(1) Briefly describe the fecal transplant procedure.
(2) What were the results of the randomized clinical trial
comparing fecal transplants with vancomycin for patients
with C. difficile infection? What was the
(overwhelmingly) best treatment?
(3) Ultimately, scientists hope to replace fecal transplants
with something better. What are the two possible alternatives to
fecal transplants mentioned in the article?
(4) Of the two alternatives stated in the previous question,
which one is considered to be more beneficial? Provide two reasons
why.
AMSTERDAM—Soon after Max Nieuwdorp started his residency at the
internal medicine department of the Academic Medical Cen- ter (AMC)
here in 2006, he was confronted with a sad case: an 81-year-old
woman hos- pitalized for a complication after a urinary tract
infection who seemed unlikely to sur- vive. She had bed sores and
high fevers and was unable to eat. After antibiotics had wiped out
her colon’s microbial population, an opportunistic bacterium called
Clostrid- ium difficile had taken over, causing terrible
diarrhea and bowel inflammation. C. difficile is a
notorious pathogen that kills at least 14,000 patients a year in
the United States alone; many patients suffer repeated bouts with
the microbe. To treat it, the woman was given several courses of
vancomycin, the standard antibiotic in such cases. But, as often
happens, the bacteria had become resistant. Nieuwdorp refused to
accept the patient’s fate—“I was young and naive,” he says— and
started searching PubMed for any- thing that could save her. When
he found a 1958 paper by Ben Eiseman, a physician who was then at
the University of Colorado, Denver, he knew what to do. “I want to
try a fecal transplant,” he told his supervisor, Joep Bartelsman.
Once he realized that Nieuwdorp wasn’t joking, Bartelsman agreed.
The plan was simple: The duo would flush the contents from the
woman’s colon, including, hopefully, the C. difficile
population, and replace it with the healthy bacterial flora from a
donor, in this case her son. To do so, they would mix the son’s
feces with saline in a blender and squirt it straight into the
patient’s duodenum, the upper part of her intestine, via a thin
plas- tic tube inserted through her nose. Three days after her
treatment, the woman left the hospital—walking. Nieuwdorp and
Bartelsman decided to treat another six C. difficile
patients in the following months. Embarrassed about the unusual
experiment, they waited for colleagues to break for lunch before
infusing the stools. Four patients recovered immediately, the other
two after another transplant from a second donor. The transplanted
bacteria were apparently restor- ing the intestinal flora to
health. But when Nieuwdorp presented the results at a hospital
meeting, an internist approached him with a condescending smile.
“If you seriously want us to treat our C. diff patients
with poop, why don’t you infuse our cardiovascular patients as
well?” the man asked, and left the room. That skepticism is gone.
Many doctors now agree that intestinal C. difficile infec-
tions can be cured by transplanting stools from healthy people.
Backed by a growing body of work linking the gut’s microbial eco-
system to overall health, researchers also think that a wholesale
replacement of the gut’s microbial flora might help treat many
other diseases, such as inflammatory bowel disease, diabetes, and
the elusive chronic fatigue syndrome. More and more doctors perform
fecal transplants, and online manu- als for patients desperate
enough to overcome the yuck factor show how to do it yourself.
What’s still missing is a truly scien- tif ic approach to fecal
transplants, says Nieuwdorp, who has become a leading advocate of
more research. A paper that the AMC group published in The New
England Journal of Medicine (NEJM) in January
described a randomized controlled clini- cal trial of the
transplants—the first such study ever reported. Nieuwdorp has also
set up collaborations with lab scientists to bet- ter understand
the underlying mechanisms. He hopes that these studies will
eventually allow doctors to move from stool transplants to a more
subtle approach: administering selected bacterial strains.
Becoming mainstream
The pioneering Eiseman paper, published in Surgery,
described how the anal infusion of liquidized stool cured four
patients from a disease called pseudomembranous entero-
colitis, which had symptoms very similar to a severe
C. difficile infection, although it was likely caused by a
different microbe. It wasn’t the first medical use of poop; fecal
suspensions to treat food poisoning and severe diarrhea were first
reported in the 4th century by a Chinese doctor and writer named Ge
Hong, and as early as the 17th century, they were used to treat
cows with intestinal problems. Eiseman’s paper was followed by
occa- sional case reports, but for decades, the medical community
paid little attention. Antibiotics had rendered the primitive, dis-
tasteful technique obsolete, it seemed. Nieuwdorp didn’t initially
put his money on it either. After his first seven patients, he went
to the University of California, San Diego, as a postdoc to study
sugar mol- ecules on the linings of blood vessels and intestines.
After his return to Amsterdam in 2008, he resumed his work on the
relation between gut microbiota and metabolism. He chose a Dutch
medical journal to publish his fecal transplant results in that
same year. But recurrent C. difficile infections were
still on the rise, as was antibiotic resistance in the bacteria.
Interest in fecal transplants grew in the United States after a
2010 article in The New York Times about the successful
treatment of a very serious C. difficile case by Alexander
Khoruts, a gastroenterologist at the University of Minnesota
Medical Cen- ter in Minneapolis. “I realized that to let this
therapy become accepted by the community of physicians, we would
have to do a random- ized clinical trial,” Nieuwdorp says. That
study compared fecal transplants with vancomycin, the standard
treatment for C. difficile, or vancomycin combined with
bowel flushing. The researchers aimed to enroll 120 patients, but
the study’s data and safety monitoring board halted the study after
just 43 patients, because continuing would be unethical:
Ninety-four percent of the transplant patients were cured, versus
31% and 23%, respectively, in the control groups. The resulting
NEJM paper “did bring the procedure closer to mainstream
medi- cine,” Khoruts says.
More evidence needed
Some doctors needed no convincing. One was gastroenterologist
Thomas Borody of the Australian Centre for Digestive Diseases in
Five Dock, who since 1988 has performed fecal transplants in more
than 3000 patients, suffering not just from C. difficile
but also from irritable bowel syndrome; inflamma- tory bowel
syndrome; constipation; arthritis; and sacroiliitis, an
inflammation of the sac- roiliac joint. Borody has published some
of his results; last year, for instance, he reported some
improvement in 92% of 62 ulcerative colitis patients treated with
fecal transplants and full recovery in 68%. But although Borody is
widely recog- nized as a pioneer, he has never carried out a
randomized trial. Other researchers have reported encouraging
results for non- gastrointestinal disorders that appear to be
associated with changes in the microbial flora, such as
Parkinson’s, autism, and multiple scler- osis. In most cases,
however, the claims are based on a few cases, or a series of cases
with- out a control group. More rigorous trials
are now under way, including one in ulcerative colitis at McMaster
University in Hamilton, Canada, and another in Crohn’s disease at
Nanjing Medical University in China. Nieuwdorp himself has just
embarked on his second trial in patients with metabolic syndrome,
the dysregulation of the body’s metabolism as a result of
overweight that is often a precursor to diabetes. Last year, his
group reported that transferring the intestinal microbiota from
lean donors increases insulin sensitivity in these patients—an
encouraging sign. Meanwhile, Lawrence Brandt of the Montef iore
Medical Center in New York City, another fecal transplant pioneer,
is doing a second trial with recurrent C. diffi- cile. The
study started before Nieuwdorp’s NEJM paper, and unlike
Nieuwdorp’s, it is blinded and includes a placebo group. Both the
patient and a donor donate their stool; the patient is infused with
either the donor stool or his own. That design is now stan- dard,
says Nieuwdorp, who uses it in the metabolic syndrome trial as
well. “Some people claimed to smell that they had not received
their own poop,” he says. “They weren’t always right, actually.”
Borody says he is “very much for blinded trials”—he is involved in
one with ulcer- ative colitis himself that is about to start at his
university. But in the case of C. difficile, Nieuwdorp’s
study wasn’t needed, he says— let alone Brandt’s—because the
evidence from case series was already overwhelming. “This trial
should not have been approved by the eth- ics committee in the
first place,” Borody says, comparing Nieuwdorp’s study to a random-
ized controlled trial to test whether parachutes can save
lives.
Begging for a transplant
As word of mouth about fecal transplants has spread, many other
doctors have gotten in on the game, and many private clin- ics see
handsome profits from a relatively simple procedure. “The first
generation of physicians involved in this technique were of the
most idealistic type I can imagine,” Khoruts says. “This changed,
unfortunately.” Patients are often desperate for the treatment;
Nieuwdorp says he receives frequent phone calls, e-mails, and
visits from people beg- ging him for a transplant. He says that he
rejects all such requests but refers some people to Borody. Meanwhile,
do it yourself transplants appear to be on the rise as well.
Instructions on how to flush out your colon, prepare donor stool—at
“chocolate milkshake thickness,” as one web-site helpfully
explains—and infuse it by enema or nasal tube have proliferated on
the Internet. In one YouTube video, a patient describes how putting
Vicks VapoRub under one’s nose can help suppress the odor. There
have even been reports about people drink- ing liquidized feces.
Such experiments are worrisome, scien tists say, because fecal
transplants aren’t with- out risks. Earlier this month, for
instance, two patients were reported to have developed norovirus
gastroenteritis and diarrhea around the time of their fecal
transplant. (The donors had tested negative for norovirus, and the
doc- tors believe the patients may have picked up the virus
somewhere else.) Also this month came a report of a 78-year-old man
whose ulcerative colitis flared up instead of disappearing after a
fecal transplant—although that may have been because his doctors
stopped administering prednisone, a drug that reduces inflammation,
prior to treatment. To reduce the risks, most doctors screen donors
for a battery of harmful viruses, bac- teria, and parasites that
might be transmitted through stool—including HIV, hepatitis B and C
viruses, cytomegalovirus, Epstein- Barr virus, Campylobacter
jejuni, and Blastocystis. But they can’t be sure
they’re catching everything, and noninfectious diseases are a
concern as well. Diabetes, athero- sclerosis, autism, and
colorectal cancer have all been shown to be associated with certain
gut microbiota compositions. Scientists are only beginning to tease
out cause and effect, but Khoruts says that it’s best to err on the
side of caution and not use donors whose gut flora might cause
trouble. Khoruts is investigating the optimal donor characteristics
and has set up a donor bank with frozen stool from healthy people
who meet a long list of criteria. So far, most of his patients have
brought in family mem- bers as donors, and few of them are in per-
fect health. “If the patient is 70 years old, you won’t need a
Greek god to cure her,” Khoruts says. “But for a younger patient,
you give bugs for the rest of his life—you want something
better.”
Underlying mechanisms
Knowing how fecal transplants work is key to making them safer.
Do the donor populations take up residence in the gut after the
trans- plant? Which strains make the difference, and how do the
transplanted microbes interact with the resident ones? Nieuwdorp
collabo- rates with Willem de Vos, a microbial ecolo- gist at
Wageningen University in the Nether- lands, whose expertise is
anaerobic bacteria, the group that dominates in the human gut. “We
have shown that in C. difficile patients, some important
species are absent, while oth- rs that you don’t want are
dominant,” De Vos says. His research has also shown that the low
microbial diversity in C. difficile patients is comparable
to that of a 1-year-old child. But after a transplant, anaerobic
bacteria from the donor settle in the recipient’s gut and the
diversity is restored. Nieuwdorp also works with Fredrik Bäck- hed
of the University of Gothenburg in Swe- den, who runs a facility
housing mice that grow up without a single bacterium in their
bodies. This allows the scientists to investi- gate the effects of
specific microbial strains. “We are playing with different donors
to find the superbacteria that make the difference between health
and disease,” Nieuwdorp says. The hope is that in the end, doctors
can abandon the poop and infuse just these bacteria. Such cultured
cocktails might have downsides, however. They could be less pow-
erful than the complete ecosystems found in stool, Borody says, and
the bacteria might mutate in the lab, losing their healing power,
as they are grown generation after generation. Still, many others
believe the cocktails are the way to go. A group led by Kenya Honda
at the University of Tokyo recently reported curing mice of colitis
and allergic diarrhea by treating them with 17 harmless
Clostridium strains that had previously been shown to
induce regulatory T cells of the immune system, quenching an
overactive immune response. In a project called RePOOPulate, a
Cana- dian team led by Elaine Petrof of Queen’s University in
Kingston and Emma Allen- Vercoe from the University of Guelph has
developed a stool-derived set of 33 micro- bial strains for the
treatment of C. diffi- cile and inflammatory bowel
disease. They hope the strains will offer the benefits of a full
fecal transplant but with less risk. Allen- Vercoe initially
cultured 70 strains, from which Petrof made a selection based on
each strain’s pathogenicity and resistance to anti- biotics. For
the final selection, she says she used her judgment: “Would I put
this bug into my mom? No? Then I would take it out.”A U.S. company
called Rebiotix is going the same route; the Food and Drug Admin-
istration recently greenlighted a phase II clinical trial of its
mix of several hundred stool-derived strains to target C.
difficile infec- tion. “We don’t consider our product a fecal
transplant,” Rebiotix founder and CEO Lee Jones writes in an
e-mail. “Instead, we are developing a microbiota restoration
therapy in the form of a biologic drug.” Nieuwdorp sees enormous
possibilities for such therapies—but he says it will take time.
“I’m 36 now. I’ll be happy if by the time I’m 60, microbiota
analysis will be standard procedure in hospital labs,” he says. For
now, he’s happy that the taboo on fecal transplants is gone. At his
own center, “specialists are lin- ing up to test the impact of
transplant on ‘their’ diseases,” Nieuwdorp says. And yes, the list
now includes cardiovascular diseases.