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Make Bacteria Work For You

New research in mice suggests that remodeling an unhealthy microbiome into a healthy one
could stave off chronic disease by improving cholesterol.
Using peptides, scientists turned an unhealthy gut microbiome into a healthy gut that worked to
help reduce cholesterol. This, they say, may help ward off certain diseases.
They presented their findings at the American Chemical Society Fall 2019 National Meeting &
Exposition, which took place in San Diego, CA.
The researchers investigated a certain type of molecule and how it interacted with and altered,
the gut microbiome.
Prof. M. Reza Ghadiri — from the Scripps Research Institute in La Jolla, CA — and the team were
able to change gut bacteria in such a way that it positively affected cholesterol levels in mice
specifically bred to develop arterial plaque when they ate a high-fat diet.
Prof. Ghadiri and colleagues used mice known as LDL receptor knockout mice, which are the
gold standard when studying statins. These are drugs that lower cholesterol in humans.
The molecules the scientists used were peptides called self-assembling cyclic D, L-alpha-
peptides, which Prof. Ghadiri developed in a laboratory to kill harmful bacteria.
Peptides are the building blocks of proteins, but self-assembling cyclic D, L-alpha-peptides do
not occur anywhere in nature. The researchers also developed them to specifically interact in
certain ways with different types of bacteria.
Our hypothesis was that instead of killing bacteria if we could selectively modulate the growth
of certain bacteria species in the gut microbiome using our peptides, more beneficial bacteria
would grow to fill the niche, and the gut would be remodeled into a [heathy] gut, says, Prof.
Ghadiri.
Our theory, he adds, was that [this] process would prevent the onset or progression of certain
chronic diseases."
To create appropriate peptides, the scientists developed a mass screening assay and selected the
two best peptides after testing them with a representative mouse microbiome in the laboratory.
The study consisted of three groups of mice:
1. One received a low-fat diet.
2. One received a high-fat diet.
3. One received a high-fat diet coupled with one of the two peptides listed above.

The team sequenced the gut microbiome from fecal samples from all three mouse groups before
and after the dietary intervention. They also examined their arteries for plaque and measured
molecules that can affect metabolism, inflammation, and the immune system itself.
Prof. Ghadiri and the team found that the peptides made a significant difference in the mice’s arterial
health.
Mice fed the high fat diet with our peptides had a 50% reduction in total plasma cholesterol, and
there was no significant plaque in the arteries, compared with the mice fed a high fat diet and no
peptides. We also saw suppressed levels of molecules that increase inflammation and rebalanced
levels of disease-relevant metabolites. These mice resembled those on a low-fat diet.
As to the possible mechanisms behind the findings, Prof. Ghadiri explains that they may be due
to how genes affect bile acids, which then can impact the metabolism of cholesterol. Genes that
influence atherosclerosis, which is an inflammatory process, may also be involved.
Although this study involved mice, it could be an important stepping stone to helping alter the
gut microbiome in humans despite their diet.
This study, which looked at certain aspects of cardiovascular disease, also shed some light on the
relationship between blood plasma cholesterol and the development of atherosclerosis.
This is the first time anyone has shown that there are molecules to purposefully remodel the gut
microbiome and turn a [unhealthy] gut into a more [healthy] one," notes Prof. Ghadiri. This
opens up clear therapeutic possibilities. We can sequence the [gut microbiomes] of individuals
and eventually develop therapies.