Fecal Microbiota Transplantation: An Update on Clinical Practice PDF

REVIEW Clin Endosc 2019;52:137-143 https://doi.org/10.5946/ce.2019.009 Print ISSN 2234-2400 On-line ISSN 2234-2443 Open Access Fecal Microbiota Transplantation: An Update on Clinical Practice Kyeong Ok Kim1,2 and Michael Gluck2 1 Division of Gastroenterology and Hepatology, Department of In...

REVIEW Clin Endosc 2019;52:137-143 https://doi.org/10.5946/ce.2019.009 Print ISSN 2234-2400 On-line ISSN 2234-2443 Open Access Fecal Microbiota Transplantation: An Update on Clinical Practice Kyeong Ok Kim1,2 and Michael Gluck2 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea, 2 Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, USA Fecal microbiota transplantation (FMT) is an infusion in the colon, or the delivery through the upper gastrointestinal tract, of stool from a healthy donor to a recipient with a disease believed to be related to an unhealthy gut microbiome. FMT has been successfully used to treat recurrent Clostridium difficile infection (rCDI). The short-term success of FMT in rCDI has led to investigations of its application to other gastrointestinal disorders and extra-intestinal diseases with presumed gut dysbiosis. Despite the promising results of FMT in these conditions, several barriers remain, including determining the characteristics of a healthy microbiome, ensuring the safety of the recipient with respect to long-term outcomes, adequate monitoring of the recipient of fecal material, achieving high-quality control, and maintaining reasonable costs. For these reasons, establishing uniform protocols for stool preparation, finding the best modes of FMT administration, maintaining large databases of donors and recipients, and assuring that oral ingestion is equivalent to the more widely accepted colonoscopic infusion are issues that need to be addressed. Clin Endosc 2019;52:137-143 Key Words: Fecal microbiota transplantation; Clostridium difficile infection; Colonoscopy Introduction and recommended for other conditions such as inflammatory bowel disease (IBD), autoimmune disorders, certain allergic Since the first modern descriptions of its use in 1958,1 fecal diseases, and metabolic disorders such as obesity.8 In recurrent microbiota transplantation (FMT) has increasingly gained CDI (rCDI), the efficacy and safety of FMT has been proven interest and rapid acceptance during the last 10 years.2 FMT by several randomized clinical trials (RCTs), and guidelines is defined as the infusion of stool from a healthy individual recommend the use of FMT as a second-line treatment.9-15 to a patient with presumed gut dysbiosis.3,4 FMT can also be Success rates approaching 92% have been demonstrated in the delivered through an enteral route either via an endoscope, treatment of rCDI.10,11 a nasoenteric tube, or capsules for ingestion. The presumed With the increasing use of FMT owing to its success in mechanism of action appears to be the establishment of a treating various diseases, there is growing demand for stan- new gut microbiota community to restore the normal gut dardizing the preparation of fecal material, using accepted function.5-7 On the basis of the concept of repopulating the standards for the delivery, ensuring safety for the recipient, gut with a healthy microbiome, FMT has been successfully monitoring long-term outcomes, and continuously improving used in the treatment of Clostridium difficile infection (CDI), the procedural processes and safety. Received: December 8, 2018 Revised: January 10, 2019 Accepted: March 6, 2019 Correspondence: Michael Gluck Indications and considerations Digestive Disease Institute, Virginia Mason Medical Center, 1100 Ninth Ave, for the recipient C3-GAS, Seattle, WA 98101, USA Tel: +1-206-223-2319, Fax: +1-206-341-1405, E-mail: [email protected] The use of FMT became rapidly accepted mainly owing ORCID: https://orcid.org/0000-0002-2048-3949 to its success in treating rCDI. Data from several RCTs and cc This is an Open Access article distributed under the terms of the Creative a large case series revealed the efficacy and safety of FMT.9-12 Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, A recent systematic review and meta-analysis of 7 RCTs and and reproduction in any medium, provided the original work is properly cited. 30 case series demonstrated the superiority of FMT over Copyright © 2019 Korean Society of Gastrointestinal Endoscopy 137 vancomycin therapy, with resolution rates as high as 92%.16 Although donor screening is well accepted, recipient screen- Moayyedi et al. showed that FMT was superior to placebo or ing is controversial and without a consensus. Performing viral vancomycin therapy.17 Fischer et al. reported that FMT clini- hepatitis, human immunodeficiency virus, and syphilis tests cally cured 91% of patients with severe rCDI that failed maxi- is recommended before FMT, so that if these diseases were to mal medical therapy.18 occur after FMT, clinicians would know that the disease was The indications for FMT include mild to moderate rCDI not transmitted from the donor to the recipient.21 Kelly et al., after a second recurrence following treatment with a standard in a large case series drawn from multiple centers in the Unit- antibiotic, moderate rCDI that is not responding to standard ed States, showed that FMT seemed safe in immunocompro- therapy after 1 week, and severe CDI that is refractory to mised patients, with the exception of neutropenic patients as a standard therapy after 48 h.3,19 The recent U.S. guidelines rec- standard precaution.34 ommend FMT in patients with 3 or more recurrences of CDI, although most clinicians prescribe FMT if CDI recurs after 2 courses of antibiotics.15 The European consensus guidelines Donor selection suggest that FMT should be considered after the first episode if the disease is severe and refractory to the initial antibiotic To minimize the risk of infection or other disease transmis- therapy.20 Although there are no strict guideline recommen- sion, potential donors undergo rigorous screening including dations stating that CDI should be initially treated with FMT thorough history taking, serological tests, and fecal tests for instead of antibiotics, there may be special situations that parasitic, virologic, and bacterial pathogens.35 Although there would justify its application, such as inability to deliver antibi- are some variations between institutions, there are existing otics to a patient with severe disease, intolerance of the patient accepted protocols for donor screening (Tables 1, 2).3,36,37 to antibiotics, or as a substitute for surgery in highly unstable Donor stool is provided from 2 sources: patient-directed patients.21 donors and universal donors through stool banks.38,39 Pa- It has been suggested that gut dysbiosis underlies the tient-directed donors are identified by the recipients, usually pathogenesis of IBD. Zhang et al.22 reported that in ulcerative colitis, there is decreased diversity in the patient’s microbiota with fewer Firmicutes bacteria and more Proteobacteria. In Table 1. Suggested Exclusion Criteria for Potential Stool Donors with a Risk of Infection or Microbiome-Associated Disease a recently reported RCT on ulcerative colitis, the response rate to FMT was 55%, with remission in 20% of the patients.23 Exclusion criteriaa) Another RCT reported similar response and remission rates Age 65 yr of 54% and 27%, respectively.24 A meta-analysis of 4 RCTs in BMI >30 kg/m2 patients with ulcerative colitis demonstrated a 28% remission Metabolic syndrome rate in patients treated with FMT compared with 8% in those Moderate to severe undernutrition who received placebo.23 FMT appears to have lower efficacy History of antibiotics use in the last 6 mo for IBD than for rCDI, suggesting that other factors are asso- Diarrhea within the last 3–6 mo ciated with IBD flares besides gut dysbiosis.25 History of Clostridium difficile colitis Several reports have implied that IBD flares were induced by FMT that was administered for CDI.2,26,27 A careful fol- Immune disorder or use of immunosuppressive medications low-up of patients with IBD treated with FMT is warranted History of drug use or other recent risk factor for HIV or viral because of this concern. An American Gastroenterology As- hepatitis sociation expert review, however, suggested that earlier FMT History of travel to a tropical region in last 3 mo in patients with IBD and CDI might be recommendable ow- Any gastrointestinal illness (IBD, IBS, gastrointestinal malignan- ing to the relevant complication rate of CDI in these patients.28 cy, or major surgery) or complaints Several RCTs in patients with Crohn’s disease are currently History of autoimmune or atopic illness under way. To date, there are no standardized practice guide- History of chronic pain syndrome (fibromyalgia, chronic fatigue lines for the use of FMT in IBD. syndrome) Besides rCDI and IBD, FMT is also being evaluated and Neurologic or neurodevelopmental disorders considered an experimental treatment for other diseases in- History of malignancy cluding irritable bowel syndrome (IBS),29 nonalcoholic steato- HIV, human immunodeficiency virus; IBD, inflammatory bowel hepatitis,30 hepatic encephalopathy,31 obesity,32 and neurologi- disease; IBS, irritable bowel syndrome. cal diseases.33,34 a) Each institution can adopt different criteria. 138  Kim KO et al. Update on FMT family members including spouses, siblings, children, or fusion or ingestion. An RCT on the application of FMT with friends. Patient-directed donors are becoming less frequently multiple donors in ulcerative colitis showed clinical remission used unless the recipient prefers a donor whose diet and oth- and endoscopic improvement as well as greater microbial di- er features are known, or if the recipient is concerned about versity in the recepients.24 More studies are needed to confirm transmissible agents that are perceived to exist in universal do- the value of multidonor FMT. nors. The use of patient-directed donor stool incurs treatment In addition, Lee et al.43 conducted a noninferiority RCT delays owing to the time required for sourcing, screening, and of FMT with frozen and thawed stool in comparison with testing donors, with resultant increased costs and scheduling fresh stool for rCDI, to ensure the viability of microbes after problems.39,40 Additionally, using patient-directed donors may freezing. They reported clinical resolution rates of 83.5% and result in the donor feeling coerced and at a risk of revealing 85.1% in each group, showing that frozen fecal material was confidential information.41 as efficacious as fresh stool. Using frozen stool from universal Using universal donors for FMT has emerged as the most donors reduces recipient costs as well as the time between the utilized method in the United States. Healthy volunteers who decision to perform FMT and the actual infusion.39,40 have a young age and a normal body mass index provide the Owing to the cost-effectiveness and convenience of use stool after undergoing thorough history taking, physical ex- of fecal material from universal donors, stool banks such as amination, and serum and fecal pathogen screening tests.42 OpenBiome have emerged. OpenBiome uses strict protocols The use of universal donors has enabled a number of ad- for the recruitment of healthy volunteers: the volunteers are vances in FMT. Decreased microbial diversity is considered screened, standardized products are generated, and the prod- a possible cause of rCDI and other diseases of an altered mi- ucts are stored after freezing and can be delivered rapidly to crobiome. Using fecal material from multiple healthy donors 99% of the entire United States.42 The additional advantages could theoretically enhance the therapeutic efficacy of an in- of stool banks are the ability to track registries and perform research on larger data obtained from multiple sites that con- duct FMT, with the goal of assuring safety and efficacy.44 The Table 2. Suggested Laboratory Tests for Potential Donors of Fecal Microbiota U.S. Food and Drug Administration (FDA) has approved stool Transplantationa) banks such as OpenBiome to provide fecal material for FMT Tests Blood Stool for the treatment of rCDI.45 For indications other than rCDI, Bacteria Treponema Enteric pathogen culture: the FDA requires an investigational drug application.46 Salmonella, Shigella, One of the main concerns about the use of stool banks is Campylobacter Helicobacter pylori EIAb) that multiple recipients could be adversely affected by a cur- VRE rently undetectable infection or transmissible process. Open- Viruses Hepatitis A virus IgM Norovirus EIA or PCR Biome has used extremely strict and detailed questionnaires to Hepatitis surface antigen Rotavirus EIA identify possibly risky donors in advance, and also to rescreen Anti-hepatitis C virus volunteers 60 days after the submission and before the release HIV 1 and 2 of the stool. Samples are also stored for future tracking.42 Parasites Entamoeba histolytica Ovum and parasite Strongyloides stercoralis Microsporidia Giardia fecal antigen/EIA Cryptosporidium EIA Processing of fecal material AFB for Isospora and Cyclospora Although there are trivial differences depending on the Others Complete blood count Clostridium difficile test individual situation, most institutes prepare the stool based Liver function test Toxin PCR on the same protocol. The donor provides fresh stool within ESR and CRP 1 month after screening.3 The potential donors collect their AFB, acid-fast bacilli; CRP, C-reactive protein; EIA, enzyme im- stool into a clean plastic bag and bring it to the microbiology munoassay; ESR, erythrocyte sedimentation rate; HIV, human laboratory. A minimum of 50 g of stool is needed.47 Then, immunodeficiency virus; IgM, immunoglobulin M; PCR, poly- the stool is diluted in normal saline, mixed in a sterile bag by merase chain reaction; VRE, vancomycin-resistant Enterococcus. hand stirring, and shaken or blenderized. It is then filtered a) The blood and stool tests should be completed within 1 month of through moistened 5-layer sterile gauze in a funnel and stored donation, and the tests could be adopted differently depending on each institution and circumstance. in a restricted safety cabinet to be delivered within 4 h of pre- b) The test for Helicobacter pylori is usually needed in the case of sentation to the endoscopy suite. upper gastrointestinal delivery. In the case of FMT with a universal donor, the fecal mate- 139 rial is processed to 250-mL aliquots in a similar standardized of C. difficile.20 Antibiotics are generally discontinued at 24–48 method and stored at −80°C until delivered on dry ice to each h before the FMT. requesting institute.42 If the FMT is delivered by colonoscopy, bowel preparation Fecal microbiota capsules could be prepared by concentra- is recommended to improve the visualization of the colon. In tion of the diluted, blended slurry, processed similarly. Then, patients with a severe ileus, bowel preparation can be replaced the fecal solution is pipetted into a capsule holding 650 mL by enemas or can be omitted.38 The standard dose of FMT is and then sealed into a second capsule. Commercially available specific to each institution or physician; however, about 50– acid-resistant, hypromellose capsules (DRcapsTM; Capsugel, 100 g of donor fecal material that has been diluted to 250–500 Cambridge, MA, USA) are usually utilized. A total of 30 cap- mL of infusate is most commonly used.9,12,43,48 sules are prepared as a single therapeutic dose from each do- FMT can be administered either directly to the colon or nor stool.48 Capsules are also stored at −80°C (−112°F) before from the upper gastrointestinal tract through capsule inges- use, maximally up to 6 months. tion.38 Delivery to the colon is generally performed using colonoscopy, and less frequently through flexible sigmoidos- copy or an enema. Colonoscopic delivery has an efficacy of Procedure and patient 84%–93%41 and is the modality of choice according to pub- management lished studies.47,50,51 If right-sided delivery of FMT is achieved using colonoscopy, the cure rate on a single infusion is 93%.9 It seems that FMT for rCDI is most efficacious in patients The most serious risk that has been reported with respect to with mild to moderate disease that responded to antibiotics lower gastrointestinal tract administration is perforation.39,52 against C. difficile by the fourth day.11 In the other patients, Theoretically, bleeding, adverse reaction to sedative drugs, the concern is that the diarrhea may be from another source. cardiovascular events, transient fevers, or infections could oc- Some clinicians have recommended the earlier use of FMT cur, as with any colonoscopy procedure. for patients with severe or severe-complicated disease, as fail- For patients with ileus, severe colitis, or objection to colo- ure of standard therapy could result in higher morbidity and noscopy, FMT can be provided through the upper gastroin- mortality.49 An accepted method of FMT is to provide antibi- testinal tract via nasoenteric tubes, esophagogastroduodenos- otics for at least 3 days before infusion to reduce the amount copy, or capsule ingestion.38 The efficacy rates were reported to Table 3. Analysis of Administration Modalities for Fecal Microbiota Transplantation Modality Strength Weakness Nasoenteric tube 1. No necessity for sedation 1. Discomfort associated with the administration 2. Low cost 2. Necessity for radiologic confirmation 3. Risk of vomiting and aspiration Upper endoscopy 1. Safely ‌ performed in patients with a high risk for 1. Same weaknesses as those of nasoenteric tube colonoscopy complications 2. Procedure-related risk 3. Necessity for sedation Capsule 1. Noninvasive 1. Large burden of the capsule 2. More aesthetic appeal 2. Risk of vomiting and aspiration 3. Cost- and time saving 3. Cost 4. Convenience of administration Colonoscopy 1. Strong evidence of efficacy for rCDI 1. Procedure-related risk 2. Useful for differential diagnosis 2. Necessity for sedation 3. Necessity for technical expertise 4. Additional cost Sigmoidoscopy 1. Can be preferred by patients 1. Procedure-related risk 2. Inability to reach the right-sided colon Retention enema 1. Low cost 1. Difficult to retain in some cases 2. Well tolerated 2. Inability to reach the right-sided colon 3. No need for sedation and can be preferred by patients 3. Modality with the lowest efficacy 4. Can be easily repeated rCDI, recurrent Clostridium difficile infection. 140  Kim KO et al. Update on FMT be between 81% and 86%.41 All forms of upper tract delivery ered late secondary nonresponders. On the basis of these data, increase the risk of vomiting or aspiration.53 Capsule delivery the authors suggested follow-up of patients approximately 4 is the most recent modality of FMT. Capsules seem to be a weeks after the FMT.57 reasonable choice for patients who have contraindications to Much of the concern about FMT arises from the fact that colonoscopy, are geographically distant from an institution the long-term risks are unknown. Screening of donors by that performs colonoscopy, and are opposed to lower gastro- means of a thorough history taking may not reveal all future intestinal tract access. Capsule delivery reduces the procedure risks. Most FMT protocols endeavor to exclude donors with time, colonoscopy cost, need for colon preparation, and risk metabolic syndrome, obesity, neuropsychiatric disorders, and of colonoscopy complications.54 Kao et al. demonstrated a malignancies; however, a disease might emerge in the donor comparable efficacy of capsule-delivered FMT to that of colo- at a later date. This represents both a concern about FMT and noscopy-delivered FMT.55 Although the standard dose per a justification for the existence of stool banks, as follow-up of capsule is not yet defined, several studies have shown that a donors and maintenance of records would be more likely in mean 1.6 g of stool per capsule yields a 70% cure rate without stool banks, allowing the earlier identification of risks. adverse events.48,56 Although no consensus has been achieved, the common impression by a number of authors is that colo- noscopic administration has an about 5%–10% higher cure Conclusions rate in rCDI,47,50,51 with the additional advantage of assuring that the fecal material reaches the colon because a water jet FMT is an established treatment for rCDI, and is considered can be used to spray the material directly onto the mucosa.21 a second-line treatment. It is also being considered for other Table 3 summarizes the strengths and weakness of each mo- gastrointestinal diseases such as IBD, IBS, hepatic steatosis, dality. and hepatic encephalopathy. Other disorders that may be The 2 most common side effects of FMT are bloating and related to gut dysbiosis, such as obesity, metabolic syndrome, loose stools for the first 24 h, which usually resolve soon autoimmune disorders, and neurological diseases, may also be thereafter.35 Most patients generally have formed stool by improved by FMT. With stool banks providing universal door 1–2 weeks. Stool testing for resolution is not recommended fecal material that has been highly screened and catalogued, in those with formed stool, but is considered if 3 or more barriers such as cost and availability can be overcome, allow- diarrhea stools per day occur after a few weeks.15,38 The poly- ing research and treatment to be simplified. Additionally, with merase chain reaction test for C. difficile toxin may remain the advent of capsule FMT, further increases in the use of this positive for 30 days after a successful treatment, which is treatment may emerge with improved convenience, reduced another reason not to test asymptomatic FMT recipients.38 A patient reluctance, and simplified procedural preparation. To confusing situation is when abdominal cramping and inter- maintain patient safety and appropriate use of FMT, standard- mittent frequent bowel movements occur in a patient who ized protocols for donor screening, stool preparation, methods might be a carrier of C. difficile and who has received an FMT. of delivery, and recipient indications for treatment are expect- Such patients most likely have post-infectious IBS. Therefore, ed to emerge. the clinician should ideally be able to distinguish post-in- fectious IBS from rCDI to avoid unnecessarily repeating the Conflicts of Interest FMT. The authors have no financial conflicts of interest. To date, there is no accepted standard protocol for fol- low-up. Most physicians and clinic staff contact the patient to assess treatment success and complications about 3–7 days References after FMT. Another follow-up contact at 4–8 weeks is recom- mended.38 1. Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an ad- If the patient develops liquid stool and recurrence of symp- junct in the treatment of pseudomembranous enterocolitis. Surgery toms with a positive stool test for C. difficile, the FMT is con- 1958;44:854-859. 2. Chin SM, Sauk J, Mahabamunuge J, Kaplan JL, Hohmann EL, Khalili sidered a failure.13 A recent study suggested that most failures H. Fecal microbiota transplantation for recurrent Clostridium difficile occur within 4 weeks.49 Allegretti et al.57 reported that of the infection in patients with inflammatory bowel disease: a single-center failed therapy cases, 25% failed within the first week and the experience. Clin Gastroenterol Hepatol 2017;15:597-599. 3. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile in- patients are described as primary nonresponders. Another fection with fecal microbiota transplantation. Clin Gastroenterol Hepa- 61% failed between weeks 1 and 4, with the patients referred tol 2011;9:1044-1049. to as early secondary nonresponders. The rest were consid- 4. Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplan- 141  tation: techniques, indications, and outcomes. Gastrointest Endosc 25. Vindigni SM, Zisman TL, Suskind DL, Damman CJ. The intestinal mi- 2013;78:240-249. crobiome, barrier function, and immune system in inflammatory bowel 5. Gerding DN. 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