http://www.eurekalert.org/pub_releases/2008-05/hms-ibp052208.php
Intestinal bacteria promote -- and prevent! -- inflammatory bowel
disease
BOSTON, Mass. (May 28, 2008)=97Scientists search for drug candidates in
some very unlikely places. Not only do they churn out synthetic
compounds in industrial-scale laboratories, but they also scour coral
reefs and scrape tree bark in the hope of stumbling upon an
unsuspecting molecule that just might turn into next year=92s big block
buster. But one region that scientists have not been searching is
their guts. Literally.
Now, a team of researchers at Harvard Medical School, Brigham and
Women=92s Hospital, and the California Institute of Technology have
demonstrated that a molecule produced by bacteria in the gut=92s
intestinal microflora can eliminate symptoms of inflammatory bowel
disease (IBD), a condition that includes Crohn=92s disease and
ulcerative colitis, in animal models.
=93Given the sheer number of bacteria in the gut, the potential for
discovering new molecules that can treat a whole range of these
diseases is promising,=94 says Dennis Kasper, co-lead author on the
study, professor of medicine and microbiology and molecular genetics
at Harvard Medical School, and director of the Channing Laboratory at
Brigham and Women=92s Hospital.
The study will appear as the cover story in the May 29 issue of
Nature.
Scientists have known for many decades that the mammalian gut is an
ecosystem teeming with approximately 1,000 different species of
bacteria, species as distinct from the host as a single-cell amoeba in
pond s***. Rather than causing disease, these bacteria are responsible
for protecting against infection and aiding digestion. An increasing
number of scientists also suspect that recent increases in asthma and
even certain food allergies are caused by disruptions in the delicate
balance of this intestinal ecosystem.
In 2005, Kasper and Sarkis Mazmanian, then a postdoc in Kasper=92s lab
and now an assistant professor of biology at the California Institute
of Technology, discovered that a species of intestinal bacteria called
Bacteroides fragilis could restore immune system balance in mice that
were bred to lack intestinal bacteria. A particular product of B.
fragilis, a sugar molecule called polysaccharide A (PSA), recovered
the equilibrium of a certain subclass of immune system cells (called
Th1 and Th2) whose levels became skewed when bacteria in the gut were
absent. The researchers referred to PSA as a =93symbiosis factor,=94 one
that established a beneficial link between bacteria and mammals. This
was the first study in which such a link was demonstrated.
Interestingly, when the study was completed, Kasper and Mazmanian
found in these mice an abundance of immune system cells that were
known to protect against colitis and Crohn=92s disease. In the current
re****t, the groups decided to expand these findings and explore
potential links between PSA and inflammatory bowel disease.
When immunocompromised mice with a specific pathogen-free microbiota
were given an intestinal bacterium called Helicobacter hepaticus, they
soon developed =93rip roaring=94 IBD, according to Kasper. However, when
Helicobacter was combined with B. fragilis, the mice were fine.
Further experiments revealed that PSA=97the special sugar molecule=97was
the key factor in preventing IBD. In fact, when mice were given
Helicobacter combined with PSA purified from B. fragilis bacteria,
they showed no symptoms of IBD.
=93But then the key question was, if PSA was essential for preventing
these animals from coming down with either colitis or Crohn=92s, how did
it do it"=94 says Kasper. =93What was the mechanism"=94
The answer came by studying a subset of interleukins, that is,
molecules secreted by immune cells.
Previous studies had shown that two particular interleukins, called
IL-17 and IL-23, promote intestinal inflammation and are present at
high levels in IBD patients. Here, while the researchers found IL-17
and IL-23 in the guts of animals who had received Heliobacter alone,
these interleukins were absent from animals who had also received both
PSA-producing B. fragilis and purified PSA.
=93We realized that something in PSA must be preventing the inflammation
that causes colitis and Crohn=92s, which would explain the reduction in
IL-17 and IL-23,=94 says Kasper.
This hunch brought the researchers to consider a third interleukin,
IL-10. The opposite of IL-17 and IL-23, IL-10 is anti-inflammatory and
had previously been shown to protect against experimental colitis.
The researchers once again administered Helicobacter and PSA-active B.
fragilis (the combination that had previously led to healthy mice),
only this time they included an antibody that blocked IL-10. As a
result, the mice all came down with IBD.
=93This demonstrated for us the mechanism by which PSA protects against
IBD,=94 says Kasper.
Indeed, the researchers deduced that PSA prompts immune system cells
to secrete IL-10, which in turn suppresses the inflammation caused by
IBD. In other words, PSA is an anti-inflammatory.
This research should encourage people (including many scientists) to
consider the vast potential for beneficial contributions to human
health by =93good=94 bacteria. And what=92s more, =93This is the first
time
that a beneficial molecule produced by intestinal bacteria has been
shown to work therapeutically in an animal model,=94 says Mazmanian.
The researchers caution that these findings do not promise any near-
term treatments for IBD. =93PSA might do the same thing in humans, and
it might not,=94 says Kasper.
However, the mechanism that they=92ve discovered should persuade
scientists and drug manufacturers to consider new sources for
expanding the drug pipeline.
=93There is currently no effort to develop molecules that are naturally
made by bacteria to use therapeutically,=94 continues Mazmanian. =93This
study opens up that possibility.=94
--
Luke
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