Current Status of Fecal Microbiota Transplantation

Current Status of Fecal Microbiota Transplantation

Chapter 16 Current Status of Fecal Microbiota Transplantation J. Reygner1 and N. Kapel1, 2 1 Faculté de pharmacie, Université Paris Descartes, Sorbo...

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Chapter 16

Current Status of Fecal Microbiota Transplantation J. Reygner1 and N. Kapel1, 2 1

Faculté de pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 2Laboratoire de Coprologie Fonctionnelle, APHP, Hôpitaux

Universitaires Pitié Salpêtrière-Charles Foix, Paris, France

INTRODUCTION The intestinal microbiota is currently respected as a well-orchestrated organism, with a major role in the development of immunity and maintenance of health, and various pathologies are associated with dysbiosis. Fecal microbiota transplantation (FMT) aims to treat diseases associated with alteration of gut microbiota by introduction of a fecal suspension from a healthy donor into the gut of a receiver [1]. The goal of FMT is to restore the phylogenetic diversity, and homeostasis of the gut microbiota. The oldest account of FMT dates back to the 4th century when a Chinese physician named Ge Hong advised to consume fresh stool from a healthy neighbor when suffering from severe diarrhea. The first report in modern medical literature appeared in 1958, when Eiseman reported the successful use of FMT via fecal enema in four patients to treat severe pseudomembranous colitis, long before Clostridium difficile was identified as the causative agent of this condition. This procedure has garnered significant attention in the last decade, in the face of the increasing prevalence, severity, and mortality related to C. difficile infection (CDI), and the growing interest in new therapeutics based on manipulation of the microbiota. Today, most cases of CDI are treated with metronidazole, vancomycin, or fidaxomicin, but recurrence ranges from 20% after the initial episode to 60% after multiple treatments. Following a first randomized clinical trial (RCT) [2], numerous studies have confirmed the efficacy of FMT, compared to conventional antibiotic treatment, for recurrent forms of C. difficile infection (rCDI). This procedure is thus recommended for this indication in the North American and European guidelines [3,4]. Since dysbiosis may be found in many other diseases, the use of FMT has been considered as a therapeutic option in non-CDI indications such as chronic inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), metabolic disorders, neuropsychiatric conditions including autism, or in antibiotic-resistant bacterial infections. Preliminary studies show encouraging results, but none of them allows recommendation to use FMT, except in a context of clinical research.

FECAL MICROBIOTA TRANSPLANTATION: REGULATORY ASPECTS The regulatory status of the fecal microbiota as a medical treatment remains to be clarified, as FMT policy and legislation differ from country to country [5]. In 2012, the FDA classified human feces as a drug. However, FMT has not undergone traditional regulatory approval process of pharmaceutical products, with sequential testing leading to large phase III trials, assessing efficacy and safety prior to clinical use. The European Medicine Agency has not defined its position, leaving each country free to assign a qualification. In France, FMT is considered a drug by the National Agency for Medicine and Health Product Safety, placing the fecal material under the jurisdiction of the hospital pharmacy [5]. Thus production should be carried out under responsibility of pharmacists and storage within the pharmacy. Other European countries such as Austria or Finland see FMT as a therapeutic intervention that should not be considered a pharmaceutical drug, and did not consider relevant to establish specific regulations. In those countries, doctors may perform FMT based on their own judgment without any approval from the drug authority [6,7].

Microbiome and Metabolome in Diagnosis, Therapy, and other Strategic Applications. https://doi.org/10.1016/B978-0-12-815249-2.00016-6 Copyright © 2019 Elsevier Inc. All rights reserved.

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FECAL MICROBIOTA TRANSPLANTATION PROCEDURE: PREPARATION, ADMINISTRATION After a first RCT by van Nood [2], which has shown that FMT is highly effective for the treatment of rCDI, this procedure has gained popularity as clinical trials have consistently confirmed its high efficacy in resolving rCDI. No serious adverse events were reported, whereas incidence, severity, and mortality due to C. difficile increased. However, fecal microbiota transplantation is a complex intervention that involves multiple components, ranging from donor selection to methods of transplantation, and the clinical use of FMT remains difficult, because of uncertainty surrounding optimal methods of fecal bacterial community processing and administration. FMT requires healthy stool donors, infrastructure for the processing and storage of donated stool, and a mechanism for introducing stool from the healthy donor into the infected patient’s small intestine or colon. Up to now, there is no clear consensus on the optimal protocol for feces preparation before FMT, and practices vary among groups. However, some standards have emerged, allowing to propose a set of steps [8].

Donor Selection Donor selection is a crucial step, which aims to reduce and prevent any adverse effects associated with fecal administration. Firstly potential donors are asked to provide detailed information about their medical history and lifestyle to identify any risk factor for transmission of infectious agents, that is, known HIV or viral hepatitis, illicit drug use, unprotected sex, and sex with high risk of HIV or hepatitis C virus acquisition. Gastrointestinal (GI) diseases such as inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), GI malignancy, or any other medical conditions or treatments that might impact the gut microbial community such as a recent international travel to areas at high risk for enteric infections or multiple drug resistant bacteria, recent antibiotic use, obesity, metabolic syndrome are equally questioned. Secondly, they are submitted to a framework of screening including serologic and stool tests, with large variation according to guidelines published by different groups (Table 16.1) [2,9e11]. Donors may or may not be related to the recipient. Some authors favor abbreviated screening, if the medical history is reassuring, and if the donor is a family member or intimate to the recipient, while others favor extensive screening for all donors. No difference in effectiveness of FMT, in the recovery of patients suffering from rCDI, has been reported according this parameter, but there are still no RCT comparing the two categories of donor.

PREPARATION OF FMT The donor should be notified to avoid any food to which a recipient may be allergic for 5 days prior to the procedure. On the day of donation, a second interview must be completed by the donor to ensure that no adverse event has occurred since screening [10e12]. The first RCTs of FMT used freshly donated stools [2,13], but results from subsequent studies have supported the equivalent efficacy of frozen stool preparation [14e18]. Considering potential logistic advantages of frozen fecal material, this option is now widely used, as it allows the development of fecal banks, and a faster management of the patient’s treatment, without the delay related to the donor recruitment phase [19]. However, such banks are not suitable when FMT is considered as a drug which has to be prepared and stored within the hospital pharmacy [12]. Processing donated stool typically involves two steps: (1) homogenization of stools with diluent and (2) filtration to remove large particles [8]. A third step, with concentration of bacteria via centrifugation may be performed for the use of frozen capsules [20]. All procedures are performed at room temperature. It is highly recommended that fecal suspension should be prepared under a hood, because stool is considered as a level 2 biohazard. As a complete screening is performed prior to selection, this will mainly avoid the risk of crosscontamination and protect lab staff [21]. Whether feces should be prepared in an anaerobic environment to preserve anaerobic bacteria is still discussed. Most laboratories lack anaerobic chambers, and most successes have been obtained with aerobic preparation, so the use of a chamber under N2 gas seems not to be absolutely required up to now [2,20]. Stools have to be diluted in an adapted volume of sterile diluent, according to the consistency of the fecal sample, that is, sterile water, 4% milk, preservative-free normal saline, or phosphate buffered saline for fresh FMT [22]. For frozen storage without risk of bacterial cell lysis, glycerol 10% e80% is advised [14e16]. After homogenization by hand or a dedicated blender, filtration of fecal solution is performed twice, using sterile gauze or stainless steel laboratory sieves, to remove debris and thus avoid clogging the administration equipment. Although stool

TABLE 16.1 Recommended Screening Tests for Stool Donors Sokol et al. [10] and French ANSM [12]

van Nood et al. [2]

Blood (serologies)

HIV types 1 and 2 Ab HAV, HBV, HCV Treponema pallidum

HIV types 1 and 2 HTLV I and II HAV, HBV, HCV EBV T. pallidum Entamoeba histolytica Strongyloides stercoralis

HIV types 1 and 2 HTLV I and II HAV, HBV, HCV, HEV CMVa T. pallidum S. stercoralis Trichinella species E. histolytica EBVb Toxoplasma gondiib

HIV-1 and HVI-2 HTLV I and II HAV, HBV, HCV, HEV CMV EBV T. pallidum E. histolytica S. stercoralis

Stools

Clostridium difficile toxin B by PCR; Routine bacterial culture for enteric pathogens Fecal Giardia antigen Fecal Cryptosporidium antigen Acid-fast stain for Cyclospora and Isospora Ova and parasites H. pylori fecal antigen (for upper GI routes of FMT)

C. difficile (toxin ELISA and culture or PCR) Routine bacterial culture for enteric pathogens Parasitological evaluation according to local standards (triple feces test or PCR)

Adenovirus, Astrovirusb Calcivirus (Norovirus, Sapovirus)b Picornavirus (Enterovirus, Aichi virus)b Bacterial culture for: C. difficile (toxin ELISA and culture or PCR) Listeria monocytogenes Vibrio cholerae/V. parahemolyticus,b Salmonella, Shigella, Yersinia, Campylobacter sp., Multiresistant-drug bacteria, S. stercoralis, Cryptosporidium species, Cyclospora species, E. histolytica, Giardia intestinalis, Isospora species Microsporidia Blastocystis hominisb Dientamoeba fragilisb

Helicobacter pylori fecal antigen Rotavirus C. difficile (toxin ELISA and culture or PCR) Bacterial culture for: Salmonella, Shigella, Campylobacter, Escherichia coli O157 H7, Yersinia, V. cholera, L. monocytogenes, Multiresistant-drug bacteria, Norovirus, Protozoa (including Blastocystis hominis, Giardia lamblia, and Cryptosporidium parvum), and helminths. Fecal occult blood testing Isospora Microsporidia

a

Cammarota et al. [11]

to exclude serodiscordance with the recipient. these recommendations have been proposed in the case of clinical trials by the French National Agency for Medicines and Health Products Safety 2016.

b

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Bakken et al. [9]

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weight is not a highly representative measure of the amount of microbiota, due to the large interindividual variability of microorganism load and water content in feces, most studies use w50 g of stool for FMT. However, a wide range of masses has been reported, and recent studies pointed out satisfactory results in the treatment of rCDI with as little as 30 g of fecal material [11,22]. When FMT is performed with fresh stools, administration should be performed within 6 h after bowel movement, to preserve sample from any alteration [10,11]. Administration of fresh stools is being gradually abandoned in favor of frozen stools. Frozen samples must be properly labeled, to be traceable as for blood. Stool preparations should be stored as aliquots for single use in order to avoid repeated freezing/thawing of the fecal suspension. The aliquots must be stored at 80 C, and storage at 20 C should be avoided as some enzymes may still be active and degrade bacteria [11]. There is currently no codified protocol for thawing (gradual thawing or use of a 37 C water bath); however, consensually the fecal suspension should be administered within 6 h after thawing.

Delivery of FMT The treatment sequence for rCDI usually involves three steps: (1) oral antibiotic therapy with vancomycin, (2) bowel preparation, and (3) delivery of the fecal suspension [10]. However, there is no general agreement on how best to prepare the recipient prior to FMT. Bowel lavage is known to significantly reduce the luminal bacterial load [23], but whether it should be performed prior to FMT is uncertain. It is typical to stop anti-CDI antibiotics 24e48 h prior to the FMT procedure; however, the impact of this timing on FMT success has not been rigorously evaluated nor is there robust evidence to support which anti-CDI antibiotic should be used prior to FMT or at which dose. There is also no general agreement on the best approach for delivering fecal microbiota or for optimal volume. The FMT dose can be administered via the upper or lower GI tract. Upper GI delivery methods include nasogastric tubes, nasoduodenal tubes, and oral capsules, while lower GI delivery methods include mainly colonoscopy and enema. A nasogastric tube has been used in the first RCTs [2,16] and in some further studies, namely in elderly and immunocompromised patients [24,25]. It requires less patient preparation, time, and inconvenience, and is technically easier to perform than colonoscopy [16,24,25]. However, this method may carry the risk of vomiting and aspirating fecal material; so a gradual administration at a flow rate of 50 mL/2e3 min should be performed, in order to avoid the risk of reflux [8]. Moreover, the engraftment of the microbiota at the colonic level remains questionable. Colonoscopy, which allows delivery of a large volume of fecal suspension (100e1000 mL) throughout the entire colon has been widely used [16,18,26e29]. Interestingly, it allows simultaneous inspection of the colon mucosa and determination of preferential sites for infusing sufficient amounts of donor feces. However, manipulation with colonoscopy through an inflamed colon can be difficult and dangerous. Studies directly comparing delivery methods are scarce. A recent metaanalysis reported a significant difference between lower GI and upper GI delivery of FMT with levels of clinical resolution of 95% (95%CI 92%e97%) versus 88% (95%CI 82%e94%), respectively (P ¼ .02) [30]. Gundacker et al. confirmed that nasogastric delivery of FMT was less effective than lower endoscopic delivery. However, when patients were stratified by illness severity, nasogastric delivery achieved similar cure rates in healthier individuals, whereas lower endoscopic delivery was preferred for relatively ill individuals [31]. Although this study was monocentric and the post-FMT follow-up was short (15 days), it has the advantage of including patients with different degrees of severity of the disease. It is worth noting that a time-varying analysis has suggested that patients treated by the upper route were two to three times more likely to face clinical failure than those treated by the lower route after 30 and 90 days post-FMT follow-up, respectively [32]. FMT by retention enema and rectal tube instillation continues to be popular due to its simplicity, low risk, and low cost [15,33,34]. Retention enema is safe, simple, and inexpensive. However, a retention time of at least 2 h is required for better efficacy. Moreover, the theory that rectal repopulation of the microbiota will lead to proximal colonization has yet to be validated and diminished rectal sphincter tone in the elderly may compromise retention of the FMT infusate and decrease success. The main drawback of this technique is that it usually requires more than one administration. In the study of Lee et al. [15], the cure rate was 50.5% after the first procedure, and 85.6% after several administrations. Recently protocols using capsules of frozen (2  15 capsules, 1 day apart) or lyophilized material have reported cure rates similar to the ones achieved with other FMT procedures, that is, w90% [20,35,36,54]. These results have been confirmed in a recent RCT, which reported that FMT via oral capsules was not inferior to delivery by colonoscopy in patients with rCDI, for preventing recurrent infection over 12 weeks of follow-up [26].

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CURRENT INDICATION: TREATMENT OF RECURRENT FORMS OF CLOSTRIDIUM DIFFICILE INFECTIONS According to recommendations, the first-line treatment for CDI remains anti-C difficile antibiotics (metronidazole, vancomycin, or fidaxomicin). This treatment is typically successful in relieving CDI symptoms, but as many as 20% of CDI patients face recurrence, and the risk of rCDI increases with each subsequent CDI episode. Molecular analyses of intestinal microbiota in patients with rCDI demonstrate lower fecal microbiota diversity compared to healthy subjects, which supports the role of FMT in the treatment of rCDI. In 2013, a Dutch team reported the first RCT of duodenal infusion of donor fresh feces, which definitively established the remarkable efficacy of FMT [2]. In fact, the trial was stopped early after an interim analysis which demonstrated superiority of FMT compared to vancomycin alone or associated with bowel lavage. Since that first RCT, enthusiasm for FMT has increased, and cumulative experience from RCT and prospective case series showed that FMT is effective (80% e90%) when used to treat rCDI, after one or sequential infusions, without severe adverse effects. An important barrier to FMT includes the limited time window to recruit and screen a suitable donor and prepare the material, and this leads to using frozen stool material. The elderly are especially vulnerable to CDI and rCDI. Recent studies have shown safety and equivalent cure rate of FMT in this population, as well as in immunocompromised patients, with or without significant comorbidities, allowing the use of FMT as an emerging treatment option. Major results about the use of FMT in the treatment of rCDI (RCT and prospective case series) are reported in Table 16.2. However there are still many open questions to be addressed, mainly related to the mechanism of action of FMT: Is the therapeutic action related to the whole microbiota, or only to a few bacteria having special properties such as those with 7a-dehydroxylase activity, which can metabolize primary to secondary bile acids [37]? Is it necessary to deliver living bacteria? One study reported a successful treatment of 5 patients with FMT, using sterile fecal filtrates free of bacteria, with a 6 months of follow-up [38]. Are the bacteria the definitive therapeutic agents, or could other components such as bacteriophages be active against rCDI [39]?

FMT BEYOND C. DIFFICILE: PERSPECTIVES FMT and Inflammatory Bowel Disease Dysbiosis, with developing evidence of fungi and viruses, contributes to development of Crohn disease (CD), ulcerative colitis (UC), and pouchitis. Characteristic compositional changes observed in patients with IBD include decrease in bacterial diversity, with expansion of putative aggressive groups (such as Proteobacteria, Fusobacterium species, and Ruminococcus gnavus) combined with decreases in protective groups (such as Bifidobacterium species, Roseburia, and Faecalibacterium prausnitzii), causing alteration of the metagenome and production of metabolites, namely short-chain fatty acids [40]. The question of FMT in these indications was therefore quickly raised. Although trials were reported as early as the end of the 1980s, studies remain limited, including small cohorts with limited follow-up. Variability is wide in FMT routine (type of donors, antibiotic pretreatment, bowel lavage, mode of administration, number and frequency of infusions) as well as corresponding results. To date, only three RCTs have been reported in UC patients, showing conflicting results, that is, two positives and one negative [41e43]. The evidence for FMT in CD is even sparser, and additional well-designed controlled studies are needed. However, encouraging results are available, with clinical response rates of 50%e60%. Of note, in the only CD cohort study to report endoscopic outcomes, no patient experienced endoscopic remission [44]. However, a recent metaanalysis suggested a significant efficacy in attaining clinical remission in the most common phenotypes of IBD, with 201/555 patients (36%) with UC, 42/83 (50.5%) with CD, and 5/23 (21.5%) with pouchitis achieving clinical remission [45]. These results are promising, but the success rate does not reach that observed for rCDI. Moreover, long-term durability and safety remain unclear, so there is no evidenced-based recommendation for the use of FMT in UC. For both CD and UC, all studies point out the importance of donor selection, which is today only based on microbiological examinations, to ensure the absence of risk of transmission of pathogens.

FMT and Irritable Bowel Syndrome IBS is a common disorder characterized by chronic abdominal pain and discomfort, associated with alterations of bowel habits, in the absence of a demonstrable pathology. Despite considerable research efforts, its treatment remains a significant challenge. During the past years, intestinal dysbiosis has been closely linked to the pathophysiology of IBS [46].

Study

Delivery Mode

Special Feature

Number of Patients

Randomized clinical trial

Upper route

Vancomycin Vancomycin þ bowel lavage FMT with fresh stools

13 13 16

End point: no diarrhea and no relapse after 10 weeks of follow-up Vancomycin group: cure rate 31% Vancomycin þ bowel lavage group: cure rate 23% FMT group: cure rate 81% after one FMT and 94% after a second infusion

[2]

Colonoscopy

Vancomycin FMT with fresh stools

19 20

Cure rate 26% Cure rate 90%

[13]

Upper route Colonoscopy

Frozen stool (storage 29e156 days at 80 C)

10 10

End point: no diarrhea and no relapse 8 weeks after FMT Upper route: cure rate 60% Colonoscopy: cure rate 80%

[16]

Colonoscopy

Fresh stool Frozen stool Lyophilized stool

25 24 23

Overall cure rate: 87% after 8 weeks of follow-up fresh stool: 100%; frozen stool 83.3%; lyophilized stool 78%

[18]

Colonoscopy

Donor stools (¼ heterologous FMT) Patient’s own stool (¼ autologous FMT)

22 24

Cure rate ¼ 90.9% Cure rate ¼ 62.5%

[27]

59 57

End point: no rCDI 12 weeks after FMT Cure rate: 96.2% in both groups

[26]

End point: no diarrhea and no relapse at week 13 Cure rate 85.6% (fresh stool) vs. 90.7% (frozen stool)

[15]

Colonoscopy Oral capsules Enema

Refractory and recurrent CDI Fresh stool Frozen stool (storage < 30 days at 20 C)

111 108

Main Results

References

Number of FMT

Fresh stools

Frozen stools

1

56

57

2

22

75

3 a` 5

12

13

>5

5

4

Total

95

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TABLE 16.2 Major RCTs and Prospective Studies on FMT for rCDI Treatment

Prospective studies

Elderly patients (>65 years) Jejunal and colonic administration

29

Cure rate 93.1%

[24]

Upper route Colonoscopy

Hematopoietic stem cell transplantation recipients with CDI

7

Cure rate 85.7% and 100% after the first FMT and second FMT, respectively

[25]

Upper route Colonoscopy

Enteroscopy and Colonoscopy in a single session

27

Cure rate 100% after 12 weeks of follow-up

[29]

Colonoscopy

Elderly patients (mean age: 83.7 years)

4

Cure rate 100% for up to 3 months without any adverse events

[28]

Colonoscopy

First use of frozen material

43

Cure rate 86% after 2 months of follow-up Similar efficacy in patients that had underlying IBD (w30%)

[14]

Oral delivery

Capsules containing frozen stool

180

Cure rate 82% after the first dose (2  15 capsules at 1 day apart), 91% after the second dose and 93% after the third dose

[35]

Oral delivery

Freeze-dried encapsulated preparation of standardized fecal microbiota

49

Cure rate 88% A single administration of the lowest dose (2.1e2.5  1011 bacteria) in a 2 or 3 capsules was highly successful

[36]

Enema

Recurrent, severe, or complicated CDI in elderly patients

146

Cure rate 82.9% and 95.9% after the first FMT and second FMT, respectively

[33]

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Upper route

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It has been demonstrated that diversity of the microbial population is reduced, the proportion of specific bacterial groups is altered, and the degree of variability in the microbiota composition is different in IBS patients when compared with healthy subjects. Furthermore, a higher degree of temporal instability of the microbiota among IBS patients has been detected [47]. FMT has thus been suggested as a potential treatment; however, results are far from conclusive yet. A first case series has been published in 1989, demonstrating approximately 50% relief in symptoms. However, the study also included IBD and CDI patients, without any distinction between these different diseases [48]. The same team has then reported the successful treatment of more than 300 IBS patients, with diarrheic phenotype [49]. Another single-center study has reported promising results with refractory disease: 69% of the patients experienced a resolution or improvement in their IBS symptoms. However, patient-specific long-term treatment goals were only achieved in 46% of the subjects [50].

FMT and Decolonization of Antibiotic-Resistant Bacteria in the Gastrointestinal Tract Selective pressures created by the clinical and agricultural use and misuse of antibiotics have resulted in the development of multidrug resistant bacteria. Several case studies have suggested the potential efficacy of FMT for the decolonization of the digestive tract of patients with multiresistant bacteria, regardless of the immune status. Recently, Bilinski et al. reported the successful decolonization of 60% (15/25) of the patients at 1 month after FMT, and more frequently in those that had no preprocedural use of antibiotics (79% vs. 36%, P < .05) [51]. In a recent French study with digestive tract colonization by carbapenem-resistant Enterobacteriaceae (CRE, n ¼ 6) or vancomycin-resistant Enterococci (VRE, n ¼ 2), FMT administered nasoduodenally allowed the eradication of carriage in 2/6 patients with CRE and 1/2 patients with VRE at 3 month follow-up, with no noticeable side effects [52]. It should be underscored that the delivery of FMT via enema has not demonstrated the ability to decolonize VRE from the gut, suggesting that the route of administration represents an important factor in efficacy [53].

FMT and Other Indications The development of high-throughput microbial sequencing has enabled the identification of a plethora of diseases (liver disease, metabolic syndrome, autism, rheumatism, and others), associated with underlying gastrointestinal microbiota dysbiosis. Interest has thus grown in the potential of microbial manipulation through the use of FMT. However, these studies remain experimental.

CONCLUSION Since 2013 and the study by van Nood [2], FMT has revolutionized the treatment of rCDI and it is now recognized and recommended as a highly efficacious and safe treatment method for rCDI. Moreover, the capacity of FMT to restore a dysbiotic microbiota has prompted various researches into its use as a therapeutic agent for other diseases associated with gastrointestinal microbial dysbiosis. However, a lot of work remains to be done to develop international recommendations and to standardize key methodological aspect of the FMT intervention such as donor selection, FMT preparation, receiver preparation, and follow-up to facilitate reporting and implementation in clinical practice in various clinical situations.

LIST OF ACRONYMS AND ABBREVIATIONS CD Crohn disease CDI Clostridium difficile infection CRE Carbapenem-resistant Enterobacteriaceae FMT Fecal microbiota transplantation GI Gastrointestinal IBD Inflammatory bowel disease IBS Irritable bowel syndrome rCDI Recurrent forms of Clostridium difficile infection RCT Randomized controlled trial UC Ulcerative colitis VRE Vancomycin-resistant Enterococci

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[13] Cammarota G, Masucci L, Ianiro G, Bibbò S, Dinoi G, Costamagna G, Sanguinetti M, Gasbarrini A. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015;41:835e43. [14] Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:761e7. [15] Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, Weese JS, Collins S, Moayyedi P, Crowther M, Ropeleski MJ, Jayaratne P, Higgins D, Li Y, Rau NV, Kim PT. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection: a randomized clinical trial. J Am Med Assoc 2016;315:142e9. [16] Youngster I, Sauk J, Pindar C, Wilson RG, Kaplan JL, Smith MB, Alm EJ, Gevers D, Russell GH, Hohmann EL. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis 2014;58:1515e22. [17] Tang G, Yin W, Liu W. Is frozen fecal microbiota transplantation as effective as fresh fecal microbiota transplantation in patients with recurrent or refractory Clostridium difficile infection: a meta-analysis? Diagn Microbiol Infect Dis 2017;88:322e9. [18] Jiang ZD, Ajami NJ, Petrosino JF, Jun G, Hanis CL, Shah M, Hochman L, Ankoma-Sey V, DuPont AW, Wong MC, Alexander A, Ke S, DuPont HL. Randomised clinical trial: faecal microbiota transplantation for recurrent Clostridium difficile infection - fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy. Aliment Pharmacol Ther 2017;45:899e908. [19] Costello SP, Tucker EC, La Brooy J, Schoeman MN, Andrews JM. Establishing a fecal microbiota transplant service for the treatment of Clostridium difficile infection. Clin Infect Dis 2016;62:908e14. [20] Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. J Am Med Assoc 2014;312:1772e8. [21] Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: techniques, indications, and outcomes. Gastrointest Endosc 2013;78:240e9. [22] Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 2013;108:500e8. [23] Jalanka J, Salonen A, Salojärvi J, Ritari J, Immonen O, Marciani L, Gowland P, Hoad C, Garsed K, Lam C, Palva A, Spiller RC, de Vos WM. Effects of bowel cleansing on the intestinal microbiota. Gut 2015;64:1562e8. [24] Girotra M, Garg S, Anand R, Song Y, Dutta SK. Fecal microbiota transplantation for recurrent Clostridium difficile infection in the elderly: longterm outcomes and microbiota changes. Dig Dis Sci 2016;61:3007e15. [25] Webb BJ, Brunner A, Ford CD, Gazdik MA, Petersen FB, Hoda D. Fecal microbiota transplantation for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients. Transpl Infect Dis 2016;18:628e33.

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[26] Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, Chang HJ, Coward S, Goodman KJ, Xu H, Madsen K, Mason A, Wong GK, Jovel J, Patterson J, Louie T. Effect of oral capsule- vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection: a randomized clinical trial. J Am Med Assoc 2017;318:1985e93. [27] Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M, Bakow B, Curran P, McKenney J, Tisch A, Reinert SE, Machan JT, Brandt LJ. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial. Ann Intern Med 2016;165:609e16. [28] Bamba S, Nishida A, Imaeda H, Inatomi O, Sasaki M, Sugimoto M, Andoh A. Successful treatment by fecal microbiota transplantation for Japanese patients with refractory Clostridium difficile infection: a prospective case series. J Microbiol Immunol Infect November 5, 2017;1182(17):30235e9. https://doi.org/10.1016/j.jmii.2017.08.027. S1684. 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[51] Bilinski J, Grzesiowski P, Sorensen N, Madry K, Muszynski J, Robak K, Wroblewska M, Dzieciatkowski T, Dulny G, Dwilewicz-Trojaczek J, Wiktor-Jedrzejczak W, Basak GW. Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibioticresistant bacteria: results of a prospective, single-center study. Clin Infect Dis 2017;65:364e70. [52] Davido B, Batista R, Michelon H, Lepainteur M, Bouchand F, Lepeule R, Salomon J, Vittecoq D, Duran C, Escaut L, Sobhani I, Paul M, Lawrence C, Perronne C, Chast F, Dinh A. Is faecal microbiota transplantation an option to eradicate highly drug-resistant enteric bacteria carriage? J Hosp Infect 2017;95:433e7. [53] Sohn KM, Cheon S, Kim YS. Can fecal microbiota transplantation (FMT) eradicate fecal colonization with vancomycin-resistant enterococci (VRE)? Infect Control Hosp Epidemiol 2016;37:1519e21. [54] Cheminet G, Kapel N, Bleibtreu A, Sadou-Yaye H, Bellanger A, Duval X, Joly F, Fantin B, de Lastours V and the French Group for Fecal Microbiota Transplantation (GFTF). Fecal microbiota transplantation with frozen capsules for relapsing Clostridium difficile infections: the first experience from 15 consecutive patients in France. J Hosp Infect. 2018 Jul 12. pii: S0195-6701(18)30369-4. https://doi.org/10.1016/j.jhin.2018. 07.00