FOR RELEASE: 1 FEBRUARY 2001 AT 14:00 ET US
Washington University School of Medicine
http://medinfo.wustl.edu/

Friendly microbes control intestinal genes, study finds

A paper in the Feb. 2 issue of Science reports the use of new molecular
technologies for unraveling the age-old mystery of the relationships between
ourselves and the microbes that live in our body. The study reveals that
microorganisms in the gut influence the expression of a number of genes that
are important to intestinal development and function.

"We live in a world predominated by microbes," explains Jeffrey I. Gordon, 
M.D.
"These organisms have co-evolved with their mammalian hosts over millions of
years. During this time, they have been forced to become master physiologic
chemists—they have had to develop strategies for satisfying their own
nutritional needs and various needs of their hosts. We wanted to figure out
some of the lessons that they have learned about us, and how they contribute 
to
our health."

Gordon, who led the study, is the Alumni Professor and Head of the Department
of Molecular Biology and Pharmacology at Washington University School of
Medicine in St. Louis. The first author is Lora V. Hooper, Ph.D., an 
instructor
in molecular biology and pharmacology and a recipient of a career development
award from the Burroughs Welcome Fund.

The human intestine contains the largest society of friendly microbes in the
body. The total number of these microbes may be equal to the total number of
cells in our body. Given its large microbial society, the intestine is the 
best
place to turn when trying to understand how friendly bacteria affect our 
genes.
These bacteria don’t simply sit and wait to be fed by the nutrients we 
consume.
Instead, they actively shape our biology so that they can establish and
maintain homes for themselves.

The researchers addressed the general question of how microbes and humans
co-exist using mice as a model system. After raising mice in a germ-free
environment, they inoculated the animals with Bacteroides thetaiotaomicron, a
bacterium normally found in healthy human and mouse intestines. Using two
relatively new technologies—DNA microarrays and laser capture
microdissection—they examined the bacterium’s effect on intestinal
functions.

DNA microarrays, or gene chips, are a direct product of the world-wide effort
to identify all of the genes in our DNA, and in the DNA of other species. 
These
microarrays allow scientists to examine expression of many genes at once. "We
did not have a preconceived notion of how many intestinal functions are
influenced by gut microbes," notes Hooper. "Gene chips allowed us to survey, 
in
a relatively unbiased way, the effects of a common gut microbe on more than
20,000 mouse genes."

The team found that B. thetaiotaomicron affected genes involved in a number of
critical gut functions. Entry of this microbe into the germ-free intestine
activated several mouse genes involved in absorption and metabolism of sugars
and fats. It also activated genes that control the integrity of the cellular
barrier that lines the intestine and separates us from dangerous organisms and
ingested substances. Other genes affected by the bacterium regulate how
potentially toxic compounds are metabolized, how blood vessels are formed and
how the gut matures during the post-natal period.

"We were amazed at the breadth of normal intestinal functions affected by a
single microbe," says Hooper.

Gordon’s group wanted to understand which intestinal cells were responsible 
for
these results. They used another relatively new technique called laser capture
microdissection, originally developed to help cancer researchers define the
molecular details of tumor formation. This method allows scientists to carve
out a particular cell from a tissue sample and to measure gene expression.

"The combination of a relatively old technique—the use of germ-free mice—and
the two newer techniques allowed us, for the first time, to take a detailed
look at how particular cells in living animals respond to the addition of a
microbe," says Gordon.

For example, the team discovered that certain populations of intestinal lining
cells in the mice responded to B. thetaiotaomicron by stepping up their
production of three proteins — co-lipase which helps break down fats, small
proline-rich protein 2a (sprr2a) which may help fortify the intestinal 
barrier,
and angiogenin-3 which stimulates blood vessel formation. Some of these
responses, such as the increased expression of sprr2a, were elicited when
germ-free mice were colonized with B. thetaiotaomicron but not with some of 
the
other normal resident bacteria of the intestine. This suggests that the
composition of our gut’s microbial society may help define the nature of our
physiology.

"One of our findings is that microbes are able to regulate intestinal genes
involved in breaking down foods into simpler units that can be absorbed,"
explains Gordon. "This raises the question of whether there are variations in
the types of intestinal microbes between individual humans, and how such
differences affect our nutritional status, our health and our predisposition 
to
certain diseases." According to Gordon, answering this question might shed
light on human diseases such as inflammatory bowel disease, irritable bowel
syndrome and other disorders. Understanding the regulation of intestinal
barrier functions might even reveal how some microbes affect our
susceptibilities to food and other allergies.

"Shortly after birth, resident microbes begin to educate the gut’s immune
system, signaling that they are safe, normal partners that do not merit an
immune response," says Gordon. "As well as preventing adverse responses to
normal bacteria, this educational process might help ensure that we don’t 
react
poorly to certain antigens we ingest.

When the alliance between microbe and host is upset, there may be serious
consequences to human health. In the future, the team hopes to learn more 
about
how normal bacteria develop an effective working relationship with humans. 
They
would like to exploit the strategies developed by our microbes over the course
of several million years to help identify new therapies for promoting health
and for treating diseases that occur inside, or even outside, our
gastrointestinal tract.