Date: August 30, 2017
Source: Rockefeller University
Summary: Scientists developed
a method to genetically engineer gut bacteria to produce molecules that have
the potential to treat certain disorders by altering human metabolism.
We have a symbiotic
relationship with the trillions of bacteria that live in our bodies -- they
help us, we help them. It turns out that they even speak the same language. And
new research from The Rockefeller University and the Icahn School of Medicine
at Mt. Sinai suggests these newly discovered commonalities may open the door to
"engineered" gut flora who can have therapeutically beneficial
effects on disease.
"We call it
mimicry," says Sean Brady, director of Rockefeller University's Laboratory
of Genetically Encoded Small Molecules, where the research was conducted. The
breakthrough is described in a paper published this week in the journal Nature.
In a double-barreled
discovery, Brady and co-investigator Louis Cohen found that gut bacteria and
human cells, though different in many ways, speak what is basically the same
chemical language, based on molecules called ligands. Building on that, they
developed a method to genetically engineer the bacteria to produce molecules
that have the potential to treat certain disorders by altering human
metabolism. In a test of their system on mice, the introduction of modified gut
bacteria led to reduced blood glucose levels and other metabolic changes in the
animals.
Molecular impersonation
The method involves the
lock-and-key relationship of ligands, which bind to receptors on the membranes
of human cells to produce specific biological effects. In this case, the
bacteria-derived molecules are mimicking human ligands that bind to a class of
receptors known as GPCRs, for G-protein-coupled receptors.
Many of the GPCRs are
implicated in metabolic diseases, Brady says, and are the most common targets
of drug therapy. And they're conveniently present in the gastrointestinal
tract, where the gut bacteria are also found. "If you're going to talk to
bacteria," says Brady, "you're going to talk to them right
there." (Gut bacteria are part of the microbiome, the larger community of
microbes that exist in and on the human body.)
In their work, Cohen and Brady
engineered gut bacteria to produce specific ligands, N-acyl amides, that bind
with a specific human receptor, GPR 119, that is known to be involved in the
regulation of glucose and appetite, and has previously been a therapeutic
target for the treatment of diabetes and obesity. The bacterial ligands they
created turned out to be almost identical structurally to the human ligands,
says Cohen, an assistant professor of gastroenterology in the Icahn School of
Medicine at Mt. Sinai.
Manipulating the system
Among the advantages of
working with bacteria, says Cohen, who spent five years in Brady's lab as part
of Rockefeller's Clinical Scholars Program, is that their genes are easier to
manipulate than human genes and much is already known about them. "All the
genes for all the bacteria inside of us have been sequenced at some
point," he says.
In past projects, researchers
in Brady's lab have mined microbes from soil in search of naturally occurring
therapeutic agents. In this instance, Cohen started with human stool samples in
his hunt for gut bacteria with DNA he could engineer. When he found them he
cloned them and packaged them inside E. coli bacteria, which is easy to grow.
He could then see what molecules the engineered E. coli strains were making.
Although they are the product
of non-human microorganisms, Brady says it's a mistake to think of the
bacterial ligands they create in the lab as foreign. "The biggest change
in thought in this field over the last 20 years is that our relationship with
these bacteria isn't antagonistic," he says. "They are a part of our
physiology. What we're doing is tapping into the native system and manipulating
it to our advantage."
"This is a first step in
what we hope is a larger-scale, functional interrogation of what the molecules
derived from microbes can do," Brady says. His plan is to systematically
expand and define the chemistry that is being used by the bacteria in our guts
to interact with us. Our bellies, it turns out, are full of promise.
Story Source:
Materials provided by Rockefeller University. Note: Content may be edited for
style and length.
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