GASTROENTEROLOGY 2013;145:946–953
PERSPECTIVES
BRIEF REVIEW
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AND
Therapeutic Potential of Fecal Microbiota Transplantation
LOEK P. SMITS,1 KRISTIEN E. C. BOUTER,1 WILLEM M. DE VOS,2,3 THOMAS J. BORODY,4 and MAX NIEUWDORP1
1
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2Laboratory of Microbiology,
Wageningen University, Wageningen, The Netherlands; 3Department of Bacteriology and Immunology, Helsinki University, Helsinki, Finland; and 4Centre for Digestive
Diseases, New South Wales, Australia
There has been growing interest in the use of fecal
microbiota for the treatment of patients with chronic
gastrointestinal infections and inflammatory bowel
diseases. Lately, there has also been interest in its
therapeutic potential for cardiometabolic, autoim-
mune, and other extraintestinal conditions that were
not previously considered to be associated with the
intestinal microbiota. Although it is not clear if
changes in the microbiota cause these conditions,
we review the most current and best methods for
performing fecal microbiota transplantation and
summarize clinical observations that have implicated
the intestinal microbiota in various diseases. We
also discuss case reports of fecal microbiota trans-
plantations for different disorders, including Clos-
tridium difficile infection, irritable bowel syndrome,
inflammatory bowel diseases, insulin resistance,
multiple sclerosis, and idiopathic thrombocytopenic
purpura. There has been increasing focus on the
interaction between the intestinal microbiome,
obesity, and cardiometabolic diseases, and we explore
these relationships and the potential roles of different
microbial strains. We might someday be able to mine
for intestinal bacterial strains that can be used in the
diagnosis or treatment of these diseases.
Keywords: Gutmicrobiota; Human Disease; Fecal Trans-
plantation; Therapy.
T he distal gastrointestinal tract contains a large and
diverse array of microorganisms, of which bacteria
are the most dominant.1 The community of at least 1014
bacteria is dominated by strict anaerobes and includes
thousands of different species, many of which have not yet
been cultured. These bacteria can interact with the intes-
tinal mucosa and influence intestinal permeability; they
are important for the absorption, distribution, meta-
bolism, and excretion of nutrients2 and can trigger (auto)
immunity.3 Recently developed high-throughput ap-
proaches, including metagenomic sequencing, have asso-
ciated the composition of the microbiota with human
health.2,4,5 The composition of the intestinal microbiota
can be altered with diet and prebiotics or probiotics, which
produce mild temporary changes, or with antibiotics,
Robert F. Schwabe and John W. Wiley, Section Editors
which produce large changes in the bacterial composition
of the intestines.5
A new and underexplored method to alter the gastro-
intestinal microbiota involves fecal microbiota trans-
plantation (FMT). The first known description of human
donor feces as a therapeutic agent came from China. In
the fourth century, Ge Hong, in the Handbook of Emergency
Medicine, prescribed ingestion of feces for a variety of
conditions.6 Much later, Ralph Lewin reported that
“.consumption of fresh, warm camel feces has been
recommended by Bedouins as a remedy for bacterial dys-
entery; its efficacy was confirmed by German soldiers in
Africa during World War II.”7 The first use of FMT in
mainstream medicine was described in 1958 for the
treatment of pseudomembranous colitis (presumably due
to Clostridium difficile infection [CDI]) by Eiseman et al.8
FMT has since increased in popularity due to its efficacy
and ease of use for the treatment of patients with CDI. We
review the methodology and safety of modern FMT and
the evidence to support its use in treating a variety of
diseases (Figure 1).
Methods of FMT
FMT comprises the administration of a fecal solution
from a donor into the intestinal tract of a recipient. How is the
donor selected, how is the solution prepared, and how is the
transplant material administered?
Donor Selection
Healthy donors are usually recruited from family mem-
bers or friends as well as by newspaper advertisements. The risk
of transmission of unknown pathogens via FMT cannot be
excluded.9 Therefore, it is important to carefully screen and select
donors to avoid causing a new disease in the recipient. Potential
donors should be questioned about their travel history, sexual
behavior, previous operations, blood transfusions, and other
factors that increase the risk of transmissible disease.10 Potential
Abbreviations used in this paper: CDI, Clostridium difficile infection;
FMT, fecal microbiota transplantation; IBD, inflammatory bowel disease;
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohe-
patitis; SCFA, short-chain fatty acid; UC, ulcerative colitis.
© 2013 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2013.08.058
November 2013 FECAL MICROBIOTA TRANSPLANTATION 947

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Figure 1. Disorders associ-
ated with alterations to the in-
testinal microbiota that could
be treated by FMT. Green in-
dicates disorders for which
FMT has shown efficacy in
randomized controlled trials
(RCT), blue indicates disorders
for which FMT has shown
efficacy in case series studies,
and black indicates disorders
that have been associated
with disruption of the intestinal
microbiota.

donors are also screened for a family history of autoimmune and
metabolic diseases as well as malignancies (in first- and second-
degree family members). Once a donor is selected, blood and
fecal samples must be screened for pathogens (see Table 1).11
In a systematic review of 317 patients with recurrent CDI and
pseudomembranous colitis, Gough et al found a slightly higher
rate of disease resolution among recipients of transplanted fecal
material from related donors (93%) than unrelated donors (84%).
There were no significant differences in disease resolution when
donors were of a different sex than the recipient.12 Studies are
under way to determine the composition of donor and recipient
microbiota, including enterotypes13; this information could in-
crease the efficiency of FMT.
Preparation of FMT Material
There has been large heterogeneity among studies in the
preparation of material for FMT. Although there have been
several reviews on preparing infusions for FMT,12,14 the lack of
sufficient numbers and controls in most studies makes it diffi-
cult to draw solid conclusions. That said, infusions for FMT
prepared using water have been reported to achieve higher rates
of disease resolution than those using normal saline (98.5% vs
86%), although relapse of CDI was >2-fold higher with water
than saline.12 Other diluents, including milk and saline with
psyllium, produced resolution rates of 94%.12
A nonsignificant trend toward an improved outcome has also
been observed with increasing weight of donor stool and volume
of prepared solution; a 97% resolution rate was achieved in pa-
tients who received infusions >500 mL versus only 80% in those
given <200 mL.12 According to the Amsterdam protocol10,15
(Table 1), donor stool (200–300 g, dissolved in 500 mL sterile
saline) is used, preferably within 6 hours of passage. In a recent
case series, standardized frozen stool samples were used in FMT
for CDI; the study reported results comparable to those of
studies that used fresh fecal samples.16 This finding indicates the
feasibility of FMT in clinical practice, with establishment of fecal
donor banks. It will be important to compare the effects of using
the saline-based mixing and straining method versus an electrical
blender to homogenize donor feces. These methods could affect
the viability of strict intestinal anaerobes (blending can introduce
air) and alter the bacterial load.
Routes of Administration
The fecal material for transplantation can be infused by
various methods, including a nasogastric tube, a nasojejunal
tube, upper tract endoscopy (esophagogastroduodenoscopy),
 948 SMITS ET AL
Table 1. Amsterdam Protocol for FMT via Gastroduodenoscopy
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Donor
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Screening for transmittable diseases
Blood: for human immunodeficiency virus, human T-lymphocytic
virus, hepatitis A virus, hepatitis B virus, hepatitis C virus,
cytomegalovirus, Epstein–Barr virus, lues, Strongyloides,
amoebiasis
Fecal pathogens: bacteria (Helicobacter pylori antigen, Yersinia,
Campylobacter, Shigella, Salmonella, enteropathogenic E coli),
viruses (rotavirus, adenovirus, enterovirus, parechovirus,
sapovirus, norovirus, and astrovirus), and parasites (triple feces
test for ova and parasites, Giardia)
Screening for other criteria
Diarrhea
Recent use of medications (within 3 months, mainly antibiotics or
proton pump inhibitors)
Risk factors for transmittable diseases
Abnormal defecation patterns and symptoms of irritable bowel
syndrome
Feces
Freshly produced (within 6 hours of treatment)
At least 150 g (directly covered in 500 mL sterile saline 0.9% solution),
subsequently filtered for a homogeneous solution
Patient
Placement of duodenal tube and small intestinal biopsies
Bowel lavage with 1–2 L of macrogol through duodenal tube
Administration of fecal solution through duodenal tube
No antibiotics before procedure
colonoscopy, or retention enema.12 In a systematic review,
Gough et al found that FMT via esophagogastroduodenoscopy,
nasogastric tube, or nasoduodenal tube resolved CDI in 76% to
79% of patients compared with the mean worldwide rates of 91%
for FMT via colonoscopy.12,14,17–22 In a recent randomized
controlled trial, duodenal infusion of donor feces was shown to
be as effective as colonoscopic administration in the treatment of
CDI.10 Fewer studies, however, have compared routes of
administration for other potential indications; the best route
most likely depends on the anatomic location of the disease. In
our experience, duodenal infusions of donor fecal material are
safe and effective for the treatment of metabolic diseases.15
Adverse Events
To date, FMT appears to be safe; we have performed more
than 200 fecal transplantation procedures at the Academic
Medical Center in Amsterdam and more than 3000 at the Centre
for Digestive Diseases in Sydney, Australia, without any serious
adverse events.10,15,23 Most patients treated with FMT experience
diarrhea on the day of infusion, and a small percentage report
belching and/or abdominal cramping or constipation. These
observations are in line with published case reports and series of
FMT for CDI12,19; adverse events were reported for only 3 of 317
patients (upper gastrointestinal tract bleeding, peritonitis, or
enteritis). In another case report, nasoduodenal FMT for Crohn’s
disease resulted in transient adverse effects, including fever and
abdominal tenderness in 3 of 4 patients. However, these effects
disappeared for all patients over the following 2 days.24 In another
case report, in which FMT was administered during colonoscopy,
these side effects were not observed25; most importantly,
long-term follow-up studies have found that FMT is relatively free
of adverse effects.26 Despite the fact that FMT appears to be safe,
there are insufficient long-term follow-up data; thus, a potential
association between FMT and infection, inflammation, or
gastrointestinal malignancies requires further study.
GASTROENTEROLOGY Vol. 145, No. 5
Clinical Use of FMT
To date, most clinical experience has focused on
the use of FMT in patients with relapsing CDI or occa-
sionally severe CDI. Subsequently, FMT was used to treat
patients with inflammatory bowel disease (IBD) compli-
cated by CDI. From there, FMT was used to treat patients
with only IBD and later, via serendipitous observations,
those with previously unconsidered conditions.
Relapsing CDI
The most frequently reported use of FMT has been
in the treatment of patients with CDI. CDI occurs most
commonly in patients with disruptions of the colonic
microbiota by antibiotics. Tvede and Rask-Madsen
(1989)27 and Khoruts et al (2010)17 reported that the in-
testinal microbiota of patients with relapsing CDI has
lower proportions of Bacteroides and Firmicutes than that of
healthy subjects. Unsurprisingly, antibiotics such as
metronidazole or vancomycin do not eradicate CDI in a
large proportion of patients and fail to correct the under-
lying microbial deficiencies.17,27 FMT, in contrast, eradi-
cates CDI and replaces missing components of the
microbiota (such as Bacteroidetes species)28 to increase bac-
terial diversity, similar to that of healthy donors.10,28 Two
systematic reviews concluded that FMT resolves recurrent
CDI in approximately 90% of patients.12,19 Duodenal
infusion of healthy donor feces resolved recurrent CDI in
82% of patients (defined by the absence of CD-associated
diarrhea, without relapse, within 10 weeks), whereas van-
comycin resolved CDI in only 31% of patients.10
Severe CDI
In the largest retrospective case series of FMT for
patients with severe or complicated CDI (n ¼ 13),29 Aro-
niadis et al collected data on patients for an average of 15
months after the procedure. They found that 84% of pa-
tients were cured by FMT as a primary treatment (reso-
lution of symptoms without recurrence within 90 days)
and 92% of patients were cured by FMT as a secondary
treatment (resolution of symptoms after a course of van-
comycin or repeat FMT).30 Other similar case studies re-
ported rapid recovery after FMT in these gravely ill
patients.30–32
CDI in IBD
Historically, the coexistence of CDI and IBD was
uncommon; tests for Clostridium difficile were rarely rec-
ommended for patients with flares of IBD. However, CDI
has been associated with increased disease severity of IBD
and mortality. The latest American College of Gastroen-
terology guidelines on CDI recommend CDI testing of all
patients hospitalized for IBD flares.33 However, although
treatment guidelines exist for CDI, there are none for
patients with CDI and IBD. In our experience with
this patient population, after FMT and eradication of
CDI, the severity of IBD is gradually reduced, and patients
have improved responses to medications for IBD.25 Reddy
November 2013
and Brandt recently extensively reviewed CDI in patients
with IBD.34
IBD
The etiology of IBD is unknown, but interactions
between bacterial and host cells seem to be involved in
pathogenesis. The intestinal microbiota of patients with
IBD appears to have reduced diversity compared with that
of healthy subjects, based on studies reporting 25% fewer
microbial genes. Patients with IBD have reduced numbers
of the phyla Firmicutes and Bacteroidetes and increased
numbers of Actinobacteria and Proteobacteria.35–37 However,
it is not clear whether these differences are a cause or
consequence of the development of IBD.
The rationale for using FMT to treat patients with ul-
cerative colitis (UC) dates back to when it was used to treat
pseudomembranous enterocolitis; CDI was not known to
be the cause at that time.8,38,39 In 1988, the first patient
with idiopathic UC was treated with FMT, resulting in
durable clinical and histological cure.40 Then, a case report
published in 2003 documented the complete clinical,
colonoscopic, and histological reversal of UC in 6 patients
with severe, relapsing UC.41 Recent studies have confirmed
these findings; a meta-analysis of FMT for patients with
IBD, conducted by Anderson et al,42 found that 63% of
patients with UC entered remission, 76% were able to stop
taking medications for IBD, and 76% experienced a
reduction in gastrointestinal symptoms. Similarly, Brandt
and Aroniadis26 performed a long-term follow-up study of
FMT in 6 patients with UC and reported that all patients
had reduced symptoms. Maximal benefits were observed
in 2 patients with newly diagnosed UC and CDI and in
one who had been taking antibiotics. These findings
indicate that remission of UC is possible with (multiple)
FMTs for a subgroup of patients. There are currently 6
registered trials testing FMT for patients with IBD (see
www.clinicaltrials.gov).
Irritable Bowel Syndrome
Some studies have associated altered composition of
the intestinal microbiota (decreased diversity and decreased
numbers of Bacteroidetes) with subsets of irritable bowel
syndrome.43,44 There are approximately 50 published cases
of use of FMT to treat patients with diarrhea-predominant
irritable bowel syndrome and constipation-predominant
irritable bowel syndrome.45–48 In a case series of 3 patients
with chronic constipation, FMT greatly reduced con-
stipation during the month after FMT; all patients defe-
cated daily (or every other day) without the assistance of
laxatives. In a long-term follow-up study, 45 patients with
chronic, severe constipation were treated with a liquid cul-
ture comprising 20 cultured, nonpathogenic enteric an-
aerobes and aerobes, including Bacteroides, Escherichia coli,
and Lactobacillus species.47 Substantial improvements were
reported in 30 patients (60%), who had improved defecation
and an absence of bloating and abdominal pain during a
follow-up period of 9 to 19 months.
FECAL MICROBIOTA TRANSPLANTATION 949
Chronic Fatigue Syndrome
PERSPECTIVES
Intestinal dysfunction is a symptom in many pa-
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tients with chronic fatigue syndrome. These patients have
been reported to have alterations in the intestinal micro-
biota compared with healthy subjects (controls).49 Pa-
tients with chronic fatigue syndrome were found to have a
reduced proportion of gram-negative E coli (49% of all
aerobic flora) compared with controls (92.3% of all aerobic
flora), whereas lactic acid–producing gram-positive facul-
tative anaerobic Enterococcus and Streptococcus species seem
to be overrepresented in patients with chronic fatigue
syndrome.50,51 In an uncontrolled study of 60 patients
with chronic fatigue syndrome and gastrointestinal
dysfunction treated with FMT, 50% had resolved sleep
deprivation, lethargy, or fatigue during a 15- to 20-year
follow-up period.52
Metabolic and Cardiovascular Disorders
Alterations in the composition of the intestinal
microbiota have also been associated with obesity and type
2 diabetes mellitus.5,53 However, the previously reported
increase in Firmicutes phylum and decrease in Bacteroidetes
observed in obese mice have not been confirmed in
humans.54 Alterations in the intestinal microbiota might
contribute to the development of cardiometabolic diseases
by increasing intestinal permeability; this would lead to
metabolic endotoxemia and chronic inflammation, which
contribute to metabolic and cardiovascular disease.5 Obese
subjects have increased postprandial plasma levels of
bacteria or their proteins (mainly lipopolysaccharide or
endotoxin),55 most likely because of increased intestinal
permeability.56
Diet-derived fibers, which are metabolized and fer-
mented to short-chain fatty acids (SCFAs; including ace-
tate, propionate, and butyrate) by intestinal bacteria,
might also be involved. The types and amounts of SCFAs
produced are believed to vary with the microbial compo-
sition of the intestine (Figure 2).5 In addition to serving as
an energy source for intestinal epithelium and liver
(SCFAs are predominantly transported via the portal vein
after intestinal absorption), SCFAs are believed to have
immunomodulatory effects in that they reduce intestinal
permeability.2 Translocation of lipopolysaccharide from
the intestine to the portal vein is believed to be involved in
the pathogenesis of obesity-associated low-grade inflam-
mation and subsequent insulin resistance in mice.57 These
phenotypes were partly reversed on administration of the
propionate-producing Akkermansia muciniphila,58 which
normalizes intestinal permeability and intestinal mucus
layer thickness. In obese men,15 FMT from lean donors
significantly increased insulin sensitivity, most likely by
increasing concentrations of butyrate-producing intestinal
bacteria in the small and large intestine. These findings
indicate that the intestinal microbiota could actually cause
obesity and insulin resistance.
There is a strong association among fatty liver
disease (nonalcoholic fatty liver disease [NAFLD] and
 950 SMITS ET AL
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nonalcoholic steatohepatitis [NASH]), the intestinal
microbiota, and obesity, which is not surprising because
NAFLD and NASH are associated with obesity and insulin
resistance. Henao-Mejia et al found that increased intes-
tinal permeability and metabolic endotoxemia, by altering
the composition of the intestinal microbiota, contribute
to the progression of NASH in mice.59 They found that
transfer of specific microbiota to mice on methionine- and
choline-deficient diets increased the severity of NAFLD
and NASH via a process that involved TLR4. These
findings indicated that the intestinal microbiota can
GASTROENTEROLOGY Vol. 145, No. 5
Figure 2. Mechanisms by
which alterations to the intesti-
nal microbiota can contribute to
disease. The composition of
the intestinal microbiota is
determined by genetic factors,
diet, and medications (such as
antibiotics) (left side). When
these change, so can the in-
testinal microbiota (right side).
Changes in the microbiota
might induce production of
specific autoantibodies (pro-
duced via molecular mimicry
and can lead to autoimmune
disorders) or allow expansion of
pathogenic species such as C
difficile. An altered intestinal
microbiota could also change
production of compounds such
as SCFA. This affects lipid and
glucose metabolism as well as
inflammation. SCFAs can also
increase intestinal permeability,
which leads to endotoxemia.
contribute to the progression of NAFLD and NASH. Data
from human studies also support the concept that
changes in the intestinal microbiota contribute to the
development of fatty liver diseases. Patients with NAFLD
have increases in intestinal permeability,60 endotoxemia,61
and numbers of Gammaproteobacteria, whereas they have
reduced numbers of Bacteroidetes62,63 compared with
healthy subjects.
Moreover, epidemiological studies have associated
NAFLD with cardiovascular disease.64 Interestingly, the
association between bacterial translocation (determined by
November 2013
plasma levels of endotoxin) and risk of cardiovascular
events was proposed 14 years ago.65 It was supported by
the detection of DNA from intestinal bacteria in inflamed
atherosclerotic plaques as well as reported differences in
the composition of the intestinal microbiota between pa-
tients with symptomatic atherosclerosis and healthy sub-
jects.66,67 Further support came from the finding that the
atherogenic compound trimethylamine-N-oxide, pro-
duced by intestinal microbiota from choline and carnitine,
contributes to vascular inflammation.68–70 FMT-based
intervention studies are currently under way to see if
this technique can reduce features of fatty liver disease and
vascular inflammation.
Autoimmune Diseases
The incidence of autoimmune diseases is
increasing worldwide, but they remain among the most
poorly understood conditions in terms of causes or cures.3
Various environmental factors and infectious agents have
been proposed to contribute to their pathogenesis. A
number of bacteria-derived proteins have been identified
that act as superantigens, inducing nonspecific activation
of self-reactive B and T cells via molecular mimicry. Mul-
tiple sclerosis, which is caused by myelin-directed auto-
immunity, might be treated by FMT. In 3 patients with
multiple sclerosis who underwent FMT daily for 1 to 2
weeks for constipation, neurological symptoms resolved
for 2 to 15 years.71 Idiopathic thrombocytopenic purpura
is believed to be caused by production of autoantibodies
against platelet surface antigens72 after viral or bacterial
infection.3 In a patient with this disorder who underwent
FMT for UC, a progressive but significant increase in
platelet levels was reported that lasted for several years.73
Discussion
The intestinal microbiota can be manipulated to
treat diseases in humans; for example, FMT seems to be a
safe and promising treatment for recurrent CDI. Well-
designed randomized controlled trials are needed to
establish the efficacy of FMT for other diseases, and these
studies should analyze the composition of the small in-
testinal and fecal microbiota before and after FMT so re-
searchers can better understand the mechanisms of this
therapy. Such studies could also help us identify microbes
and their products involved in the pathogenesis of these
disorders. Future research could lead to the development
of specific beneficial (probiotic) microbes27,58 or inhibitors
of specific microbes and/or their products that can
improve human health via the intestinal microbiota.74
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Received July 14, 2013. Accepted August 26, 2013.
Reprint requests
Address requests for reprints to: Max Nieuwdorp, MD, PhD,
Department of Vascular Medicine, Academic Medical Center, University
of Amsterdam, Meibergdreef 9, Room F4-159.2, 1105 AZ Amsterdam,
The Netherlands. e-mail: m.nieuwdorp@amc.uva.nl;
fax: (31) 20 5669343.
FECAL MICROBIOTA TRANSPLANTATION 953
Conflicts of interest
PERSPECTIVES
The authors disclose the following: Thomas J. Borody has a
REVIEWS
pecuniary interest in the Centre for Digestive Diseases, where
AND
fecal microbiota transplantation is a treatment option for patients
and he has filed patents in this field. The remaining authors disclose
no conflicts.
Funding
L. P. Smits, W. M. de Vos, and M. Nieuwdorp were supported by a
grant from CVON (IN-CONTROL) (CVON number 2012). K. E. C. Bouter
was supported by a Rembrandt Grant 2012. W. M. de Vos was also
supported by grants from the Academy of Finland, European
Research Council, and the Netherlands Scientific Research
Organization (NWO).