co-senior author of the study.
The researchers are now trying to isolate the human-associated bacteria that carry IsmA for further study, and have additional questions about whether coprostanol has any effect on human health. But they say their results validate the idea that the makeup of a person's microbiome can impact their metabolic 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," she adds. "If it is, that provides a strong motivation for developing some cholesterol-lowering interventions based around the microbiome."
These findings were published on the same day as a second study, in mice, was published in Nature Biotechnology, in which scientists discovered that altering the gut microbiome of mice can slow the progression of atherosclerosis by reducing cholesterol and dramatically slowing the buildup of fatty deposits in arteries.
Scientists at Scripps Research, California, developed molecules that can remodel the bacterial population of intestines to a healthier state and they have shown—through experiments in mice—that this reduces cholesterol levels and strongly inhibits the thickened-artery condition known as atherosclerosis.
The study involved the creation of a set of molecules called peptides that can slow the growth of less-desirable species of gut bacteria.
In mice that develop high cholesterol and atherosclerosis from a high-fat diet, they found that the peptides beneficially shifted the balance of species in the gut microbiome, which refers to the trillions of bacteria that live inside the digestive system. This shift reduced cholesterol levels and dramatically slowed the buildup of fatty deposits in arteries—symptoms that are the hallmarks of atherosclerosis.
Atherosclerosis is the condition that leads to heart attacks and strokes, the two leading causes of death among humans.
“It was surprising to us that simply remodelling the gut microbiome can have such an extensive effect,” says study co-senior author Reza Ghadiri, professor in the department of chemistry at Scripps Research.
Cyclic peptides for microbiome modulation
The team has been working on a method that involves delivering small molecules to kill or slow the growth of bad gut bacteria without affecting good gut bacteria.
Co-senior author Luke Leman, an assistant professor in the Department of Chemistry at Scripps Research, adds: “Our approach, using small molecules called cyclic peptides, is inspired by nature.
“Our cells naturally use a diverse collection of molecules including antimicrobial peptides to regulate our gut microbe populations.”
Prior to the experiments, the team already had a small collection of cyclic peptides that had been made using chemistry techniques. For the study, they set up a screening system to determine if any of those peptides could beneficially remodel the mammalian gut microbiome by suppressing undesirable gut bacterial species.
Using mice that are genetically susceptible to high cholesterol, they fed the animals a Western-type diet that swiftly and reliably produces high blood cholesterol and atherosclerosis, as well as adverse shifts in the gut microbiome.
The researchers then sampled the animals’ gut contents and applied a different cyclic peptide to each sample. A day later, they sequenced the bacterial DNA in the samples to determine which peptides had shifted the gut bacteriome in the desired direction.
The scientists soon identified two peptides that had significantly slowed the growth of undesirable gut bacteria, shifting the species balance closer to what is seen in mice that are fed a healthier diet.
Using these peptides to treat atherosclerosis-prone mice that were eating a high-fat Western diet, they found striking reductions in the animals’ blood levels of cholesterol compared to untreated mice—about 36% after two weeks of treatment.
They also found that after 10 weeks, the atherosclerotic plaques in the arteries of the treated mice were about 40 percent reduced in area, compared to those in untreated mice.
“These were really remarkable effects,” Ghadiri says.
The cyclic peptides used in the study apparently interact with the outer membranes of certain bacterial cells in ways that slow or stop the cells’ growth. Ghadiri and his team have been researching these peptides for years and have put together a set of dozens that show no toxicity to the cells of mammals.
The molecules also transit through the gut without entering the bloodstream. In the study, the peptides were delivered to the mice in drinking water and were not associated with any adverse side effects.
Cheered by the proof-of-principle demonstration, the researchers are now testing their peptides in mice that model diabetes, another common condition that has been linked to an unhealthy microbiome.
Source: Cell Host & Microbe
Douglas J. Kenny et al.
"Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level"
Source: Nature Biotechnology
Chen, P.B., Black, A.S., Sobel, A.L. et al.
“Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis”