YSM Issue 90.4

molecular biology
FEATURE
a professor at Rockefeller University whose lab conducted the
study. According to Brady, bacteria are an incredibly common
source for those compounds. “Most of our antibiotics and immunosuppressants
come from looking at products produced by
bacteria,” Brady said. Many of these drugs were found by searching
soil bacteria to see if they produced molecules with antibiotic
properties, which is one of the main focuses of Brady’s lab.
However, in this project, the lab decided to screen the human microbiome—the
set of bacteria that live within the human body—
for molecules that might be able to interact directly with human
cells. The crux of the idea is simple: these bacteria already live in
our bodies, so researchers wanted to find out whether we can use
these microbes to manipulate human physiology.
To get there, the scientists had a challenge to overcome: searching
through the thousands of bacterial species living in the human
body to find just one or two that can “talk” to human cells.
A few decades ago, researchers would have had to do so by hand,
culturing every bacterial strain individually and testing it for active
molecules. In the twenty-first century, however, this task is
much more feasible. The researchers had already identified one
bacterial molecule, commendamide, that interacted with a class
of human cell receptors called G-protein coupled receptors (GP-
CRs). Commendamide is an N-acyl amide, a type of biologically
active organic molecule, that is often produced by bacteria. Taking
advantage of this fact, the researchers used the Human Microbiome
Project database to search for all of the bacterial genes
in the human microbiome encoding proteins that can produce
N-acyl amides like commendamide. They identified a total of 143
human microbial genes that code for such proteins, of which 44
were unique enough to merit testing in the lab for biological activity.
The researchers determined that these 44 genes comprised
six distinct classes of N-acyl amides that are naturally produced
by bacteria, four of which are produced by gut bacteria.
The bacterial molecules identified by the researchers are quite
similar to signaling molecules already produced by the human
body; their structures mimic human signaling molecules incredibly
closely. Furthermore, the bacterial molecules bind to the
GPCR receptors just as well as the human signaling molecules
do, such that the physiological result of GPCR activation is indiscernible
between the human and bacterial molecules. Brady
hypothesizes that as we learn more about the chemistry of the
human microbiome, we’re going to find more cases of bacterial
mimicry in the future. “More and more often you’re going to find
molecules that maybe aren’t identical to, but resemble, the molecules
that we as humans already make to target our own receptors,”
Brady said.
Since the molecules these bacteria produce have such a strong
effect on human physiology, the researchers decided to see if they
could harness that ability for medical purposes. These commensal
bacteria can interact with GPCRs, which is a lucky coincidence
for researchers because GPCRs are implicated in a wide variety of
metabolic disorders. These receptors are the largest and most diverse
group of human cell receptors, and GPCRs make up about
one third to one half of all drug targets are. Many GPCRs are
located in the human gut as well, which is where the N-acyl-amide-producing
bacteria were isolated from. In fact, GPCRs in the
gut have been implicated in hunger, glucose absorption, and diabetes,
which is exactly what the researchers decided to study.
IMAGE COURTSY OF WIKIMEDIA COMMONS
►An electron microscopy image of E. coli cells isolated from the
human small intestine—just one of the many bacterial species living
in the human gastrointestinal tract.
The different N-acyl amide ligands were surveyed to see if they
would bind to 240 different GPCRs. Of these, one GPCR in particular—denoted
GPR119—bound the bacterial molecules particularly
well. GPR119 is implicated in the regulation of glucose
homeostasis, and has historically been a drug target for Type 2
Diabetes. Specifically, activation of GPR119 receptors in the gut
can prevent the rapid change of blood sugar levels in hyperglycemic
patients. Brady and his team wanted to see that activation
of GPR119 with the bacterial N-acyl amides could produce the
same effects as human signaling molecules.
To see if the bacterial molecules were capable of affecting
GPR119 receptors strongly enough to regulate glucose levels, the
researchers infected mice with E. coli engineered to produce the
molecules of interest. They then measured the blood sugars of the
mice. As predicted, the mice that were infected with N-acyl-amide-producing
bacteria had lower blood sugar levels than mice
that weren’t infected with the genetically engineered bacteria.
This shows that some bacteria produce biologically active molecules
that not only can interact with GPR119 in the gut, but can
also regulate blood sugar in ways similar to many blood sugar
medications.
Like any recently published study, these findings still have a
long way to go from the lab to becoming viable medical treatments
for diseases like diabetes. According to Brady, human
physiology is incredibly complicated, and people are still working
on how to apply these findings in mice and cell culture models to
the human body. But that doesn’t stop Brady and his team from
thinking about ways that these bacterial molecules could be harnessed
as a drug. He suggests that perhaps people can ingest the
pure molecule just like any other drug. “You could also imagine
introducing the organism regularly, like in a yogurt,” Brady said.
This is perhaps more enjoyable than taking a pill! Whatever the
mode of action, these commensal bacteria provide us with ways
to manipulate the human body in new, inventive, and potentially
less invasive ways in the hopes of providing new treatments for
common diseases.
www.yalescientific.org
October 2017
Yale Scientific Magazine
31