Microbes might manage your cholesterol
Researchers discover mysterious bacteria that break down cholesterol in
the gut

Date:
June 17, 2020
Source:
Harvard University
Summary:
Researchers discover a link between human blood cholesterol levels
and a gene in the microbiome that could one day help people manage
their cholesterol through diet, probiotics, or entirely new types
of treatment.



FULL STORY ==========================================================================
In the darkest parts of the world where light fails to block out the unfathomable bounty of the stars, look up. There are still fewer specks illuminating the universe than there are bacteria in the world, hidden
from sight, a whole universe inside just one human gut.


==========================================================================
Many species are known, like E. coli, but many more, sometimes referred
to as "microbial dark matter," remain elusive. "We know it's there,"
said Doug Kenny, a Ph.D. candidate in the Graduate School of Arts and
Sciences, "because of how it affects things around it." Kenny is co-first author on a new study in Cell Host and Microbe that illuminates a bit
of that microbial dark matter: a species of gut bacteria that can affect cholesterol levels in humans.

"The metabolism of cholesterol by these microbes may play an
important role in reducing both intestinal and blood serum cholesterol concentrations, directly impacting human health," said Emily Balskus,
professor of chemistry and chemical biology at Harvard University
and co-senior author with Ramnik Xavier, , core member at the Broad, co-director of the Center for informatics and therapeutics at MIT and investigator at Massachusetts General Hospital. The newly discovered
bacteria could one day help people manage their cholesterol levels through diet, probiotics, or novel treatments based on individual microbiomes.

According to the Centers for Disease Control and Prevention (CDC), in
2016, over 12 percent of adults in the United States age 20 and older
had high cholesterol levels, a risk factor for the country's number one
cause of death: heart disease. Only half of that group take medications
like statins to manage their cholesterol levels; while such drugs are
a valuable tool, they don't work for all patients and, though rare,
can have concerning side effects.

"We're not looking for the silver bullet to solve cardiovascular
disease," Kenny said, "but there's this other organ, the microbiome,
another system at play that could be regulating cholesterol levels that
we haven't thought about yet." The hog sewage lagoon Since the late
1800s, scientists knew that something was happening to cholesterol in
the gut. Over decades, work inched closer to an answer. One study even
found evidence of cholesterol-consuming bacteria living in a hog sewage
lagoon. But those microbes preferred to live in hogs, not humans.



========================================================================== Prior studies are like a case file of clues (one 1977 lab even isolated
the telltale microbe but the samples were lost). One huge clue is
coprostanol, the byproduct of cholesterol metabolism in the gut. "Because
the hog sewage lagoon microbe also formed coprostanol," said Balskus,
"we decided to identify the genes responsible for this activity, hoping
we might find similar genes in the human gut." Meanwhile, Damian
Plichta, a computational scientist at the Broad Institute and co-first
author with Kenny, searched for clues in human data sets. Hundreds of
species of bacteria, viruses and fungi that live in the human gut have
yet to be isolated and described, he said. But so-called metagenomics
can help researchers bypass a step: Instead of locating a species of
bacteria first and then figuring out what it can do, they can analyze
the wealth of genetic material found in human microbiomes to determine
what capabilities those genes encode.

Plichta cross-referenced massive microbiome genome data with human
stool samples to find which genes corresponded with high levels of
coprostanol. "From this massive amount of correlations," he said,
"we zoomed in on a few potentially interesting genes that we could then
follow up on." Meanwhile, after Balskus and Kenny sequenced the entire
genome of the cholesterol- consuming hog bacterium, they mined the data
and discovered similar genes: A signal that they were getting closer.

The human connection Then Kenny narrowed their search further. In the
lab, he inserted each potential gene into bacteria and tested which
made enzymes to break down cholesterol into coprostanol. Eventually,
he found the best candidate, which the team named the Intestinal Steroid Metabolism A (IsmA) gene.



==========================================================================
"We could now correlate the presence or absence of potential bacteria that
have these enzymes with blood cholesterol levels collected from the same individuals," said Xavier. Using human microbiome data sets from China, Netherlands and the United States, they discovered that people who carry
the IsmA gene in their microbiome had 55 to 75 percent less cholesterol
in their stool than those without.

"Those who have this enzyme activity basically have lower cholesterol,"
Xavier said.

The discovery, Xavier said, could lead to new therapeutics -- like a
"biotic cocktail" or direct enzyme delivery to the gut -- to help people
manage their blood cholesterol levels. But there's a lot of work to do
first: The team may have identified the crucial enzyme, but they still
need to isolate the microbe responsible. They need to prove not just correlation but causation -- that the microbe and its enzyme are directly responsible for lowering cholesterol in humans. And, they need to analyze
what effect coprostanol, the reaction byproduct, has on human health.

"It doesn't mean that we're going to have answers tomorrow, but we have
an outline of how to go about it," Xavier said.


========================================================================== Story Source: Materials provided by Harvard_University. Original written
by Caitlin McDermott-Murphy. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Douglas J. Kenny, Damian R. Plichta, Dmitry Shungin, Nitzan
Koppel, A.

Brantley Hall, Beverly Fu, Ramachandran S. Vasan, Stanley Y. Shaw,
Hera Vlamakis, Emily P. Balskus, Ramnik J. Xavier. Cholesterol
Metabolism by Uncultured Human Gut Bacteria Influences
Host Cholesterol Level. Cell Host & Microbe, 2020; DOI:
10.1016/j.chom.2020.05.013 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200617121511.htm

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