Source: Harvard Medical School

Released: Thu 22-May-2008, 11:40 ET
Embargo expired: Wed 28-May-2008, 13:00 ET

Intestinal Bacteria Promote—and Prevent!—Inflammatory Bowel Disease

Keywords
INFLAMMATORY BOWEL DISEASE, IBD, COLITIS, CROHN'S DISEASE, INTESTINAL
BACTERIA, INTESTINAL FLORA, AUTOIMMUNITY

Description

A sugar molecule produced by a beneficial bacterium in the intestinal
microflora appears to have anti-inflammatory effects that can mitigate
symptoms of colitis in experimental animals. When the molecule is
administered to animal models of colitis, disease symptoms did not
develop.

FINDINGS
A sugar molecule produced by a beneficial bacterium in the intestinal
microflora appears to have anti-inflammatory effects that can mitigate
symptoms of colitis in experimental animals. When the molecule is
administered to animal models of colitis, disease symptoms did not
develop.

RELEVANCE
Between 1 and 2 million Americans suffer from inflammatory bowel
disease (IBD), which includes Crohn’s disease and ulcerative colitis.
This is the first time in the literature that a naturally evolved
molecule produced by intestinal bacteria has been shown to work to
prevent colitis in an animal model. These findings suggest new ways to
begin thinking about developing therapies for preventing or even
treating IBD. Our intestinal microflora make up a biosphere that may
be teeming with potential drug candidates.

INVESTIGATORS
-Dennis Kasper, Professor of Medicine and Microbiology and Molecular
Genetics, Harvard Medical School; Senior Physician, Brigham and
Women’s Hospital
http://www.channing.harvard.edu/kasper.htm
-Sarkis Mazmanian, Assistant Professor of Biology, California
Institute of Technology
http://biology.caltech.edu/Members/Mazmanian

FUNDING SOURCES
National Institutes of Health/National Institute of Allergy and
Infectious Disease; the Searle Scholars Program; the Damon Runyon
Cancer Research Foundation; and the
Crohn’s and Colitis Foundation of America

JOURNAL
Nature, May 29, 2008

Newswise — Scientists 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’s 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’s Hospital, and the California Institute of Technology have
demonstrated that a molecule produced by bacteria in the gut’s
intestinal microflora can eliminate symptoms of inflammatory bowel
disease (IBD), a condition that includes Crohn’s disease and
ulcerative colitis, in animal models.

“Given 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,” 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’s 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 scum. 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’s 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 “symbiosis factor,” 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’s disease. In the current
report, 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 “rip roaring” IBD, according to Kasper. However, when
Helicobacter was combined with B. fragilis, the mice were fine.
Further experiments revealed that PSA—the special sugar molecule—was
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.

“But then the key question was, if PSA was essential for preventing
these animals from coming down with either colitis or Crohn’s, how did
it do it?” says Kasper. “What was the mechanism?”

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.

“We realized that something in PSA must be preventing the inflammation
that causes colitis and Crohn’s, which would explain the reduction in
IL-17 and IL-23,” 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.

“This demonstrated for us the mechanism by which PSA protects against
IBD,” 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 “good” bacteria. And what’s more, “This is the first time
that a beneficial molecule produced by intestinal bacteria has been
shown to work therapeutically in an animal model,” says Mazmanian.

The researchers caution that these findings do not promise any near-
term treatments for IBD. “PSA might do the same thing in humans, and
it might not,” says Kasper.

However, the mechanism that they’ve discovered should persuade
scientists and drug manufacturers to consider new sources for
expanding the drug pipeline.

“There is currently no effort to develop molecules that are naturally
made by bacteria to use therapeutically,” continues Mazmanian. “This
study opens up that possibility.”

Full citation:

Nature, May 29, 2008, 453 (7195), 620-624

“A microbial symbiosis factor prevents intestinal inflammatory
disease”

Sarkis K. Mazmanian(1), June L. Round(1) & Dennis L. Kasper(2,3)

1-Division of Biology, California Institute of Technology, Pasadena,
California.
2-Channing Laboratory, Brigham & Women’s Hospital, Harvard Medical
School, Boston, Massachusetts
3-Department of Microbiology and Molecular Genetics, Harvard Medical
School, Boston, Massachusetts

Harvard Medical School (http://hms.harvard.edu/hms/home.asp) has more
than 7,500 full-time faculty working in 11 academic departments
located at the School's Boston campus or in one of 47 hospital-based
clinical departments at 18 Harvard-affiliated teaching hospitals and
research institutes. Those affiliates include Beth Israel Deaconess
Medical Center, Brigham and Women's Hospital, Cambridge Health
Alliance, Children's Hospital Boston, Dana-Farber Cancer Institute,
Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife,
Joslin Diabetes Center, Judge Baker Children's Center, Immune Disease
Institute, Massachusetts Eye and Ear Infirmary, Massachusetts General
Hospital, McLean Hospital, Mount Auburn Hospital, Schepens Eye
Research Institute, Spaulding Rehabilitation Hospital, and VA Boston
Healthcare System.

Brigham and Women’s Hospital (http://www.brighamandwomens.org/) is a
747-bed nonprofit teaching affiliate of Harvard Medical School and a
founding member of Partners HealthCare, an integrated health care
delivery network. BWH is committed to excellence in patient care with
expertise in virtually every specialty of medicine and surgery. BWH is
an international leader in basic, clinical and translational research
on human diseases, involving more than 860 physician-investigators and
renowned biomedical scientists and faculty supported by more than $416
M in funding. BWH is also home to major landmark epidemiologic
population studies, including the Nurses’ and Physicians’ Health
Studies and the Women’s Health Initiative.

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