人體上的細菌

Tending the Body’s Microbial Garden

By CARL ZIMMER NYT 2012-6-18

For
a century, doctors have waged war against bacteria, using antibiotics as their weapons. But that
relationship is changing as scientists become more familiar with the 100
trillion microbes that call us home — collectively known as the microbiome.

“I
would like to lose the language of warfare,” said Julie Segre, a senior
investigator at the National Human Genome Research Institute. “It does a
disservice to all the bacteria that have co-evolved with us and are maintaining
the health of our bodies.”

This
new approach to health is known as medical ecology. Rather than conducting
indiscriminate slaughter, Dr. Segre and like-minded scientists want to be
microbial wildlife managers.

No
one wants to abandon antibiotics outright. But by nurturing the invisible
ecosystem in and on our bodies, doctors may be able to find other ways to fight
infectious diseases, and with less harmful side
effects. Tending the microbiome may also help in the treatment of disorders
that may not seem to have anything to do with bacteria, including obesity and diabetes.

“I
cannot wait for this to become a big area of science,” said Michael A. Fischbach, a microbiologist at the
University of California, San Francisco, and an author of a medical ecology
manifesto published this month in the journal Science Translational
Medicine.

Judging
from a flood of recent findings about our inner ecosystem, that appears to be
happening. Last week, Dr. Segre and about 200 other scientists published the most ambitious survey
of the human microbiome yet. Known as the Human Microbiome Project,
it is based on examinations of 242 healthy people tracked over two years. The
scientists sequenced the genetic
material of bacteria recovered from 15 or more sites on their
subjects’ bodies, recovering more than five million genes.

The
project and other studies like it are revealing some of the ways in which our
invisible residents shape our lives, from birth to death.

A
number of recent reports shed light on how mothers promote the health of their
children by shaping their microbiomes. In a study published last week in the journal PLoS
One, Dr. Kjersti Aagaard-Tillery, an obstetrician at Baylor College of
Medicine, and her colleagues described the vaginal microbiome in pregnant
women. Before she started the study, Dr. Aagaard-Tillery expected this microbiome
to be no different from that of women who weren’t pregnant.

“In
fact, what we found is the exact opposite,” she said.

Early
in the first trimester of pregnancy, she found, the diversity of vaginal
bacteria changes significantly. Abundant species become rare, and vice versa.

One
of the dominant species in the vagina of a pregnant woman, it turns out, is
Lactobacillus johnsonii. It is usually found in the gut, where it produces
enzymes that digest milk. It’s an odd species to find proliferating in the
vagina, to say the least. Dr. Aagaard-Tillery speculates that changing
conditions in the vagina encourage the bacteria to grow. During delivery, a
baby will be coated by Lactobacillus johnsonii and ingest some of it. Dr.
Aagaard-Tillery suggests that this inoculation prepares the infant to digest breast milk.

The
baby’s microbiome continues to grow during breast-feeding. In a study of 16 lactating women
published last year, Katherine M. Hunt of the University of Idaho
and her colleagues reported that the women’s milk had up to 600 species of
bacteria, as well as sugars called oligosaccharides that babies cannot digest.
The sugars serve to nourish certain
beneficial gut bacteria in the infants, the scientists said. The
more the good bacteria thrive, the harder it is for harmful species to gain a
foothold.

As
the child grows and the microbiome becomes more ecologically complex, it also
tutors the immune system. Ecological disruptions can halt this education. In
March, Dr. Richard S. Blumberg of Harvard and his colleagues reported an experiment
that demonstrates how important this education is.

The
scientists reared mice that lacked any microbiome. In their guts and lungs, the
germ-free mice developed abnormally high levels of immune cells called
invariant natural killer T cells. Normally, these cells trigger a swift
response from the immune system against viruses and other pathogens. In Dr.
Blumberg’s microbe-free mice, however, they caused harmful inflammation. As
adults, the mice were more likely to suffer from asthma and inflammatory bowel disease.

This
experiment parallels studies of children in recent years. Children who take
high levels of antibiotics may be at greater
risk of developing allergies and asthma later on, many researchers
have suggested.

Dr.
Blumberg and his colleagues found that they could prevent the mice from
becoming ill by giving them bacteria while they were still young. Acquiring a
microbiome as an adult did not help the rodents.

The
Good With the Bad

The
diversity of species that make up the microbiome is hard to fathom. But it is
even more difficult to understand how the immune system copes with this
onslaught. In any one person’s mouth, for example, the scientists of the Human
Microbiome Project found about 75 to 100 species. Some that predominate in one
person’s mouth may be rare in another person’s. Still, the rate at which they
are being discovered indicates that there may be as many as 5,000 species of
bacteria that live in the human mouth.

“The
closer you look, the more you find,” said Susan M. Huse of the Marine
Biological Laboratory in Woods Hole, Mass., a contributor to the microbiome
project.

Although
the project has focused largely on bacteria, the microbiome’s diversity is
wider. For example, our bodies also host viruses.

Many
species in the human “virome” specialize in infecting our resident bacteria.
But in the DNA samples stored in the Human Microbiome Project’s database,
Kristine Wylie of Washington University and her colleagues are finding a wealth
of viruses that target human cells. It is normal, it seems, for people to have
a variety of viruses busily infecting their human hosts. “It’s really pretty
striking that even in these healthy people, there really is a virome,” Dr. Wylie
said.

The
microbiome also includes fungi. In the June 8 issue of the journal Science, David Underhill, a
research scientist at Cedars-Sinai hospital in Los Angeles, and his colleagues reported on a
wealth of fungal species in the guts of humans and other mammals. In mice, for
example, they cataloged 100 species of fungi that are new to science, along
with 100 already known. This diversity is all the more remarkable when you
consider that it is tolerated by an immune system that has evolved to fight off
microbes. Scientists have only a dim understanding of how the system decides
which to kill and which to tolerate.

Immune
cells fight fungal infections, for example, with a protein called dectin-1,
which attaches only to fungi. But Dr. Underhill and his colleagues found that
dectin-1 is also essential for tolerating harmless fungi. When they engineered
mice that couldn’t produce dectin-1, the mice responded to harmless fungi by
producing so much inflammation that their own tissues were damaged.

It’s
a good thing that the immune system can rein itself in, because the microbiome
carries out many services for us. In the gut, microbes synthesize vitamins and break down tough plant compounds
into digestible bits.

Skin
bacteria are also essential, Dr. Segre said. “One of the most important
functions of the skin is to serve as a barrier,” she said. Bacteria feed on the
waxy secretions of skin cells, and then produce a moisturizing film that keeps
our skin supple and prevents cracks — thus keeping out invading pathogens.

Restoring
Order to the System

Antibiotics
kill off harmful bacteria, but broad-spectrum forms can kill off many desirable
species, too. Dr. Fischbach likens antibiotics to herbicides sprayed on a
garden. The herbicide kills the unwanted plants, but also kills off the
tomatoes and the roses. The gardener assumes that the tomatoes and roses will
grow back on their own.

In
fact, there’s no guarantee the microbial ecosystem will automatically return to
normal. “It’s one of those assumptions we make today that will seem silly in
retrospect,” Dr. Fischbach said. Indeed, some bacteria are adapted for invading
and establishing themselves in disrupted ecosystems. A species called
Clostridium difficile will sometimes invade a person’s gut after a course of
antibiotics. From 2000 to 2009, the number of hospitalized patients in the
United States found to have C. difficile more than doubled, to 336,600 from
139,000. Once established, the antibiotic-resistant C. difficile can be hard to
eradicate.

Now
that scientists are gaining a picture of healthy microbiomes, they are
optimistic about restoring devastated ones. “I don’t know that we’re quite on
the cusp of being able to do that well at this point. But I think at least the
data is starting to argue that these might be possibilities,” said Barbara Methé of the J. Craig Venter Institute, a
principal investigator on the microbiome project.

One
way to restore microbiomes may be to selectively foster beneficial bacteria. To
ward off dangerous skin pathogens like Staphylococcus aureus, for instance, Dr.
Segre envisions applying a cream infused with nutrients for harmless skin
bacteria to feed on. “It’s promoting the growth of the healthy bacteria that
can then overtake the staph,” she said.

Bacterial
Transplants

Adding
the bacteria directly may also help. Unfortunately, the science of so-called
probiotics lags far behind their growth in sales. In 2011, people bought $28
billion of probiotic foods and supplements, according to the research firm
EuroMonitor International. But few of them have been tested as rigorously as
conventional drugs.

“I
think the science has been shoddy and flimsy,” said Dr. Fischbach (who is on
the scientific advisory board of Schiff Nutrition International).

Nonetheless,
he sees a few promising probiotic treatments. A growing number of doctors are
treating C. difficile with fecal transplants: Stool from a healthy donor is
delivered like a suppository to an infected patient. The idea is that the good
bacteria in the stool establish themselves in the gut and begin to compete with
C. difficile. This year, researchers at the University of Alberta reviewed 124 fecal
transplants and concluded that the procedure is safe and effective,
with 83 percent of patients experiencing immediate improvement as their internal
ecosystems were restored.

Dr.
Alexander Khoruts of the University of Minnesota and his colleagues want to make fecal transplants
standard practice. They can now extract bacteria from stool, “removing the
‘ick’ factor,” as he puts it.

Dr.
Khoruts and his colleagues have federal approval to start formal clinical
trials on fecal transplants. Eventually, he would like to develop probiotic
pills that contain just a few key species required to build the intestinal
ecosystem.

“People
are starting to take this seriously,” Dr. Fischbach said. “This is a therapy
that’s going to help a lot of people.”

Other
conditions potentially could be treated by manipulating the microbiome.
Scientists have linked obesity, for example, to changes to the gut’s ecosystem.
When scientists transfer bacteria from obese mice to lean ones, the lean mice
put on weight.

How
this happens is still unclear, but some studies suggest that an “obese”
microbiome sends signals to the body, changing how cells use sugar for energy
and leading the body to store extra fat.

Researchers
at the Academic Medical Center in Amsterdam are running a clinical trial
to see if fecal transplants can help treat obesity. They have recruited 45
obese men; some are getting transplants from their own stool, while others get
transplants from lean donors. The scientists are finding that the transplants
from lean donors are changing how the obese subjects metabolize sugar.

While
these initial results are promising, there is no evidence yet that the obese
subjects are losing weight. Dr. Fischbach cautions that it may take a while to
figure out how to manipulate the microbiome to make people healthy.

And
it may take even longer to persuade doctors to think like ecologists.

“The
physicians I know really like things that are clear and crisp,” Dr. Fischbach
said. “But like any ecosystem, the microbiome is not the kind of place to find
simple answers.”