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-   -   Going with His Gut Bacteria ( 08-11-2008 09:40 AM

Going with His Gut Bacteria
The body and its intestinal flora produce chemicals with hidden health
information, Jeremy Nicholson has found. Someday treating disease
may mean treating those bacteria BY MELINDA WENNER

Jeremy Nicholson was only trying tobe thorough. It was 1981, and the
young biochemist was using a techniquecalled nuclear magnetic
spectroscopy, which can identify chemicalsbased on the magnetic
properties of
atomic nuclei. In particular,Nicholson wanted to study
how red blood cells absorbcadmium, a metal that causes
cancer. Realizing that hewould achieve the best results
if he could mimic the cells’natural environment, he added
a few drops of blood to thecells and ran the test.
“Suddenly there was ahuge variety of signals that we
hadn’t seen before—therewere these amazing sets of
spectra coming out,” Nicholsonrecalls. A sample of blood
or urine contains thousandsof metabolites—signatures of
all the chemical reaction soccurring in the body at a given
time. If he could find a wayto identify those chemical signatures
and their significance,he reasoned, he would be able
not only to better understand different diseases—based on
chemical reactions that had gone awry—but also to identify
early warning signs and potential interventions. That
kind of science, he decided, was his kind of science.
Today the 51-year-old Nicholson is one of the world’s
foremost experts on the socalled metabolome, the collection of
chemicals produced
by human metabolism. Whereas the genome provides detailed information
about a person’s genetic makeup, the metabolome is a few steps down
the line—
it reveals how genes interact with the environment, providing a
complete snapshot of
a person’s physical health. “The genome is really like a telephone
directory without
any of the names or addresses filled in. On a very basic level, it’s
got a lot of numbers,”
explains Nicholson, who now heads the department of biomolecular
medicine at
Imperial College London. The metabolome “helps to give
value to genome information and put it in perspective.”
But first it has to be deciphered, and that is no easy
task. The job requires the analysis of blood, urine,
breath and feces within large populations. For instance, to
find potential chemical signatures, or biomarkers, for high blood
pressure, Nicholson
and his colleagues analyzed the urine of 4,630 individuals from the
U.K., the U.S. and
Asia and compared the urinary metabolites with blood pressure data to
determine if
any consistent metabolic differences exist between individuals with
and those without it. It is kind of like doing science backward:
instead of
making hypotheses and then devising experiments to test them, he
performs experiments
first and tries to decipher his results later. He must sift through
the range of
chemicals produced by the genes people have, the food they eat, the
drugs they take,
the diseases they suffer from and the intestinal bacteria they harbor.

BACTERIAL CLUES: By analyzing the products of intestinal bacteria,
Nicholson hopes to fashion new tools for diagnosis and new targets
for drugs.
POPULATION BOOM: The human gut contains some 10 trillion individual
bacteria in 1,000 different species.
FATHER OF DISCIPLINES: Nicholson’s work has spawned two new
fields: metabolomics, which studies the metabolites that cellular
leave behind, and metabonomics, which characterizes the metabolic
changes a biological system experiences in response to stressors.
GROWING ON HIM: On first noticing metabolic fingerprints that
cells leave behind: “I was thinking of them as extremely annoying
interferences with mammalian biochemistry. Now I’m almost becoming
evangelical about the bloody things.”

Those bacteria in particular have become Nicholson’s prime focus. They
influence how our bodies break down food and drugs and may explain why
affects people differently. For instance, some people cannot derive
benefit from
one of soy’s components because they lack the gut microbes necessary
to process it.
Although deciphering which metabolites come directly from our gut
microbes can
be difficult, in some cases it is easy—they are the chemicals that are
not produced by
cells or ingested in food. Nicholson focuses on these chemicals both
because little is known about them and because they appear to be
highly relevant: recent research suggests
that gut microbes play a crucial role in human health and disease.
help us absorb nutrients and fight off viruses and “bad” bacteria;
disrupting intestinal colonies, such as with a course of antibiotics,
often leads to digestive sickness. In fact, Nicholson says, “almost
every sort of disease has a gut bug connection somewhere.” Perhaps the
most well-known disease- causing gut organism is the bacterium
Helicobacter pylori, which can trigger peptic ulcer. In the past few
years, scientists have linked obesity to the relative abundance of two
intestinal bacterial phyla and found that dysfunctional intestinal
bacteria are associated with nonalcoholic fatty liver disease,
bowel disease and some types of cancer. Nicholson even speculates that
the organisms
could play a role in neurological disorders, such as attention-deficit
disorder, Tourette’s syndrome and autism. “We have some evidence now
shows that if you mess around with the gut microbes, you mess around
with brain
chemistry in major ways,” Nicholson remarks. He currently collaborates
microbiologists to match metabolites with specific bacteria—there are
thought to be
1,000 species and more than 10 trillion bacterial cells inside us at
any given time.
This identification process has only recently become possible.
Although scientists
have been able to extract gut bacteria from fecal samples for many
years, it has
been next to impossible to culture the samples afterward because they
survive only in
highly acidic, oxygen-free environments. Thanks to new DNA-sequencing
scientists can now identify gut bacteria fairly easily, and there is
growing interest
in doing so: the National Institutes of Health launched its Human
Project last December with the goal of fully characterizing the human
gut flora.
Once investigators can correlate metabolites with health, it may one
day be possible,
Nicholson says, to make urine sticks similar to those used in
pregnancy tests to
regularly check the fitness of our gut flora. Some companies have
already begun selling
food products to help keep these populations in line—with live
beneficial bacteria
(probiotics) or compounds that help these species grow (prebiotics),
or combinations
of the two (synbiotics). Unfortunately, these medications typically
into the category of “functional foods,” which means they are rarely
tested in clinical
trials. One exception is VSL #3, a combination of eight bacterial
species sold
in packet form by the Gaithersburg, Md.– based VSL Pharmaceuticals. In
placebo-controlled trials, the colonies effectively treated ulcerative
colitis and irritable bowel syndrome. Many possibilities exist for bug-
based drugs, and there is a strong need for them,
Nicholson maintains. According to a study published by scientists at
the pharmaceutical
giant Pfizer, the human genome offers only about 3,000 potential drug
targets, because just a subset of genes produces proteins that can be
bound and modified by druglike molecules. But “there are 100 times as
many genes in the microbial pool,” says Nicholson,
who regularly works with drug companies to better elucidate how people
metabolize medicines. He is “one of a few academics I’ve met who’s
in the pharmaceutical industry for its problems rather than just for
cash,” comments Ian Wilson, a scientist working in England for the
company AstraZeneca.

Wilson adds that Nicholson is always full of potential solutions,
referring to
him as “a bubbling mass of ideas.” Because genes provide only limited
information about a person’s risk for disease, Nicholson dreams of a
when physicians can provide personalized health care on the
Simple blood or urine tests would detect the risk of cancer or heart
early enough to begin preventive therapy; drugs would be tailored to
person’s metabolic profile—and in many cases, they would not target
our organs
but our bacteria. “It opens up visions of a future that we would never
have suspected
even a few years ago,” Nicholson says. “Many microbiologists might
argue this
is fanciful, but you only make huge progress unthinkable.” n
Melinda Wenner is a freelance science
writer based in New York City. A Q&A
version of her interview with Nicholson
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