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Sunday, July 26, 2015

Fecal transplant, not just for C. difficile, it could cure various diseases.


 Gut of the matter


In a study published in January in the New England Journal of Medicine
a Dutch team found that these transplants (using the real stuff, not synthetic) 
cured 15 of 16 people with recurring C. diff
Antibiotics cured three of 13, and four of 13, in two separate groups. 
Fecal transplant was “significantly more effective” than the use of v
ancomycin, the study concluded

“It’s a proof of principle that restoring a normal intestinal ecosystem 
can cure an important disease,” says Dr. Martin Blaser, an infectious 
diseases specialist at New York University’s Langone Medical Center, who 
was not involved in that study. 

“It suggests that if the microbial ecosystem is disturbed, and you 
can [fix] it, you could cure various diseases.” In other words, 
not just C. difficile.
Fecal transplant, which has been practised for centuries 
(takethrough the mouth, it was called “yellow soup” in 
traditional Chinese medicine), gives scientists a window 
into the ecosystems of bacteria that inhabit our bodies: 
a vast, interconnected web called the human microbiome, 
which remains terra incognita—and our next medical frontier.

A miracle cure, not for the squeamish

Are fecal transplants the next treatment for 
heart disease, Crohn’s and even autism?


Cynthia Morgan-Robson always prided herself on her independence.
She raised four kids (her husband died of cancer 45 years ago),
including a daughter with Down’s syndrome. She lived on her
own in Port Hope, Ont., well into her senior years, and every
Sunday night, she’d drop into daughter Linda Harness’s house
for dinner. In 2009, following a string of hospital
visits related to knee-replacement surgery,
Morgan-Robson acquired a vicious
Clostridium difficile (C. diff) infection.
Laid low by crippling diarrhea, she could no longer care 
for herself. At times, she was incoherent. 
Vancomycin, a powerful antibiotic prescribed for C. diff,
seemed to help, but as soon as she went off the drug,
her symptoms returned.
Harness moved her mother, now 75, into a nursing home in
early 2012. “Her cognition was completely gone,” says Harness,
a nurse. “She couldn’t eat, couldn’t use the toilet, couldn’t walk.”
A doctor at the nursing home referred her to infectious diseases
specialist Dr. Elaine Petrof, who works with C. diff patients at
the Kingston General Hospital. Petrof suggested a fecal
transplant—transferring a donor’s stool, by colonoscopy or
enema, into the patient’s colon.
Harness, who was tapped to supply her mother’s dose, was
initially horrified. “Dr. Petrof said, ‘Go buy a Magic Bullet [blender].
You’re only going to use it once, and it’s not going to be for
a drink,” she says. The idea of fecal transplant is that “good”
bacteria from healthy stool move in and take up residence,
crowding out “bad” bacteria such as C. diff. The donor (typically
a patient’s family member) is screened for conditions that could
disqualify her, including hidden disease or parasites. She’s
instructed to produce a sample at home, put it on ice and
take it to hospital for the procedure. “I almost broke into
hysterics,” Harness continues. “Even as a nurse, I’d never heard
of this.”
The Magic Bullet was spared. Instead of calling for Harness’s
sample, Petrof recruited Morgan-Robson into a clinical study
using synthetic feces—the first of its kind—produced with the
 help of the “robo-gut” at the University of Guelph, a bioreactor
that approximates the human colon. “Elaine contacted me because
she knew I could culture a lot of the bugs found in the human
gut,” says Guelph microbiologist Emma Allen-Vercoe. They found
a donor who’d rarely taken antibiotics and was thought to have
a healthy, diverse communty of gut bacteria, then seeded the
robo-gut with the donor’s fecal sample. The scientists chose
33 strains of bacteria they knew could be knocked out with
antibiotics (so there would be an “antidote” if anything went
wrong), and added them to a saline solution. The synthetic
stool, called “Repoopulate,” is “way less gross” than the real
thing, says Allen-Vercoe, who adds that it looks a bit like a
 vanilla milkshake.
Amazingly, it seems to have cured Morgan-Robson and the other C. diff patient who was treated as part of the study. Both received
Repoopulate by colonoscopy at Kingston General in May 2012;
since then, their symptoms have disappeared. Morgan-Robson,
who remains in the nursing home, has returned to her former
self. After the treatment, she was able to recognize Harness’s
three daughters again. “We were amazed,” Harness says.
“She’s back.”
Canada has become a hotbed for C. difficile infection, which
can be fatal: Between 1997 and 2005, hospitals saw an almost
fourfold increase in associated deaths, according to the Public
Health Agency of Canada, partly due to the spread of a more
dangerous strain of the bug. Those at risk aren’t just the elderly
and hospital-bound. Increasingly, “community-acquired cases”
are being reported among young and otherwise healthy people,
Petrof says, such as women who’ve received antibiotics prior
to Caesarean sections, or patients who get antibiotics from
their family doctors for sinus infections. “I have Queen’s University
students in my clinic,”
says Petrof, who is also an associate professor there. “I see
people in their twenties. I’ve been contacted about children
[with C. diff].”
Fecal transplant appears to be a powerful way to treat them,
maybe even more effective than antibiotics. Emerging evidence
suggests many of the illnesses that plague us today, including 
asthma, heart disease, diabetes, allergies and even autism, 
could be related to the billions of bacteria in, on, and around 
us—and the success of fecal transplant in combatting C. diff 
hints at potential fixes for a range of conditions.
In a study published in January in the New England Journal 
of Medicine, a Dutch team found that these transplants
(using the real stuff, not synthetic) cured 15 of 16 people with
recurring C. diff. Antibiotics cured three of 13, and four of 13,
in two separate groups. Fecal transplant was “significantly more
effective” than the use of vancomycin, the study concluded. “It’s
a proof of principle that restoring a normal intestinal ecosystem can
cure an important disease,” says Dr. Martin Blaser, an infectious
diseases specialist at New York University’s Langone Medical Center,
who was not involved in that study. “It suggests that if the
microbial ecosystem is disturbed, and you can [fix] it, you could
cure various diseases.” In other words, not just C. difficile.
The world of medicine is always looking for the next high-tech
cure: stem cells, mind-controlled prosthetics, a brand-new wonder
drug. Yet one of the most talked-about treatments today is
extraordinarily primitive. Fecal transplant, which has been practised
for centuries (taken through the mouth, it was called “yellow soup”
in traditional Chinese medicine), gives scientists a window into
the ecosystems of bacteria that inhabit our bodies: a vast,
interconnected web called the human microbiome, which
remains terra incognita—and our next medical frontier.
Judging from the hand sanitizers, antibacterial soaps and
 other germ-fighting products that have now become standard
nearly everywhere, many people think of all bacteria as
pathogens—invisible organisms that cause disease. In fact,
even the healthiest among us carry far more bacterial cells than
human ones: They outnumber us 10 to one. As Julian Davies,
a reknowned microbiologist at the University of British Columbia
(now emeritus) puts it, “We are only 10 per cent human and the
rest of us is microbes.” That population of microbes is established
early in life—starting with a baby’s voyage through the birth canal,
when he’s doused in his mother’s bacteria—and remains as unique
as a fingerprint. In the gut, microbes extract nutrients from
food; they synthesize vitamins, fight off infection and reduce
inflammation, to name just a few of their roles.
Our modern microbiomes are thought to look quite different
than those of our ancestors. A 2012 study of 1,000-year-old
human fecal samples (collected from three archaeological digs
in the Americas) shows that ancient-human gut microbiomes
looked more like those of non-human primates and rural,
non-Western communities than the average Canadian or
American, concluding that the last century has seen a seismic
shift in our gut bacteria populations, at least in Western cities.
Scientists believe it’s no coincidence that, since the advent
of antibiotics, conditions such as inflammatory bowel disease,
Celiac disease, childhood asthma and allergies, heart disease,
obesity and autism, to name a few, have been on the rise. And
while no one doubts the importance of antibiotics in fighting
infectious disease, we’re exposed to a lot of them these days.
Kids receive 17 courses of antibiotics, on average, before their
twentieth birthdays, according to Blaser, who notes that
antibiotics are also fed at low levels to the farm animals we
eat, to promote growth.
Antibiotics don’t just attack pathogens; they can take out
beneficial bacteria, too. That’s why patients with C. diff tend
to relapse once they stop taking vancomycin, a powerful antibiotic
that wipes out good bugs and bad. Like seeds, C. difficile produces
spores. To cause a full-blown infection, these spores must take root
and germinate in the gut, which is much more easily accomplished
when the microbial ecosystem is diminished—such as after
a course of drugs like vancomycin. Allen-Vercoe compares the gut
to a rainforest.
“If it’s nice and healthy, with lots of different plants and animals,
that ecosystem will be resistant to disease.” But if loggers clear-cut
the trees, the ecosystem collapses, creating an opportunity for
pathogens to take root.
Antibiotics aren’t the only culprit. In developed countries, more
babies than ever are born by Caesarean section (in Canada,
it’s about 25 per cent), and a recent study in the Canadian Medical Association Journal found that babies born by C-section lacked
a type of gut bacteria found in those delivered vaginally, even
if they were breastfed. Infants who received formula (and no
breast milk) showed big differences in their gut bacteria, too.
A baby’s gut microbiota composition is linked to his or her growth
rate, noted a recent Norwegian study that examined fecal samples
from 218 newborns.
Disorderly microbiomes are being linked to a range of conditions,
including obesity. Dr. Jeffrey Gordon of the Washington University
school of medicine has shown that obese people and thin people
have different microbial populations in their guts. If fat people
diet and become thin, their bacterial makeup changes. After
transplanting the gut bacteria of an obese person into a
germ-free mouse, that mouse becomes overweight; the same
thing happens (in reverse) with bacteria from a malnourished
subject, producing a malnourished mouse. One of Allen-Vercoe’s
projects, with the B.C. Cancer Agency, looks at colorectal cancer.
In certain patients, it seems that a bug normally found in the
mouth lives instead in the gut, causing problems we don’t yet
understand.
One of the biggest surprises has been a potential link between
the microbiome and autism. “It’s a disease thought of as behavioural,”
says Dr. Derrick MacFabe, director of the Kilee Patchell-Evans Autism 
Research Group at the University of Western Ontario in London, Ont.
But it looks as though metabolic and immune changes could be
at least partly responsible for the behaviours involved.
MacFabe has found that certain gut bacteria associated with
autism spectrum disorders (ASD) produce a waste product,
called propionic acid, after eating the carbohydrates we consume,
foods that many autistics crave. When lab rats were given this
same substance, they started showing behavioural and brain
changes seen in ASD, such as repetitive behaviour, decreased 
social interaction and seizures.
MacFabe is co-author of a recent study that screened 213 kids
with ASD. It found that 17 per cent of them had blood metabolic
markers predicted by the lab-rat model. At the same time,
his team looked for genetic changes in these children, but
none was found, suggesting environmental causes, possibly
from the gut. He says long-term antibiotic use in mothers or 
their kids, which alters the microbiome, is “a potential risk factor 
for autism.” MacFabe believes 
a product such as Repoopulate could one day help certain autistic
patients, although no trials have yet been done.
Allen-Vercoe is working with MacFabe to sample the gut microbes
of autistic patients, She’s also studying fecal samples from autistic
kids inside the robo-gut, which mimics the distal colon, the end
point of our digestive tract and where the greatest diversity of bugs
 can be found. “We can add vancomycin,” she says, or alter what
sort of diet goes into the robo-gut—limiting carbohydrates, casein
or gluten, which some parents believe helps their kids’ symptoms
—to see how the autism-associated bacteria respond. She’s
also using the robo-gut to build microbial ecosystems such as
those found in patients with Crohn’s disease or ulcerative colitis,
where, as she puts it, the “ecosystem is really out of whack.”
Working with McMaster University, she plans to transfer different
ecosystems into germ-free mice, creating a model to study
each disease.
Beyond these conditions, gut bacteria have even been implicated
in heart disease. A recent study from a group led by Dr. Stanley 
Hazen of Cleveland Clinic’s Lerner Research Institute found that
when bacteria in our digestive tracts metabolize a compound
called carnitine (abundant in red meat), they make a byproduct 
called trimethylamine N-oxide, TMAO for short, which is linked to 
atherosclerosis. The more carnitine we consume, the more
these bacteria thrive. Following 4,000 patients over three years,
Hazen’s team found that higher blood levels of TMAO were
associated with higher risk of death, as well as non-fatal
heart attack or stroke.
“Microbes only know how to eat and replicate,” Hazen says.
However, as their by-products are pumped through the
bloodstream, influencing our bodies in various ways, “they are
functioning as hormones,” he continues. “Our gut microbiome
is really our largest endocrine organ.” But it’s a flexible one,
he notes, because what it’s “fed” can influence over time what
this microbiome becomes. “In our future, we will drug the microbiome,”
Hazen predicts. “We will give it drugs to treat diseases, like
cardiac disease or diabetes or obesity. We just have to work
out what the language [the bacteria] are speaking—the chemical
Braille.” Then it becomes a druggable target.
“That’s our long-term future; it’s so much easier to take a pill. 
Nobody wants to do a fecal transplant to treat their diabetes.”
Repoopulate represents the future of medicine, one in which the
patient’s own microbiome is manipulated to cure or prevent disease.
Until we understand and master those techniques, our body’s
crudest waste product—which teems with literally millions
of bacteria, representing hundreds of different species, many of
which are still barely known to science—is gaining recognition
as a wonder drug, but one that’s still considered experimental.
There’s a powerful “ick” factor associated with working with raw
feces, even among doctors and nurses. The ones who do perform
the procedure typically find themselves resorting to it when
confronted with patients who might not have any other choice.
Dr. Elaine Petrof performed her first fecal transplant only four
years ago. Her elderly patient “had an unrelated infection and
then got C. diff. She was maxed out; I couldn’t put her on any
more antibiotics.” Her desperate family kept coming to the
hospital with a “pot of poop” and asking Petrof to try a fecal
transplant. “I finally thought, ‘Why not? She’ll die otherwise,’ ”
she says. Within three days, the patient dropped from 20 bowel
movements to two. She was soon able to return home. Petrof
says she performed several more fecal transplants before Health
Canada tightened its restrictions in 2011.
Today, Health Canada considers the use of fecal transplant
to be “investigational,” meaning it can only be conducted within
a clinical trial. (Kingston General partnered with McMaster and
continues to perform fecal transplants under the umbrella of a
clinical trial.) In mid-June,  the U.S. Food and Drug Administration (FDA) changed its stance slightly on fecal transplant. The FDA
had formerly required an “investigational new drug application”
whenever the treatment was used; following an outcry from
doctors and patients, who found this to be burdensome, the FDA
promised it would use its discretion in enforcement. (Patients
must, at minimum, give informed consent and be told the
treatment is “investigational.”)
Some patients who can’t find a doctor to perform a fecal transplant
will take the drastic step of doing it themselves. Jim Hughes,
59, was one of them. About four years ago, after taking antibiotics
to fight a sinus infection, he contracted C. diff; Hughes, who is
five feet, eight inches tall, dropped from 160 to 145 lb. He took
vancomycin for about a year, but whenever the doctor tried to
taper his dose, “the symptoms came roaring back.” Three years
ago, Hughes’s doctor put him in touch with Dr. Michael Silverman,
an infectious diseases specialist and assistant professor at
the University of Toronto, who published a paper describing
DIY fecal transplants. “He said, ‘If you’re willing, here’s
something,’ ” Hughes says. “I said, ‘Sign me up.’ ”
Hughes’s two daughters and daughter-in-law were screened as
potential donors. (Silverman insists on this step before self-
administering a fecal transplant, which he says is done with
a home enema kit.) Hughes’s daughter-in-law ended up providing
the sample. It took three attempts to complete the procedure,
but eventually, it worked. Within a day or so, Hughes’s symptoms
started to disappear. “Within a week, it was fine,” and he
remains healthy today. Patients considering DIY transplants
must talk to their doctors first, says Silverman, who believes
that at-home transplants can “fill a gap” for patients when local
health care providers won’t do it.
Dr. Colleen Kelly, a gastroenterologist with the Women’s
Medicine Collaborative in Providence, R.I., cautions
against DIY fecal transplants due to the risk of infection. 
Still, she’s frustrated more doctors 
won’t perform the procedure. “I was getting annoyed because
[patients] were coming from really far away,” Kelly says. “
One from North Carolina had to fly to Rhode Island with their
donor. I had an 88-year-old drive down from New Hampshire.”
She surveyed other doctors about why they weren’t doing fecal
transplants and many told her it was because safety and efficacy
data were lacking. As a result, she’s leading the first randomized
controlled clinical trial of fecal transplant to treat C. diff in
the U.S., with funding from the National Institutes of Health.
One of several Canadian trials, at St. Joseph’s Healthcare Hamilton,
is looking at whether frozen stool works as well as fresh, which
could allow for anonymous donor banks. (It would also eliminate
the problem of stage fright, when a donor can’t perform the
morning of the procedure.)
Now that fecal transplant is increasingly accepted to treat
C. diff, severe inflammatory bowel disease, including ulcerative
colitis, is a candidate to come next, according to Dr. Ciaran Kelly,
a professor of medicine at Harvard Medical School. As our
understanding of the human microbiome continues to grow, 
one day maybe hospitals everywhere will have a bioreactor such 
as the robo-gut, churning out powerful “super-probiotics” to treat 
a range of diseases. For doctors and patients, it can’t come 
fast enough.

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