Secondary Logo

Journal Logo

Invited Review

Fecal Microbial Therapy

Promises and Pitfalls

Merenstein, Daniel*; El-Nachef, Najwa; Lynch, Susan V.

Author Information
Journal of Pediatric Gastroenterology and Nutrition: August 2014 - Volume 59 - Issue 2 - p 157-161
doi: 10.1097/MPG.0000000000000415
  • Free

Abstract

The rapidly developing field of microbiome research, that is, studies of the diverse microbial communities, their genomes, and interactions within and on the human host, has increased our appreciation for the impact of microbial community composition and function on a variety of human diseases ranging from metabolic (1) to neurological (2) and respiratory (3–5) disorders. Diseases as diverse as asthma and autism have links to perturbed gastrointestinal microbiota composition (2,6), implicating the gut microbiome as a major mediator of host health status. These diseases are typically characterized by loss of microbial diversity coupled with species overgrowth and, as a result, depletion of critical microbial functions necessary for maintaining host health. A classic example of gastrointestinal microbiome perturbation and species outgrowth is evident in Clostridium difficile overgrowth, a common occurrence in hospitalized patients treated with antimicrobials. Reduced microbiome diversity as a consequence of antimicrobial administration permits overgrowth of opportunistic C difficile, which, with increasing frequency, does not respond to subsequent antimicrobial therapy targeted to this species, for example, vancomycin. Because of the growing number of patients with recalcitrant C difficile infection (CDI) and the diminishing impact of antimicrobial therapy, alternative therapeutic strategies have been examined for treatment of such patients. Recently fecal microbial transplant (FMT), that is, transfer of stool (containing both microbes and the bioactive molecules they produce) from a healthy donor to a patient with CDI, has been used to treat patients with high rates of efficacy (7). The success of this approach has increased interest in expanding the therapy to other diseases in which a gut microbiome dysbiosis is known or suspected to play a role in disease development. Here we discuss the present state of science behind FMT, including background on the gut microbiome, approaches to transfer fecal material as a therapeutic modality, and a review of the studies performed to date and those in the active stages of patient enrollment.

THE GASTROINTESTINAL MICROBIOME

The recent expansion of the field of human microbiome research has largely been fueled by technological advances to profile the diversity of organisms present (biomarker gene, eg, 16S ribosomal RNA–based microbiota profiling), their collection of genomes (metagenomics), transcriptional activity (metatranscriptomics), and the dominant products biosynthesized (metaproteomics, metabolomics) by these microbial communities. These studies, although largely at the descriptive stage, have demonstrated the staggering diversity of organisms that inhabit humans, with the greatest burden housed in the lower gastrointestinal tract. This large “microbial organ” houses an approximate 1 trillion bacterial cells, and estimates place the number of species present anywhere from 800 to 400,000 species of microbes (8). Fungi, archaea, protozoa, bacteriophage, and viral species are also detected in this niche, although the majority of studies to date have focussed on the bacterial fraction of these communities. These organisms represent a thriving microbial bioreactor, producing essential metabolites for the host such as vitamin K and hormones, and degradative enzymes capable of digesting a range of otherwise indigestible dietary fibers. Developmental studies in mice have demonstrated a role for the microbiome in appropriate mucosal and immunological development; germ-free animals develop physiologically aberrant gastrointestinal-associated lymphoid tissue (9). More recent murine studies have shown that the composition of the gut microbiome is distinct in a murine model of autism spectrum disorder that, compared with control animals, exhibits distinct behavioral patterns, implicating bioactive molecules produced by the microbial community in neurological function (2). The emerging implication is that this coevolved microbial bioreactor may play a significantly larger role in defining a wide variety of human physiological attributes than appreciated in the past. By extension, novel therapeutic strategies to manipulate these communities toward a more beneficial composition and function may prove greatly efficacious in treatment for a broad spectrum of human diseases.

Given the key role the microbiome plays in the human host, it is predictable that several studies have described microbiome disturbances associated with a variety of chronic inflammatory diseases. Characteristically, diseases such as inflammatory bowel disease (IBD (10)), type 2 diabetes mellitus (11), and even chronic sinusitis (12) have demonstrable collapse of the normal microbial community structure, depletion of species with the capacity to produce anti-inflammatory molecules such as short-chain fatty acids, and enrichment of pathogenic species. Several studies, particularly those in the gastrointestinal tract, have clearly demonstrated the capacity of discrete species within the microbiome to induce distinct host immune responses. For example, Clostridia species belonging to clades IV or XIV induce anti-inflammatory T-regulatory cells (13), whereas segmented filamentous bacterium, a colonizer of the murine ileum, induces proliferation of Th17 cells in the terminal ileum lamina propria (14). The latter species was identified using high-resolution comparative microbiome profiling, which identified segmented filamentous bacteria as one of the most highly enriched species in the ileum of mice with a preponderance of Th17 cells (14), indicating the utility of such approaches to move beyond description of the community toward identification of key species that influence particular host phenotypes. Beyond their role in influencing immune responses, studies of the sinus mucosa have revealed that species such as Corynebacterium tuberculostearicum, which had never been considered in the past to be pathogenic (because of its prevalence as a commensal sinus inhabitant), can, in the context of a disturbed and species-depleted microbiome, behave in a pathogenic manner (12). This suggests that the pattern of microbial co-colonization defines the behavior of bacterial species in a given niche and that competition in more diverse communities may serve to prevent species outgrowth and inflammatory or infectious disease development.

FECAL MICROBIAL TRANSPLANT

The concept that microbial community composition influences the abundance and behavior of its component members is strongly supported by reports of the efficacy of FMT, as a viable therapeutic option for patients with recalcitrant CDI. Provision of a diversity of mircoorganisms and their products associated with a healthy gut microbiome to a patient with CDI leads, with high frequency, to infection remission. This suggests that the microbes, their products, or a combination of these factors sufficiently reduces the numbers and activity of the pathogenic species and modulates host immune responses in a manner that affords clinical efficacy. FMT has enjoyed a recent revival, largely because of our increasing understanding of the critical role played by the gut microbiome in providing crucial functions that influence host immune activation status. Clinical medicine's first published report of the potential therapeutic benefits of stool transplant appears in the literature in 1958, when Eiseman et al described the use of an adjunctive, enema-delivered stool as treatment for pseudomembranous colitis (15). The use of fecal material for treatment for gastrointestinal disorders has been recorded historically. Accounts widely reported by German soldiers in the 1940s, during their African campaign, describe the native Arabian population ingesting fresh camel stool as an effective means of preventing dysentery, a practice that had been passed down through the generations (16).

Although it enjoyed popularity among the medical profession in the 1940s and 1950s, the advent of an ever-expanding repertoire of broad-spectrum antimicrobials in the 1950s and 1960s superseded the use of FMT. Because the rate of antibiotic-resistant infection has significantly increased during the past several decades, alternative approaches to treating resistant infections are now paramount. More recently, FMT has resurfaced as a greatly efficacious therapeutic option for treatment for CDI refractory to traditional antimicrobial therapy. Approximately 20% of patients treated for primary CDI develop recurrent antimicrobial-resistant CDI (17–20) and are at significantly higher risk for developing additional infections. The mortality rate associated with CDI is high and represents a substantial health care burden. One Canadian study examining appropriate approaches to accurately quantify CDI-attributable deaths in adults found, using death within 30 days of infection as a marker for CDI-attributable death, that 80% of deaths in their cohort of patients with CDI were directly or strongly attributable to CDI (21). This percentage increased to 86% if clinical recurrences were considered (21). Largely because of the limited options to treat CDI and the high degree of efficacy observed on FMT treatment, coupled with a greater public awareness of the role the gut microbiome plays in promoting host health, FMT has been recently widely promoted in both the scientific and lay press, and is rapidly being adopted as a therapeutic option for CDI and potentially for other diseases and disorders in which disturbances in the gut microbiome are described.

FMT PROCEDURE

The procedure for FMT varies across practitioners, and no single standardized protocol has been widely adopted. Donor fecal material has been used with success from both recipient-selected donors (typically family members) and universal (nonfamilial) donors. Fresh and frozen specimens have been used for FMT procedures; both exhibit similar efficacy (22). At a minimum, selection of donors entails screening stool for pathogens with tests for toxigenic C difficile, ova, and parasites, and bacterial culture and antibiotic sensitivity. In research settings, more in-depth testing of donors is pursued including serologic studies for hepatitis A, B, and C, HIV types 1 and 2, and syphilis. Additional stool testing extends to assessments for Giardia, Cryptosporidium, and Isospora parasites and gastrointestinal viral pathogens such as rotavirus. Helicobacter pylori screening of donors is also recommended. Donors are typically excluded if they have been treated with antibiotics within 3 months of FMT. Because of the potential serious implications of altering the intestinal microbiome, some researchers recommend even more rigorous criteria and exclude donors with chronic medical conditions including atopy, chronic fatigue, obesity, IBD, irritable bowel syndrome, and other conditions (23).

The process of FMT requires a healthy donor to provide feces to the recipient patient. Processing donor stool for FMT requires that the material be liquefied by resuspension in any of a variety of solutions. Water, milk, or, most commonly, nonbacteriostatic saline has been used in published reports. Resuspension approaches range from simply mixing the constituents in a beaker to homogenizing stool and fluid in a sterile benchtop blender to create the slurry. The slurry is then typically filtered to remove larger particulate matter and facilitate delivery. At least 50 g of stool is recommended, and is typically resuspended in 250 to 300 mL fluid (24). In preparation for FMT, recipients are advised to discontinue antibiotics 1 to 3 days before the procedure. Regardless of route of administration, most recipients are given large bowel lavage with 4 L of polyethylene glycol to decrease microbial contents of the large intestine before FMT. On the day of the procedure, it is common practice for patients to be administered loperamide, a piperidine derivative opioid, which acts on μ-opioid receptors to increase residence time of the transferred fecal material in the gut (25).

Several modalities have been used in the delivery of FMT, including nasoduodenal infusion, retention enemas, and administration through a colonoscope. All 3 techniques have been shown to be effective in the treatment for recurrent CDI (25). In delivery of FMT by colonoscope, the entire colonic mucosa can be visualized allowing for the identification of potential comorbid conditions. Additionally, biopsies can be obtained for histologic evaluation at the time of the procedure. Proximal colonic instillation through the biopsy channel of the colonoscope may be advantageous because the entire length of colonic mucosa is exposed to and repopulated with donated microbes. Risks associated with colonoscopy are minimal, but the cost of this procedure exceeds that of retention enema and nasoduodenal administration. At this time, no clear consensus exists as to which is the optimal mode for delivery of FMT (26).

REGULATORY ASPECTS OF FMT

On a daily basis physicians use many drugs and surgical procedures that have not been approved for the purpose for which they are administered. The Food and Drug Administration (FDA) has been particularly rigorous in regulating the use of live microbes as a treatment modality, primarily because of concerns associated with administration of live microorganisms. As a result, the agency has required a much higher approval level for products such as probiotics and FMT. In an effort to enforce regulations, the FDA initially imposed a mandatory shutdown of all FMT and associated research that did not have a full investigational drug (IND) approval in place. (For those interested in obtaining such an approval, the following link is provided that outlines steps to ensure compliance with FDA regulations: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM153222.pdf.) The IND approval process typically takes 12 to 18 months to obtain, with defined period of response set out from the FDA in which they must review the application and make recommendations. For most FDA-approved drugs, an IND waiver is granted if the drug is to be studied for a different indication, but this did not apply, at least at the outset to microbial-based therapeutics, including FMT. Following the publication of a high-impact manuscript demonstrating high rates of efficacy of FMT for CDI (7), in July 2013, the FDA revised their requirements for FMT stating, “We, FDA, are informing members of the medical and scientific community, and other interested persons that we intend to exercise enforcement discretion regarding the investigational new drug (IND) requirements for the use of fecal microbiota for transplantation (FMT) to treat Clostridium difficile (C. difficile) infection not responding to standard therapies.” FDA intends to exercise this discretion, provided that the treating physician obtains adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products. Informed consent should include, at a minimum, a statement that the use of FMT products to treat C difficile is investigational and a discussion of its potential risks. FDA intends to exercise this discretion on an interim basis while the agency develops appropriate policies for the study and use of FMT products under IND (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm361379.htm). This FDA ruling extends to only CDI; full IND applications are necessary for all other applications of FMT or probiotics, which has resulted in the majority of ongoing probiotic and FMT research being conducted outside the United States.

FMT STUDIES AND TRIALS

In an effort to assess the present literature in this field, a review was conducted in September 2013, via PubMed, using the search terms “fecal OR stool OR feces OR microbiota AND transplant*,” resulting in recovery of 1530 citations. These were then filtered to include only clinical trials, resulting in a total of 86 publications. The large majority of reports on FMT examined the role for FMT in treating CDI, but a more recent trend in the published literature indicated growing interest in other opportunities for application of this treatment for diseases such as IBD or obesity (25,27–29).

In 2009, Bakken published a review examining FMT for recurrent CDI infection and identified 13 published case reports encompassing a total of 100 patients (16). Approximately 25% of patients received FMT via upper GI tract delivery methods, such as nasogastric tube, whereas the remainder received bacteriotherapy via a variety of lower tract delivery methods, such as colonoscopy. The review found an approximately 90% reported cure rate of CDI via FMT. A subsequent review by Gough et al included all but 1 of the articles in the Bakken review but also included 15 additional studies that meet their inclusion criteria, resulting in a total sample size of 317 patients (24). Although the majority of reports were journal articles, they also included letters (15%), abstracts (12%), and unpublished data (3%). Both reviews were composed entirely of case series or case reports. Even with the additional 217 patients, Gough et al reported a nearly identical rate of resolution of CDI at 92%. The most recent review by Kassam et al, published in 2013, included 11 studies (30). This was a methodologically robust review that included only full peer-reviewed studies and did not limit by language. As expected, at the time of the review Kassam et al identified no randomized controlled trials (RCTs) and the total number of patients was 273. Although only 2 of the studies were the same as those identified by Bakken, Kassam et al also reported a 90% cure rate across this metadata set. Hence, based on various reviews of the literature using variable numbers of patients across different study, the preponderance of evidence indicates that FMT is at least 90% efficacious in curing recurrent CDI, although the caveat that none of these studies were RCTs but rather case studies or reports should be noted.

At the time of writing the present article, there is only 1 published RCT that examined the role of FMT in recurrent CDI (7). In an eloquent design that included 2 control arms and a third group receiving FMT, active treatment included a vancomycin regimen (500 mg orally 4 times per day for 4 days), followed by bowel lavage and subsequent infusion of a solution of donor feces through a nasoduodenal tube. The primary outcome was resolution of diarrhea from CDI without relapse in 10 weeks. Control arms received either the standard vancomycin regimen (500 mg orally 4 times per day for 14 days) or the standard vancomycin regimen with bowel lavage. The data safety monitoring board requested that the study be halted prematurely after 13 of 16 patients in the FMT group had resolution of CDI, following a single FMT treatment. The remaining 3 patients in this group received a second infusion, following which 2 of the 3 patients responded with full resolution of their CDI. In contrast, resolution of CDI occurred in only 4 of 13 patients receiving vancomycin alone and 3 of 13 patients receiving vancomycin with bowel lavage, indicating a significant increase in efficacy in the FMT-treated group (P < 0.001 (7)). Similarly to the case report reviews, the patients studied in this RCT had many comorbid conditions (mean age of FMT group 73) and all but 8 of the 43 patients enrolled in the trial had CDI relapses more than once before enrollment.

Although only 1 RCT of FMT has been published, the recent interest in bacteriotherapy is reflected in the increasing number of ongoing trials. As of October 2013, ClinicalTrials.gov lists 46 trials using the terms “fecal” and “transplant,” although only 19 are relevant to the topic of the present article. Nine of those studies are being conducted in the United States. One US study anticipates enrolling 100 participants, whereas a separate trial aims to include 53 subjects; the remaining 7 studies are considerably smaller and plan to enroll a total of 107 participants. One Canadian trial (NCT01372943) plans to transfer synthetic stool, a published mix of 33 culturable bacterial species from healthy stool, including members of the Acidaminococcus, Bacteroides, Bifidobacterium, Clostridia, and Eubacterium. As expected, all of the other studies are using a variety of donors and methods of delivering the stool to the recipients. The studies are examining the role of FMT for a variety of conditions. One study is examining the efficacy of FMT for treatment for diabetes, 9 for CDI, and the remainder for IBD. Only 3 studies in the United States are examining the FMT for treatment for IBD, with a cumulative total of 40 participants across all 3 studies. From a review of the NIH database, it appears that there is only one FMT study funded by the NIH, through their R21 mechanism, which funds pilot, exploratory research. This study represents a phase I safety study, examining the role of FMT to treat recurrent CDI.

FMT for Non-CDI Indications: Concerns and Considerations

Although it has primarily been used with great efficacy for treatment for recalcitrant CDI, the growing number of diseases characterized by gut microbiome dysbiosis has led to rising enthusiasm regarding the application of FMT to treatment for a variety of diseases beyond CDI. Although, again, this is a nascent field, a limited number of studies with small cohort sizes have examined the application of FMT as a therapeutic modality for other gastrointestinal disorders that are characterized by a dysbiotic microbiome, such as IBD. Of the published studies to date, efficacy has been variable. In 1 recent small study of 5 patients with IBD, FMT resulted in fever and a temporary increase in C-reactive protein. Whereas the numerically dominant bacteria in the donor feces were deemed to have established in the recipients, the effectiveness of therapy and the stability of resulting community that developed in the patients varied greatly across participants. Only 1 patient exhibited a positive clinical response 12 weeks post-FMT, and this patient exhibited successful colonization by donor-derived Faecalibacterium prausnitzii, Rosebura faecis, and Bacteroides ovatus(31). Similar results were noted in a study of pediatric and young adult patients with IBD who underwent FMT (32). Again, in this study, establishment of the donor microbiome in the recipient patient was variable, as was longevity of the resulting microbiome and reported efficacy. Moreover, these patients also recorded mild to moderate, although self-limiting, adverse events at the time of treatment (32).

Part of the issue of FMT for nonindicated ailments is the overwhelming lack of understanding of human gastrointestinal microbiome function in the context of host genetics and environmental exposures (particularly diet). These factors exert significant impact on the composition and, by extension, function of the gut microbiome, although they are not readily considered in FMT studies. For example, risk genes associated with IBD, such as Nod2 and ATGL13, are associated with the presence of particular bacterial species within the fecal microbiome (33). These risk alleles, while frequently associated with the disease in European populations, are not risk genes in cohorts of Asian patients with IBD, suggesting that ethnically distinct populations may possess discrete microbial assemblages that require distinct community rehabilitation strategies to afford optimal efficacy. Moreover, diet, because it represents the largest carbon and nitrogen source for the microbial communities resident in the gastrointestinal tract, is one of the most influential factors on community composition and function (34). A large existing body of work has identified a variety of nondigestible food ingredients, known as prebiotics, that promote the growth of beneficial species. To date, no studies have considered either post-FMT dietary restrictions or supplementation with specific prebiotics as a means to further enhance the establishment and longevity of the donor community in the recipient patient.

To further complicate microbiome rehabilitation efforts, the composition of the microbial community is distinct and specific to particular regions of the gastrointestinal tract in healthy individuals. This has implications for diseases that manifest at particular sites in the GI tract. For example, although it can manifest without ileal involvement, Crohn disease often presents in the ileum, which houses a compositionally and functionally distinct microbiome to that of the colon. Therefore, supplementation with fecal material, which largely represents microbial species adapted to life and function in the distal colon, may not provide the appropriate species to competitively colonize the ileum. Clearly, clinicians need to determine where a patient's disease predominates because those with primarily distal colonic disease would presumably benefit most from FMT. Other important considerations include the age and sex of the donor and recipient. Gut microbiome composition is dynamic and changes with age (35,36), and has been shown in separate studies to be related to the degree of immune activation in individuals with underlying disease (37). Given our lack of knowledge regarding the long-term implications of FMT, it is incumbent on those in the field to consider age and sex matching between donors and recipients, particularly when the recipients are pediatric patients who are in the developmental stage of life.

Many questions remain unanswered about FMT, including appropriate testing of donor material, appropriate FMT delivery, and when it is best indicated. Because of the lack of RCTs and the inherent microbial variability of donated fecal material, it is difficult to properly assess adverse events. Most of the case reports do not address even acute adverse events. When adverse events are reported, they are generally considered as unattributable to FMT. The adverse effects reported included a flare of ulcerative colitis that had been inactive for 20 years (27) and bacteremia in a patient with Crohn disease and CDI (38). One of the most important issues is the long-term implication of this therapeutic strategy. In general, studies are not designed to address long-term safety and can only address immediate adverse events. As we learn more about the microbiome, this may provide us with specific biomarkers, either host- or microbial-derived, that predict long-term outcomes. One multi-institutional study did try to examine long-term complications by following up patients (n = 77) at least 3 months (mean = 17 months) after their FMT for CDI (39). Similar to other studies, this cohort was sickly, with patients reporting a mean of 11 months’ duration of experiencing symptoms before FMT, and, on average, 5 conventional antimicrobial regimens. The average cure rate of initial FMT treatment was 91%—almost identical to that reported in other studies. The survey found that 97% of patients reported they would repeat FMT for CDI; 2 patients associated FMT with an improvement in allergic sinusitis and arthritis, whereas 4 patients reported a new medical condition, peripheral neuropathy, Sjögren syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis. Seven patients were deceased at the time of the follow-up survey but family members participated in the survey, and death was not believed attributable to FMT (39).

Clearly, manipulation of the gastrointestinal microbiome has profound implications for both gastrointestinal diseases and diseases that manifest at sites remote from the gastrointestinal tract, and underscore the importance and far-reaching impact of this microbial organ on human health. Approaches such as FMT that rehabilitate perturbed microbial ecosystems within the human host have obvious promise and open up a host of new possibilities for treatment for a range of recalcitrant diseases. For the reasons outlined in the present article, great caution must be urged in considering FMT for indications other than CDI. Moreover, use of this therapeutic modality should be considered a first step toward development of rationally designed next-generation probiotics. Ultimately, development of therapeutic microbial communities based on a solid understanding of the mechanistic basis of how these organisms afford protection in a given anatomical niche and the long-term implications of such supplementation interventions represents the most practical approach to microbiome manipulation as a viable therapy for human disease.

REFERENCES

1. Karlsson F, Tremaroli V, Nielsen J, et al. Assessing the human gut microbiota in metabolic diseases. Diabetes 2013; 62:3341–3349.
2. Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013; 155:1451–1463.
3. Huang YJ, Nelson CE, Brodie EL, et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol 2011; 127:372–381.e1–e3.
4. Zemanick ET, Harris JK, Wagner BD, et al. Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations. PLoS One 2013; 8:e62917.
5. Han MK, Huang YJ, Lipuma JJ, et al. Significance of the microbiome in obstructive lung disease. Thorax 2012; 67:456–463.
6. Fujimura KE, Demoor T, Rauch M, et al. House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection. Proc Natl Acad Sci U S A 2014; 111:805–810.
7. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368:407–415.
8. Frank DN, Pace NR. Gastrointestinal microbiology enters the metagenomics era. Curr Opin Gastroenterol 2008; 24:4–10.
9. Rhee KJ, Sethupathi P, Driks A, et al. Role of commensal bacteria in development of gut-associated lymphoid tissues and preimmune antibody repertoire. J Immunol 2004; 172:1118–1124.
10. Walker AW, Sanderson JD, Churcher C, et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol 2011; 11:7.
11. Vaarala O. Human intestinal microbiota and type 1 diabetes. Curr Diab Rep 2013; 13:601–607.
12. Abreu NA, Nagalingam NA, Song Y, et al. Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis. Sci Transl Med 2012; 4:151ra124.
13. Nagano Y, Itoh K, Honda K. The induction of Treg cells by gut-indigenous Clostridium. Curr Opin Immunol 2012; 24:392–397.
14. Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009; 139:485–498.
15. Eiseman B, Silen W, Bascom GS, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958; 44:854–859.
16. Bakken JS. Fecal bacteriotherapy for recurrent Clostridium difficile infection. Anaerobe 2009; 15:285–289.
17. Fekety R, McFarland LV, Surawicz CM, et al. Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial. Clin Infect Dis 1997; 24:324–333.
18. McFarland LV, Surawicz CM, Rubin M, et al. Recurrent Clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp Epidemiol 1999; 20:43–50.
19. McFarland LV. Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig Dis 1998; 16:292–307.
20. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002; 97:1769–1775.
21. Hota SS, Achonu C, Crowcroft NS, et al. Determining mortality rates attributable to Clostridium difficile infection. Emerg Infect Dis 2012; 18:305–307.
22. Hamilton MJ, Weingarden AR, Sadowsky MJ, et al. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107:761–767.
23. Brandt LJ, Reddy SS. Fecal microbiota transplantation for recurrent Clostridium difficile infection. J Clin Gastroenterol 2011; 45 (suppl):S159–S167.
24. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011; 53:994–1002.
25. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011; 9:1044–1049.
26. Borody TJ, Brandt LJ, Paramsothy S. Therapeutic faecal microbiota transplantation: current status and future developments. Curr Opin Gastroenterol 2014; 30:97–105.
27. De Leon LM, Watson JB, Kelly CR. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol 2013; 11:1036–1038.
28. Borody TJ, Warren EF, Leis S, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 2003; 37:42–47.
29. Borody TJ, Warren EF, Leis SM, et al. Bacteriotherapy using fecal flora: toying with human motions. J Clin Gastroenterol 2004; 38:475–483.
30. Kassam Z, Lee CH, Yuan Y, et al. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 2013; 108:500–508.
31. Angelberger S, Reinisch W, Makristathis A, et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol 2013; 108:1620–1630.
32. Kunde S, Pham A, Bonczyk S, et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr 2013; 56:597–601.
33. Frank DN, Robertson CE, Hamm CM, et al. Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis 2011; 17:179–184.
34. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 2011; 334:105–108.
35. Palmer C, Bik EM, DiGiulio DB, et al. Development of the human infant intestinal microbiota. PLoS Biol 2007; 5:e177.
36. Costello EK, Lauber CL, Hamady M, et al. Bacterial community variation in human body habitats across space and time. Science 2009; 326:1694–1697.
37. Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut microbiota is associated with hiv disease progression and tryptophan catabolism. Sci Transl Med 2013; 5:193ra91.
38. Quera R, Espinoza R, Estay C, et al. Bacteremia as an adverse event of fecal microbiota transplantation in a patient with Crohn's disease and recurrent Clostridium difficile infection. J Crohns Colitis 2014; 8:252–253.
39. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107:1079–1087.
Keywords:

clinical efficacy; clinical trials; fecal microbiota transplant; gastrointestinal microbiome

© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,