The Promise of Poop - Davidson

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MEDICAL RESEARCH fully, the C. difficile population, and replace it Downloaded from www.sciencemag.org on February 23, 2015
with the healthy bacterial flora from a donor,
The Promise of Poop in this case her son. To do so, they would mix
the son’s feces with saline in a blender and
Fecal transplants offer hope for treating many diseases. But they need to be studied squirt it straight into the patient’s duodenum,
more scientifically, says one of the treatment’s pioneers the upper part of her intestine, via a thin plas-
tic tube inserted through her nose.
AMSTERDAM—Soon after Max Nieuwdorp it, the woman was given several courses of CREDIT: TIM WONG/AMC PRESS OFFICE
started his residency at the internal medicine vancomycin, the standard antibiotic in such Three days after her treatment, the woman
department of the Academic Medical Cen- cases. But, as often happens, the bacteria left the hospital—walking. Nieuwdorp and
ter (AMC) here in 2006, he was confronted had become resistant. Bartelsman decided to treat another six
with a sad case: an 81-year-old woman hos- C. difficile patients in the following months.
pitalized for a complication after a urinary Nieuwdorp refused to accept the patient’s Embarrassed about the unusual experiment,
tract infection who seemed unlikely to sur- fate—“I was young and naive,” he says— they waited for colleagues to break for lunch
vive. She had bed sores and high fevers and started searching PubMed for any- before infusing the stools. Four patients
and was unable to eat. After antibiotics had thing that could save her. When he found a recovered immediately, the other two after
wiped out her colon’s microbial population, 1958 paper by Ben Eiseman, a physician another transplant from a second donor. The
an opportunistic bacterium called Clostrid- who was then at the University of Colorado, transplanted bacteria were apparently restor-
ium difficile had taken over, causing terrible Denver, he knew what to do. “I want to try ing the intestinal flora to health.
diarrhea and bowel inflammation. a fecal transplant,” he told his supervisor,
Joep Bartelsman. But when Nieuwdorp presented the
C. difficile is a notorious pathogen that results at a hospital meeting, an internist
kills at least 14,000 patients a year in the Once he realized that Nieuwdorp wasn’t approached him with a condescending
United States alone; many patients suffer joking, Bartelsman agreed. The plan was smile. “If you seriously want us to treat our
repeated bouts with the microbe. To treat simple: The duo would flush the contents C. diff patients with poop, why don’t you
from the woman’s colon, including, hope- infuse our cardiovascular patients as well?”
the man asked, and left the room.

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CREDITS: (PHOTO) KARI LOUNATMAA/SCIENCESOURCE; (SOURCES) CURR. OPIN. GASTROENTEROL. 29 (2013); GASTROINTESTINAL ENDOSCOPY 78 (2013); CURR. GASTROENTEROL. REP. 15 (2013) Golden brown. Max Nieuwdorp prepares a human Researchers have reported positive That study compared fecal transplants
stool for transplantation. effects with fecal transplants in more with vancomycin, the standard treatment for
than 15 different diseases, but for most, C. difficile, or vancomycin combined with
That skepticism is gone. Many doctors the evidence is still weak. bowel flushing. The researchers aimed to
now agree that intestinal C. difficile infec- enroll 120 patients, but the study’s data and
tions can be cured by transplanting stools Recurrent infection with safety monitoring board halted the study
from healthy people. Backed by a growing C. difficile (photo above) 4 after just 43 patients, because continuing
body of work linking the gut’s microbial eco- would be unethical: Ninety-four percent of
system to overall health, researchers also Irritable bowel syndrome 3 the transplant patients were cured, versus
think that a wholesale replacement of the Chronic constipation 3 31% and 23%, respectively, in the control
gut’s microbial flora might help treat many Ulcerative colitis 3 groups. The resulting NEJM paper “did bring
other diseases, such as inflammatory bowel Crohn's disease 3 the procedure closer to mainstream medi-
disease, diabetes, and the elusive chronic cine,” Khoruts says.
fatigue syndrome. More and more doctors Metabolic syndrome 4
perform fecal transplants, and online manu- Chronic fatigue syndrome 2 More evidence needed
als for patients desperate enough to overcome Multiple sclerosis 2 Some doctors needed no convincing. One
the yuck factor show how to do it yourself. Idiopathic thrombocytopenic purpura 2 was gastroenterologist Thomas Borody of the
Autism 2 Australian Centre for Digestive Diseases in
What’s still missing is a truly scien- Parkinson's disease 1 Five Dock, who since 1988 has performed
tific approach to fecal transplants, says Rheumatoid arthritis 1 fecal transplants in more than 3000 patients,
Nieuwdorp, who has become a leading Sacroiliitis 1 suffering not just from C. difficile but also
advocate of more research. A paper that the Halitosis 1 from irritable bowel syndrome; inflamma-
AMC group published in The New England Acne 1 tory bowel syndrome; constipation; arthritis;
Journal of Medicine (NEJM) in January Insomnia 1 and sacroiliitis, an inflammation of the sac-
described a randomized controlled clini- Depression 1 roiliac joint. Borody has published some of
cal trial of the transplants—the first such his results; last year, for instance, he reported
study ever reported. Nieuwdorp has also set KEY: some improvement in 92% of 62 ulcerative
up collaborations with lab scientists to bet- 4 Randomized, controlled trial colitis patients treated with fecal transplants
ter understand the underlying mechanisms. 3 Case series published and full recovery in 68%.
He hopes that these studies will eventually 2 Isolated case(s) published
allow doctors to move from stool transplants 1 Unpublished clinical observations But although Borody is widely recog-
to a more subtle approach: administering nized as a pioneer, he has never carried
selected bacterial strains. chose a Dutch medical journal to publish his out a randomized trial. Other researchers
fecal transplant results in that same year. have reported encouraging results for non-
Becoming mainstream gastrointestinal disorders that appear to be
The pioneering Eiseman paper, published in But recurrent C. difficile infections were associated with changes in the microbial flora,
Surgery, described how the anal infusion of still on the rise, as was antibiotic resistance such as Parkinson’s, autism, and multiple scler-
liquidized stool cured four patients from a in the bacteria. Interest in fecal transplants osis. In most cases, however, the claims are
disease called pseudomembranous entero- grew in the United States after a 2010 article based on a few cases, or a series of cases with-
colitis, which had symptoms very similar in The New York Times about the successful out a control group. (See table, left.)
to a severe C. difficile infection, although treatment of a very serious C. difficile case
it was likely caused by a different microbe. by Alexander Khoruts, a gastroenterologist More rigorous trials are now under
It wasn’t the first medical use of poop; at the University of Minnesota Medical Cen- way, including one in ulcerative colitis at
fecal suspensions to treat food poisoning ter in Minneapolis. “I realized that to let this McMaster University in Hamilton, Canada,
and severe diarrhea were first reported in therapy become accepted by the community and another in Crohn’s disease at Nanjing
the 4th century by a Chinese doctor and of physicians, we would have to do a random- Medical University in China. Nieuwdorp
writer named Ge Hong, and as early as the ized clinical trial,” Nieuwdorp says. himself has just embarked on his second trial
17th century, they were used to treat cows in patients with metabolic syndrome, the
with intestinal problems. dysregulation of the body’s metabolism as a
result of overweight that is often a precursor to
Eiseman’s paper was followed by occa- diabetes. Last year, his group reported that
sional case reports, but for decades, the transferring the intestinal microbiota from
medical community paid little attention. lean donors increases insulin sensitivity in
Antibiotics had rendered the primitive, dis- these patients—an encouraging sign.
tasteful technique obsolete, it seemed.
Meanwhile, Lawrence Brandt of the
Nieuwdorp didn’t initially put his money Montefiore Medical Center in New York
on it either. After his first seven patients, he City, another fecal transplant pioneer, is
went to the University of California, San doing a second trial with recurrent C. diffi-
Diego, as a postdoc to study sugar mol- cile. The study started before Nieuwdorp’s
ecules on the linings of blood vessels and NEJM paper, and unlike Nieuwdorp’s, it is
intestines. After his return to Amsterdam in blinded and includes a placebo group. Both
2008, he resumed his work on the relation the patient and a donor donate their stool;
between gut microbiota and metabolism. He the patient is infused with either the donor

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Regulators Grapple With an Unorthodox Therapy

Taking one person’s stool and putting it into the gut of another may be infection—where the evidence that fecal transplants work is strongest—

simple enough—but regulating it is not. The rapid rise of fecal trans- after hospital lawyers told him to stop.

plantation, coupled with pressure from enthusiastic patients and doc- Patients and doctors have long urged the agency not to interfere with

tors, has regulators wondering how to respond. The procedure occupies the treatment. At the Bethesda workshop, FDA officials heard testimony

an odd place somewhere between tissue transplants and “probiotic” from Catherine Duff, a 57-year-old former medical case manager from

therapies—infusions of beneficial bacteria—and its risks are unknown. Carmel, Indiana, who related how a fecal transplant had cured her recur-

Coming up with sensible regulation is even harder because unlike, say, a rent C. difficile infection—and saved her life. “Please, do something not

blood transfusion, anyone can perform only for me, but for all those around the country and everywhere,” she

a stool transplant at home. implored the FDA. “Please do something quickly.”

So far, the European Medicines Duff’s appearance “definitely left an impression on the FDA offi-

Agency has not stepped in to regulate cials,” says Alexander Khoruts, a gastroenterologist at the University of

fecal transplants; the only thing that Minnesota Medical Center in Minneapolis who attended the meeting. In

doctors need to do is get the patient’s new guidelines issued on 18 July, the agency announced it would “exer-

informed consent and comply with a cise enforcement discretion” in the case of C. difficile—meaning that,

donor screening protocol. Australia, if they meet certain conditions, doctors can perform fecal transplants

where gastroenterologist Thomas Borody without prior approval. An IND is still needed for all other diseases and

has carried out thousands of fecal trans- for C. difficile therapy in infants. The new guidance is widely regarded as

plants (see main story, p. 954), has Patient’s voice. Catherine Duff a stopgap measure that gives the agency time to develop more compre-

similarly relaxed regulations. spoke up at an FDA workshop hensive regulations.

In the United States, by contrast, in May. FDA’s task might get easier if scientists can replace fecal transplants

the Food and Drug Administration with standardized mixes of microbial strains grown in the lab, which are

(FDA) recently asserted its authority over the procedure. At a workshop on simpler and presumably less risky. On 29 July, FDA approved a phase II

2 and 3 May in Bethesda, Maryland, FDA’s Jay Slater said that transplants trial with such a cocktail, developed by a company called Rebiotix. But

are considered “an unapproved new drug.” That meant any transplant Canada’s federal regulatory agency clamped down on a similar product.

can be done only as part of an official clinical trial, and doctors need After an academic collaboration named RePOOPulate treated two C. dif-

to file an Investigational New Drug (IND) application—which can take ficile patients with a mixture of 33 stool-derived microbial strains, Health

months. (The agency said it might make exceptions for life-threatening Canada ordered a halt to the procedure in 2011; it said the mix is a “syn-

conditions on a case-by-case basis.) thetic” product for which drug approval is needed and gave the scientists

An FDA spokesperson says that Slater’s comments didn’t represent a a long list of criteria to meet.

policy change. But many researchers interpreted them as a clampdown. “Actually, they are not unreasonable,” says RePOOPulate project

Lawrence Brandt of the Montefiore Medical Center in New York City says leader Elaine Petrof. “Health Canada realizes this technique is not going

that he rejected 25 patients suffering from recurrent Clostridium difficile away, and they want to sort this out with us.” –JDV

stool or his own. That design is now stan- simple procedure. “The first generation of tists say, because fecal transplants aren’t with-
dard, says Nieuwdorp, who uses it in the
metabolic syndrome trial as well. “Some physicians involved in this technique were out risks. Earlier this month, for instance,
people claimed to smell that they had not
received their own poop,” he says. “They of the most idealistic type I can imagine,” two patients were reported to have developed
weren’t always right, actually.”
Khoruts says. “This changed, unfortunately.” norovirus gastroenteritis and diarrhea around
Borody says he is “very much for blinded
trials”—he is involved in one with ulcer- Patients are often desperate for the treatment; the time of their fecal transplant. (The donors
ative colitis himself that is about to start at his
university. But in the case of C. difficile, Nieuwdorp says he receives frequent phone had tested negative for norovirus, and the doc-
Nieuwdorp’s study wasn’t needed, he says—
let alone Brandt’s—because the evidence from calls, e-mails, and visits from people beg- tors believe the patients may have picked up
case series was already overwhelming. “This
trial should not have been approved by the eth- ging him for a transplant. He says that he the virus somewhere else.) Also this month
ics committee in the first place,” Borody says,
comparing Nieuwdorp’s study to a random- rejects all such requests but refers Online came a report of a 78-year-old
ized controlled trial to test whether parachutes some people to Borody. man whose ulcerative colitis flared
can save lives. sciencemag.org up instead of disappearing after a
Meanwhile, do-it-yourself fecal transplant—although that
Begging for a transplant transplants appear to be on the Podcast interview may have been because his doctors
As word of mouth about fecal transplants rise as well. Instructions on how with author Jop de stopped administering prednisone,
has spread, many other doctors have gotten to flush out your colon, prepare Vrieze (http://scim.ag/ a drug that reduces inflammation,
in on the game, and many private clin- donor stool—at “chocolate milk- pod_6149).
ics see handsome profits from a relatively
shake thickness,” as one web- prior to treatment. CREDIT: COURTESY OF CATHERINE DUFF

site helpfully explains—and infuse it by To reduce the risks, most doctors screen

enema or nasal tube have proliferated on donors for a battery of harmful viruses, bac-

the Internet. In one YouTube video, a patient teria, and parasites that might be transmitted

describes how putting Vicks VapoRub under through stool—including HIV, hepatitis B

one’s nose can help suppress the odor. There and C viruses, cytomegalovirus, Epstein-

have even been reports about people drink- Barr virus, Campylobacter jejuni, and

ing liquidized feces. Blastocystis. But they can’t be sure they’re

Such experiments are worrisome, scien- catching everything, and noninfectious dis-

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eases are a concern as well. Diabetes, athero- 2
sclerosis, autism, and colorectal cancer have Exact preparations vary, but
all been shown to be associated with certain usually the stool is blended with
gut microbiota compositions. Scientists are saline and put through a strainer.
only beginning to tease out cause and effect, It can be frozen before use.
but Khoruts says that it’s best to err on the
side of caution and not use donors whose gut 1
flora might cause trouble. In a fecal transplant, stool from a healthy donor

Khoruts is investigating the optimal is used to replace a patient’s gut microbial flora.
donor characteristics and has set up a donor
bank with frozen stool from healthy people 3
who meet a long list of criteria. So far, most The stool can be applied into the small intestine
of his patients have brought in family mem-
bers as donors, and few of them are in per- via a tube through the nose or mouth (a) or deep
fect health. “If the patient is 70 years old,
you won’t need a Greek god to cure her,” into the colon, using a colonoscopy (b). Enemas
Khoruts says. “But for a younger patient,
you give bugs for the rest of his life—you are popular for at-home treatments, but they only
want something better.”
reach the lower end of the colon (c). 4
Underlying mechanisms
Knowing how fecal transplants work is key to In the future, scientists
making them safer. Do the donor populations
take up residence in the gut after the trans- hope to replace fecal
plant? Which strains make the difference, and
how do the transplanted microbes interact transplants with an
with the resident ones? Nieuwdorp collabo-
rates with Willem de Vos, a microbial ecolo- odorless mix of bacterial
gist at Wageningen University in the Nether-
lands, whose expertise is anaerobic bacteria, strains derived from
the group that dominates in the human gut.
“We have shown that in C. difficile patients, a b c human stool, grown in
some important species are absent, while oth-
ers that you don’t want are dominant,” De Vos the lab. It could be
says. His research has also shown that the low
microbial diversity in C. difficile patients is applied using existing
comparable to that of a 1-year-old child. But
after a transplant, anaerobic bacteria from methods or in capsules.
the donor settle in the recipient’s gut and the
ILLUSTRATION: P. HUEY/SCIENCE diversity is restored. diarrhea by treating them with 17 harmless the same route; the Food and Drug Admin-
Clostridium strains that had previously been istration recently greenlighted a phase II
Nieuwdorp also works with Fredrik Bäck- shown to induce regulatory T cells of the clinical trial of its mix of several hundred
hed of the University of Gothenburg in Swe- immune system, quenching an overactive stool-derived strains to target C. difficile infec-
den, who runs a facility housing mice that immune response. tion. “We don’t consider our product a fecal
grow up without a single bacterium in their transplant,” Rebiotix founder and CEO Lee
bodies. This allows the scientists to investi- In a project called RePOOPulate, a Cana- Jones writes in an e-mail. “Instead, we are
gate the effects of specific microbial strains. dian team led by Elaine Petrof of Queen’s developing a microbiota restoration therapy
“We are playing with different donors to find University in Kingston and Emma Allen- in the form of a biologic drug.”
the superbacteria that make the difference Vercoe from the University of Guelph has
between health and disease,” Nieuwdorp says. developed a stool-derived set of 33 micro- Nieuwdorp sees enormous possibilities
bial strains for the treatment of C. diffi- for such therapies—but he says it will take
The hope is that in the end, doctors can cile and inflammatory bowel disease. They time. “I’m 36 now. I’ll be happy if by the time
abandon the poop and infuse just these hope the strains will offer the benefits of a I’m 60, microbiota analysis will be standard
bacteria. Such cultured cocktails might have full fecal transplant but with less risk. Allen- procedure in hospital labs,” he says. For now,
downsides, however. They could be less pow- Vercoe initially cultured 70 strains, from he’s happy that the taboo on fecal transplants
erful than the complete ecosystems found in which Petrof made a selection based on each is gone. At his own center, “specialists are lin-
stool, Borody says, and the bacteria might strain’s pathogenicity and resistance to anti- ing up to test the impact of transplant on ‘their’
mutate in the lab, losing their healing power, biotics. For the final selection, she says she diseases,” Nieuwdorp says. And yes, the list
as they are grown generation after generation. used her judgment: “Would I put this bug now includes cardiovascular diseases.
into my mom? No? Then I would take it out.”
Still, many others believe the cocktails –JOP DE VRIEZE
are the way to go. A group led by Kenya A U.S. company called Rebiotix is going
Honda at the University of Tokyo recently Jop de Vrieze is a science writer in Amsterdam.
reported curing mice of colitis and allergic

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