Faecal microbiota transplantation
Faecal microbiota transplantation (FMT) is defined as the infusion of faeces from a healthy donor to a recipient to treat a specific disorder associated with the impairment of gut microbiota. The first published experience of FMT dates back to the late 1950s, when Ben Eiseman used faecal enemas to manage pseudomembranous colitis (which is an endoscopic/radiological marker of severe Clostridium difficile infection (CDI)) in subjects who were unfit for surgery.1
Following this first report, several other reports, including large cohort studies and randomised controlled trials (RCTs), used FMT to treat recurrent CDI (RCDI), with excellent results (90–94% in RCTs).2–7
The successful outcomes achieved in the treatment of RCDI, together with increased knowledge on the influence of gut microbiota on human health and disease, have raised interest in FMT as a treatment option for several other digestive disorders, although with varying results. In the first European consensus conference on FMT, recurrent and refractory CDI were the only indications for which FMT was recommended in clinical practice.8 In this article, we will cover the procedural protocol and the outcomes of FMT produced in different gastro-intestinal diseases.
FMT procedural protocol
Selection of donors
Although immunological donor–recipient matching is not required to transplant microbiota (as required for transplantation of solid organs), the donor should be thoroughly screened before FMT to avoid transmission of infectious disorders and to prevent the infusion of ineffective microbiota. In the infancy of FMT, potential donors were usually chosen among relatives, spouses or friends of the recipient, to improve patient acceptance of the prospect of the procedure. Nowadays, however, requests for FMT to treat CDI are increasing, and the use of anonymous donors is needed to accommodate demand.
Anonymous donors are necessary for stool banking enterprises, such as OpenBiome (www.openbiome.org
), which are facilitating greater access and acceptability of FMT as a mainstream treatment option where indicated. According to current evidence, the use of related or unrelated donors does not influence efficacy nor safety outcomes when FMT is used to treat CDI.2–9
The outcomes of FMT using related versus unrelated donors for other indications, such as inflammatory bowel disease (IBD), require further evaluation.
The selection of donors starts with a medical history of potential candidates. They usually undertake a written questionnaire, aimed at excluding individuals with, or at risk of, infectious diseases, and those with conditions that can impair gut microbiota. Exclusion criteria include:
- Known viral hepatitis
- Syphilis, human immunodeficiency virus (HIV)
- Substance misuse
- High-risk sexual behaviour
- Recent history of tattoos or piercings
- Travel to areas in which diarrhoeal disorders are endemic
- Risk factors for Creutzfeldt–Jakob disease.
History of gastrointestinal and extra-intestinal disorders associated with impairment of gut microbiota:
- Gastrointestinal cancer
- IBD, irritable bowel syndrome (IBS)
- Metabolic syndrome
- Autoimmune and atopic disorders
- History of major abdomen surgery
- Use of immunosuppressive drugs
- Antibiotics or chemotherapy within the last three months.2,3,8
If the questionnaire is unremarkable, potential donors undergo blood and stool testing for viral hepatitis, HIV, syphilis, C. difficile toxin, stool culture and parasitological exams.
This protocol for donor screening is commonly used when FMT is performed to treat CDI, with satisfactory efficacy and safety results.2–7 When dealing with other disorders, additional exclusion criteria and testing could affect outcomes; however, further studies are needed to identify those that improve outcomes.
Preparation of faecal material
Before the procedure, stools are suspended in saline or water, and then filtered to exclude gross debris. According to the European consensus conference on FMT, at least 30g of faeces should be used for a single procedure, and should be diluted with a 3–5-fold higher volume of solvent.8,10
To avoid the continuous need to source available donors, frozen and thawed faeces can be used because they have been shown to achieve comparable cure rates and safety outcomes to fresh faecal microbiota.4 Glycerol should be added to the faecal material to preserve microbes during freezing.8,10 The faecal material should be delivered within six hours of the donation if fresh, or from thawing, if frozen.10
Usually, a single-infusion FMT is sufficient to cure recurrent CDI, although severe disease appears to need multiple procedures.3,11,12 Repeated infusions are likely to be convenient when FMT is used to treat chronic disorders, as shown by data from IBD studies.13
Preparation of patients and routes of administration
Recipients receive bowel-cleansing preparations 24–48 hours before FMT procedures by colonoscopy or by upper route. If faeces are delivered by the upper route, recipients are additionally given proton-pump inhibitors, to avoid microbiota damage by gastric acid.14
Different routes of administration have been used to perform FMT, including upper routes (such as gastroscopy, nasogastric tube, nasoduodenal/nasojejunal tube and delivery by gastrostomy tube) and lower routes (colonoscopy and enemas).15 Upper routes of delivery appear to be less effective than lower routes in curing CDI.9,15,16
Low costs and ease of administration are the biggest advantages of enemas. However, colonoscopy allows for evaluation of the severity of the disease (through assessment of pseudomembranous colitis), and further management of the disease.3
FMT through a nasojejunal tube has been investigated in patients with metabolic syndrome, with promising findings.19 The choice of delivery route should depend of the outcome of the study, the disease and the population to be treated.
FMT in gastrointestinal disorders
CDI arises as a consequence of extensive antibiotic regimens, especially in immuno-compromised in-patients.20 It represents one of the best models of disorders associated with the impairment of microbiota.
Based on this theoretical background, a large body of evidence shows FMT to be a highly effective therapeutic option against RCDI, achieving excellent cure rates (85–94%) for this condition in large cohort studies, RCTs, systematic reviews and meta-analyses.2–7,9,15,16 These results have led to FMT being increasingly considered as a treatment option for recurrent disease in the guidelines published by the American College of Gastroenterology as well as in those published by the European Society for Clinical Microbiology and Infectious Diseases for the management of CDI.17,18 In a recent consensus conference on FMT, recurrent and refractory CDI are the only indications that were approved for the use of FMT in clinical practice.8
Imbalance of gut microbiota is one of the most relevant pathogenic pathways of IBD. Lower diversity and higher bacterial instability, together with the reduction of Firmicutes and Bacteroides and increase of Enterobacteriaceae and Actinobacteria, characterise the microbiota composition in patients with IBD.21 Currently, the most promising results of FMT come from studies involving patients with ulcerative colitis (UC), as studies in subjects with Crohn’s disease are only few and uncontrolled.22
A recent meta-analysis identified 14 cohort studies and two RCTs that investigated FMT as a treatment for UC.23 Among them, non-controlled studies are biased as they differ in terms of population, FMT methodology and outcomes.23
Although the two RCTs from Moayyedi et al and Rossen et al provided conflicting results, they were able to identify several key points for the therapeutic success of FMT in UC, including the use of repeated infusions to assure recipient–donor engraftment, lower route of delivery, and the choice of patients with early diagnosis.13,24 Key future steps to improve outcomes of FMT for UC include improved donor selection criteria and finding the right place for FMT within the currently available treatment options. Further data are needed before FMT can be considered as a treatment option for IBD in clinical practice.8
Functional gastrointestinal disorders
Gut microbiota is known to have a key pathogenic role in the development of IBS, including the modulation of the intestinal barrier and the impairment of gut–brain axis.25 Quantitative and qualitative changes of gut microbiota, including reduction of butyrate producers Roseburia (E. rectale) group and the increase of sulphate-reducing bacteria, have been found in patients with IBS.26,27
Data on FMT in patients with IBS are lacking and fragmented. Early papers show a relevant selection bias, as the data sets did not exclude results from patients with IBD or chronic constipation.28 In contrast, more recent studies focus on patients with diagnosed IBS achieving satisfactory relief of IBS symptoms,29–31 together with the proof of a change in gut microbiota after FMT.31 These results suggest that microbiota transfer could be a reliable option to treat IBS, but also highlight that well designed studies are needed to clarify the role of FMT for the treatment of IBS.8
A considerable body of evidence supports the role of gut microbiota imbalance in the pathogenesis of metabolic disorders. Decreased microbial diversity and Bacteroidetes, together with an increase in Firmicutes, have been found in obese mice and humans.32,33
An increase in the presence of Gram-negative bacteria has been found to promote the low-grade inflammation status (which is typical of metabolic disorders), by promoting the adsorption of lipopolysaccharide.34,35
Although there is a considerable interest into manipulation of microbiota as a therapeutic approach to obesity and metabolic disorders, to date only a pilot RCT from Vrieze et al has investigated FMT in subjects with metabolic syndrome. Subjects experienced a significant increase in insulin sensitivity and in butyrate-producing bacteria after microbiota transfer from healthy lean donors.19 Also in this case, FMT is still far from being considered a reliable treatment for metabolic diseases, and further research is needed to confirm findings.8
Gut microbiota play a fundamental role in health and disease of human beings. Improved knowledge of functions and composition of microbiota is increasing therapeutic avenues to treat disorders associated with microbiota impairment.
FMT represents a key therapeutic option for the management of recurrent CDI. The recent standardisation of treatment protocols,8,14 as well as the development of stool banking enterprises, is likely to increase use of this technique worldwide. Although promising results have been published, future research will be necessary to evaluate if FMT can be a useful treatment for other disorders (including IBD, IBS and metabolic disorders).
Conflicts of interest
1 Eiseman B et al. Faecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854–9.
2 Van Nood E et al. Duodenal infusion of donor faeces for recurrent Clostridium difficile. N Engl J Med 2013;31;368:407–15.
3 Cammarota G et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015;41:835–43.
4 Lee CH et al. Frozen vs fresh faecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile Infection: A randomized clinical trial. JAMA 2016;315:142–9.
5 Youngster I et al. Faecal 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;58:1515–22.
6 Lee CH et al. The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple faecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis 2014;33:1425–8.
7 Mattila E et al. Faecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology 2012;142:490–6.
8 Cammarota G et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 2017;66:569–80.
9 Kassam Z et al. Faecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 2013;108:500–8.
10 Satokari R et al. Simple faecal preparation and efficacy of frozen inoculum in faecal microbiota transplantation for recurrent Clostridium difficile infection – an observational cohort study. Aliment Pharmacol Ther 2015;41:46–53.
11 Weingarden AR et al. Resolution of severe Clostridium difficile infection following sequential faecal microbiota transplantation. J Clin Gastroenterol 2013;47:735–7.
12 Fischer M et al. Predictors of early failure after faecal microbiota transplantation for the therapy of Clostridium difficile infection: A multicenter study. Am J Gastroenterol 2016;111(7):1024–31.
13 Moayyedi P et al. Faecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 2015;149:102–9.
14 Bakken JS et al. Treating Clostridium difficile infection with faecal microbiota transplantation. Clin Gastroenterol Hepatol 2011;9:1044–9.
15 Cammarota G et al. Faecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol 2014;48:693–702.
16 Drekonja D et al. Faecal microbiota transplantation for Clostridium difficile Infection: A systematic review. Ann Intern Med 2015;162:630–8.
17 Surawicz CM et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108:478–98.
18 Debast SB, Bauer MP, Kuijper EJ; European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20 Suppl 2:1–26.
19 Vrieze A et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012;143(4):913–6.e7
20 Bakken JS et al. Treating Clostridium difficile infection with faecal microbiota transplantation. Clin Gastroenterol Hepatol 2011;9:1044–9.
21 Cammarota G et al. The involvement of gut microbiota in inflammatory bowel disease pathogenesis: potential for therapy. Pharmacol Ther 2015;149:191–212.
22 Ianiro G et al. Faecal microbiota transplantation in inflammatory bowel disease: beyond the excitement.Medicine (Baltimore) 2014;93(19):e97.
23 Shi Y et al. Faecal microbiota transplantation for ulcerative colitis: A systematic review and meta-analysis. PLoS One 2016;11:e0157259.
24 Rossen NG et al. Findings from a randomized controlled trial of faecal transplantation for patients with ulcerative colitis. Gastroenterology 2015;149:110–18.
25 Simrén M et al. Rome Foundation Committee. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 2013;62(1):159–76.
26 Chassard C et al. Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome. Aliment Pharmacol Ther 2012; 35:828–838.
27 Rajilic-Stojanovic M et al. Global and deep molecular analysis of microbiota signatures in faecal samples from patients with irritable bowel syndrome. Gastroenterology 2011;141:1792–801.
28 Borody TJ et al. Bowel flora alteration: a potential cure of inflammatory bowel disease and irritable bowel syndrome? Med J Aust 1989;150:604.
29 Andrews P et al. Bacteriotherapy for chronic constipation – long-term follow-up. Gastroenterology 1995;108:A563.
30 Pinn DM et al. Is faecal microbiota transplantation the answer for irritable bowel syndrome? A single-center experience. Am J Gastroenterol 2014;109:1831–2.
31 Holvoet T et al. Assessment of faecal microbial transfer in irritable bowel syndrome with severe bloating. Gut 2016; 10 August [Epub ahead of print].
32 Ley RE et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 2005;102:11070–5.
33 Tilg H et al. Obesity and microbiota. Gastroenterology 2009;136:1476–83.
34 Cani PD et al. The gut microbiome as therapeutic target. Pharmacol Ther 2011;130:202–12.
35 Esteve E et al. Gut microbiota interactions with obesity, insulin resistance and type 2 diabetes: did gut microbiote co-evolve with insulin resistance? Curr Opin Clin Nutr Metab Care 2011;14:483–90.