“Microbiota Dynamics in Patient Treated with Fecal Microbiota Transplantation for Recurrent Clostridium Difficile Infection”

Microbiota Dynamics in Patient Treated with Fecal Microbiota Transplantation for Recurrent Clostridium Difficile Infection” by Yang Song, Shashank Gard
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Microbiota Dynamics in Patients Treated with Fecal
Microbiota Transplantation for Recurrent Clostridium
difficile Infection
Yang Song1, Shashank Garg2, Mohit Girotra2, Cynthia Maddox1, Erik C. von Rosenvinge3, Anand Dutta2,
Sudhir Dutta2,4, W. Florian Fricke1*
1 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America, 2 Division of Gastroenterology, Sinai Hospital
of Baltimore, Baltimore, Maryland, United States of America, 3 Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore,
Maryland, United States of America, 4 Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
Clostridium difficile causes antibiotic-associated diarrhea and pseudomembraneous colitis and is responsible for a large and
increasing fraction of hospital-acquired infections. Fecal microbiota transplantation (FMT) is an alternate treatment option
for recurrent C. difficile infection (RCDI) refractory to antibiotic therapy. It has recently been discussed favorably in the
clinical and scientific communities and is receiving increasing public attention. However, short- and long-term health
consequences of FMT remain a concern, as the effects of the transplanted microbiota on the patient remain unknown. To
shed light on microbial events associated with RCDI and treatment by FMT, we performed fecal microbiota analysis by 16S
rRNA gene amplicon pyrosequencing of 14 pairs of healthy donors and RCDI patients treated successfully by FMT. Post-FMT
patient and healthy donor samples collected up to one year after FMT were studied longitudinally, including one post-FMT
patient with antibiotic-associated relapse three months after FMT. This analysis allowed us not only to confirm prior reports
that RCDI is associated with reduced diversity and compositional changes in the fecal microbiota, but also to characterize
previously undocumented post-FMT microbiota dynamics. Members of the Streptococcaceae, Enterococcaceae, or
Enterobacteriaceae were significantly increased and putative butyrate producers, such as Lachnospiraceae and
Ruminococcaceae were significantly reduced in samples from RCDI patients before FMT as compared to post-FMT patient
and healthy donor samples. RCDI patient samples showed more case-specific variations than post-FMT patient and healthy
donor samples. However, none of the bacterial groups were invariably associated with RCDI or successful treatment by FMT.
Overall microbiota compositions in post-FMT patients, specifically abundances of the above-mentioned Firmicutes,
continued to change for at least 16 weeks after FMT, suggesting that full microbiota recovery from RCDI may take much
longer than expected based on the disappearance of diarrheal symptoms immediately after FMT.
Citation: Song Y, Garg S, Girotra M, Maddox C, von Rosenvinge EC, et al. (2013) Microbiota Dynamics in Patients Treated with Fecal Microbiota Transplantation
for Recurrent Clostridium difficile Infection. PLoS ONE 8(11): e81330. doi:10.1371/journal.pone.0081330
Editor: Gabriele Berg, Graz University of Technology (TU Graz), Austria
Received August 29, 2013; Accepted October 20, 2013; Published November 26, 2013
Copyright: ! 2013 Song et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study or parts thereof were funded by the Institute for Genome Sciences (IGS), University of Maryland School of Medicine, Baltimore, MD and
Gastroenterology Research Funds from the Division of Gastroenterology, Department of Medicine, Sinai Hospital of Baltimore, Baltimore, MD. The funders had no
role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: wffricke@som.umaryland.edu
Clostridium difficile, the pathogen associated with the majority of
infective antibiotic-associated diarrhea and causative agent of
pseudomembraneous colitis [1], is responsible for a large fraction
of nosocomial, or hospital-acquired, disease [2]. Today, in parts of
the U.S., the incidence of infections with C. difficile is higher than
that of methicillin-resistant Staphylococcus aureus [3]. C. difficile
infection (CDI) is believed to result from gastrointestinal dysbiosis,
i.e., the disruption of the resident microbiota, often caused by
antibiotic treatment, which enables C. difficile to establish an
infection. C. difficile can be acquired via fecal-oral transmission of
spores that survive atmospheric oxygen and gastric acid exposure
and germinate in the large intestine. However, carriage of C.
difficile is not always associated with disease, as asymptomatic C.
difficile colonization is well recognized [4], especially in newborns
and infants of ,1 year age [5].
Besides treatment with almost any antibiotic [6–14], other
factors associated with increased risk for C. difficile infection include
old age, recent hospitalization, tube feeding, use of gastric acidsuppressing
drugs and underlying chronic disease, including
inflammatory bowel disease [15–19]. Recent evidence suggests
that excessive inflammatory responses in the human host enhance
the severity of CDI [20].
Standard treatment for C. difficile infection consists of metronidazole
or vancomycin administration and, more recently, fidaxomicin.
However, the rate of recurrent C. difficile infection (RCDI)
after initial therapy is about 20% [21] and even higher after
subsequent antibiotic courses and recurrences [8,22]. Consequently,
despite current therapeutic options, RCDI treatment has
become increasingly challenging and the incidence of RCDI has
been rising during the past decade resulting in increased
healthcare cost and significant morbidity [23].
PLOS ONE | www.plosone.org 1 November 2013 | Volume 8 | Issue 11 | e81330
Fecal microbiota transplantation (FMT), which aims to restore a
normal, functional intestinal microbiota from a healthy donor in
the RCDI patient, has recently received increasing attention in
clinical and research communities [24–27] and has also become a
popular subject of discussion in other media. First documented in
the fourth century in China and in 1958 in the U.S., FMT was
shown in a recent systematic review of 317 patients in 27 separate
studies to have an overall success rate of 92% [28]. The exact
mechanism of action responsible for the success of FMT to treat
RCDI remains unknown and there is no clinically validated set of
parameters to define a suitable donor or ideal donor microbiota,
although attempts in this direction have been made [29]. Shortand
long-term effects of FMT on the recipient microbiota remain
a concern, especially in light of the growing body of literature that
implicates the gastrointestinal microbiota in a large number of
diseases [30]. For the same reason, there is significant clinical
interest in therapeutic options to target the microbiota to treat
microbiota-associated health problems besides RCDI. As a result,
attempts to treat IBD [31–33], metabolic syndrome [34] and other
diseases [35,36] by FMT have been made.
Clinical concerns and the increasing number of FMT procedures
performed by U.S. physicians recently led the U.S. Food
and Drug Administration (FDA) to release new guidelines that
define FMT as a biologic therapy that requires physicians to
obtain an investigational new drug (IND) application [37]. Shortly
after this guideline was a released, however, the FDA announced a
decision to exercise enforcement discretion in order to allow
physicians to perform FMT in patients with RCDI not responsive
to standard therapy. The urgency for further research into the
short- and long-term effects of FMT is highlighted by the fact that
the public awareness of FMT as a treatment option for RCDI has
increased to a degree where do-it-yourself protocols have become
available over the Internet and the procedure is being performed
without medical surveillance.
In this study, we applied 16S rRNA amplicon pyrosequencing
to analyze fecal samples from RCDI patients and their
corresponding donors before and after FMT. For the first time,
we included longitudinal simultaneous sampling of both post-FMT
patients and healthy donors for up to one year after FMT. This
unique sample set allowed us to describe previously undocumented
microbiota dynamics in post-FMT patients after resolution of
CDI. In addition, inclusion of a patient, who was initially treated
successfully by FMT but experienced relapse after new antibiotic
treatment, provided us with the unique opportunity to distinguish
microbiota changes seen in a previously asymptomatic patients
after relapse of CDI from those apparent in RCDI patients with
long-term disease and multiple courses of anti-C. difficile antibiotic
Materials and Methods
Study cohort and sample collection
The Institutional Review Board of Sinai Hospital Baltimore
approved the study under protocol number #1826 and all subjects
provided their written informed consent to participate in the study.
FMT was performed at Sinai Hospital of Baltimore, Baltimore,
MD by infusion of a fecal solution prepared by a predefined
protocol (Dutta et al., submitted) based on Aas et al. [38]. Potential
donors were thoroughly clinically evaluated based on history,
physical examination and serological screening for HIV, syphilis,
hepatitis A, B and C and Helicobacter pylori infection. Fecal
specimens of patients and donors were tested 3–5 days before
FMT for the presence of pathogenic bacteria (salmonella, shigella,
yersinia), parasites (entamoeba, giardia, worms), and C. difficile.
Patients were admitted to the hospital the day before and bowel
prep administered the night before FMT. Patients were also
administered a proton pump inhibitor (omeprazole, 20 mg) on the
evening and morning before the procedure. Donor fecal samples
(25–30 g) were mixed with 250 ml of sterile saline buffer, mixed
into slurry and filtered once with surgical gauze for large particles
and twice with a coffee filter. The volume of the filtrate was
increased to 450 ml with sterile saline buffer and divided into 5
aliquots of 90 ml. For FMT, two aliquots (180 ml) were
endoscopically delivered by spray catheter into the jejunum. The
remaining three aliquots were instilled by colonoscopy into the
right colon (180 ml) and transverse and upper descending colon
(90 ml).

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