Using bacteria to get well

Dr. Alexander Khoruts had run out of options. In 2008, Khoruts, a
gastroenterologist at the University of Minnesota, took on a patient suffering
from a vicious gut infection of Clostridium difficile. She was crippled by
constant diarrhoea, which had left her in a wheelchair wearing diapers. Khoruts
treated her with an assortment of antibiotics, but nothing could stop the bacteria.
His patient was wasting away, losing 27 kilograms over the course of eight
months. “She was just dwindling down the drain, and she probably would have
died,” Khoruts said.

Khoruts decided his patient needed
a transplant. But he didn’t give her a piece of someone else’s intestines, or a
stomach, or any other organ. Instead, he gave her some of her husband’s
bacteria.

Khoruts mixed a small sample of her
husband’s stool with saline solution and delivered it into her colon. Writing
in the Journal of Clinical Gastroenterology last month, Khoruts and his
colleagues reported that her diarrhoea vanished in a day. Her Clostridium
difficile infection disappeared as well and has not returned since.

The procedure – known as
bacteriotherapy or fecal transplantation – had been carried out a few times
over the past few decades. But Khoruts and his colleagues were able to do
something previous doctors could not: They took a genetic survey of the
bacteria in her intestines before and after the transplant.

Before the transplant, they found,
her gut flora was in a desperate state. “The normal bacteria just didn’t exist
in her,” said Khoruts. “She was colonized by all sorts of misfits.”

Two weeks after the transplant, the
scientists analysed the microbes again. Her husband’s microbes had taken over.
“That community was able to function and cure her disease in a matter of days,”
said Janet Jansson, a microbial ecologist at Lawrence Berkeley National
Laboratory and a co-author of the paper. “I didn’t expect it to work. The
project blew me away.”

Scientists are regularly blown away
by the complexity, power and sheer number of microbes that live in our bodies.
“We have over 10 times more microbes than human cells in our bodies,” said Dr.
George Weinstock of Washington University in St. Louis. But the microbiome, as
it’s known, remains mostly a mystery. “It’s as if we have these other organs,
and yet these are parts of our bodies we know nothing about.”

International effort

Weinstock is part of an
international effort to shed light on those puzzling organs. He and his
colleagues are cataloguing thousands of new microbe species by gathering their
DNA sequences. Meanwhile, other scientists are running experiments to figure
out what those microbes are actually doing. They’re finding that the microbiome
does a lot to keep us in good health. Ultimately, researchers hope, they will
learn enough about the microbiome to enlist it in the fight against diseases.

“In just the last year, it really
went from a small cottage industry to the big time,” said Dr. David Relman of
Stanford University.
The microbiome first came to light in the mid-1600s, when the Dutch
lens-grinder Antonie van Leeuwenhoek scraped the scum off his teeth, placed it
under a microscope and discovered that it contained swimming creatures. Later
generations of microbiologists continued to study microbes from our bodies, but
they could only study the ones that could survive in a laboratory. For many
species, this exile meant death.

In recent years, scientists have
started to survey the microbiome in a new way: by gathering DNA. They scrape
the skin or take a cheek swab and pull out the genetic material. Getting the
DNA is fairly easy. Sequencing and making sense of it is hard, however, because
a single sample may yield millions of fragments of DNA from hundreds of
different species.

A number of teams are working
together to tackle this problem in a systematic way. Weinstock is part of the
biggest of these initiatives, known as the Human Microbiome Project. The $150
million initiative was started in 2007 by the National Institutes of Health.
The project team is gathering samples from 18 different sites on the bodies of
300 volunteers.

Sequencing

To make sense of the genes that
they’re gathering, they are sequencing the entire genomes of some 900 species
that have been cultivated in the lab. Before the project, scientists had only
sequenced about 20 species in the microbiome. In May, the scientists published
details on the first 178 genomes. They discovered 29,693 genes that are unlike
any known genes. (The entire human genome contains only around 20,000
protein-coding genes.)

“This was quite surprising to us,
because these are organisms that have been studied for a long time,” said Karen
E. Nelson of the J. Craig Venter Institute in Rockville, Maryland.
The new surveys are helping scientists understand the many ecosystems our
bodies offer microbes. In the mouth alone, Relman estimates, there are between
500 and 1,000 species. “It hasn’t reached a plateau yet: The more people you
look at, the more species you get,” he said. The mouth in turn is divided up
into smaller ecosystems, like the tongue, the gums, the teeth. Each tooth – and
even each side of each tooth – has a different combination of species.

Scientists are even discovering
ecosystems in our bodies where they weren’t supposed to exist. Lungs have
traditionally been considered to be sterile because microbiologists have never
been able to rear microbes from them. A team of scientists at Imperial College
London recently went hunting for DNA instead. Analysing lung samples from
healthy volunteers, they discovered 128 species of bacteria. Every square
centimetre of our lungs is home to 2,000 microbes.

Some microbes can only survive in
one part of the body, while others are more cosmopolitan. And the species found
in one person’s body may be missing from another’s. Out of the 500 to 1,000
species of microbes identified in people’s mouths, for example, only about 100
to 200 live in any one person’s mouth at any given moment. Only 13 percent of
the species on two people’s hands are the same. Only 17 percent of the species
living on one person’s left hand also live on the right one.

This variation means that the total
number of genes in the human microbiome must be colossal. European and Chinese
researchers recently catalogued all the microbial genes in stool samples they
collected from 124 individuals. In March, they published a list of 3.3 million
genes.
The variation in our microbiomes emerges the moment we are born.

“You have a sterile baby coming
from a germ-free environment into the world,” said Dr. Maria Dominguez-Bello, a
microbiologist at the University of Puerto Rico. Recently, she and her
colleagues studied how sterile babies get colonized in a hospital in the
Venezuelan city of Puerto Ayacucho. They took samples from the bodies of
newborns within minutes of birth. They found that babies born vaginally were
coated with microbes from their mothers’ birth canals. But babies born by Caesarean
section were covered in microbes typically found on the skin of adults.
“Our bet was that the Caesarean section babies were sterile, but it’s like
they’re magnets,” said Dominguez-Bello.

We continue to be colonized every
day of our lives. “Surrounding us and infusing us is this cloud of microbes,”
said Dr. Jeffrey Gordon of Washington University. We end up with different
species, but those species generally carry out the same essential chemistry
that we need to survive. One of those tasks is breaking down complex plant
molecules. “We have a pathetic number of enzymes encoded in the human genome,
whereas microbes have a large arsenal,” said Gordon.

Good germs

In addition to helping us digest,
the microbiome helps us in many other ways. The microbes in our nose, for
example, make antibiotics that can kill the dangerous pathogens we sniff. Our
bodies wait for signals from microbes in order to fully develop. When
scientists rear mice without any germ in their bodies, the mice end up with
stunted intestines.

In order to co-exist with our
microbiome, our immune system has to be able to tolerate thousands of harmless
species, while attacking pathogens. Scientists are finding that the microbiome
itself guides the immune system to the proper balance.
One way the immune system fights pathogens is with inflammation. Too much
inflammation can be harmful, so we have immune cells that produce
inflammation-reducing signals. Last month, Sarkis Mazmanian and June L. Round
at Caltech reported that mice reared without a microbiome can’t produce an
inflammation-reducing molecule called IL-10.

The scientists then inoculated the
mice with a single species of gut bacteria, known as Bacteroides fragilis. Once
the bacteria began to breed in the guts of the mice, they produced a signal
that was taken up by certain immune cells. In response to the signal, the cells
developed the ability to produce IL-10.

Scientists are not just finding new
links between the microbiome and our health. They’re also finding that many
diseases are accompanied by dramatic changes in the makeup of our inner
ecosystems. The Imperial College team that discovered microbes in the lungs,
for example, also discovered that people with asthma have a different
collection of microbes than healthy people. Obese people also have a different
set of species in their guts than people of normal weight.

In some cases, new microbes may
simply move into our bodies when disease alters the landscape. In other cases,
however, the microbes may help give rise to the disease. Some surveys suggest
that babies delivered by Caesarian section are more likely to get skin
infections from multiply-resistant Staphylococcus aureus. It’s possible that
they lack the defensive shield of microbes from their mother’s birth canal.

Caesarean link

Caesarean sections have also been
linked to an increase in asthma and allergies in children. So have the
increased use of antibiotics in the United States and other developed countries.
Children who live on farms – where they can get a healthy dose of microbes from
the soil – are less prone to getting autoimmune disorders than children who
grow up in cities.

Some scientists argue that these
studies all point to the same conclusion: When children are deprived of their
normal supply of microbes, their immune systems get a poor education. In some
people, untutored immune cells become too eager to unleash a storm of inflammation.
Instead of killing off invaders, they only damage the host’s own body.

A better understanding of the
microbiome might give doctors a new way to fight some of these diseases. For
more than a century, scientists have been investigating how to treat patients
with beneficial bacteria. But probiotics, as they’re sometimes called, have
only had limited success. The problem may lie in our ignorance of precisely how
most microbes in our bodies affect our health.
Khoruts and his colleagues have carried out 15 more fecal transplants, 13 of
which cured their patients. They’re now analysing the microbiome of their patients
to figure out precisely which species are wiping out the Clostridium difficile
infections. Instead of a crude transplant, Khoruts hopes that eventually he can
give his patients what he jokingly calls “God’s probiotic” – a pill containing
microbes whose ability to fight infections has been scientifically validated.

Weinstock, however, warns that a
deep understanding of the microbiome is a long way off.

“In terms of hard-boiled science,
we’re falling short of the mark,” he said. A better picture of the microbiome
will only emerge once scientists can use the genetic information Weinstock and
his colleagues are gathering to run many more experiments.

“It’s just old-time
science. There are no shortcuts around that,” he said.

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