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Two reviews published in the Cochrane Database of Systematic Reviews look at the use of faecal microbiota transplantation (FMT) for the treatment of recurrent Clostridium difficile infection and for inflammatory bowel disease (IBD).
The following comments were provided by our colleagues at SMC Germany:
Prof. Dr. Alexander Link, Head of the Section of Molecular Gastroenterology and Microbiota-associated Diseases in the Department of Gastroenterology, Hepatology and Infectiology, University Hospital Magdeburg, Germany:
On the review regarding FMT in inflammatory bowel disease:
“Microbiota are increasingly recognised as one of the most important factors in the onset and development of many diseases, particularly inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. The Cochrane review looked at the evidence for the effectiveness of faecal microbiota transplantation (FMT) in treating these conditions.
“In summary, the review suggests a beneficial effect of FMT in patients with ulcerative colitis, while there is still a lack of studies to evaluate the role of FMT in Crohn’s disease.
“It is difficult to provide a definitive assessment at this time, as only twelve studies were included, eleven of which focused on ulcerative colitis. Regardless of the biology of the disease, which is a multifactorial immune dysregulation (a malfunction of the molecular control of immune system processes that depends on various factors; editor’s note), the heterogeneity in the studies is very high: this includes different routes of application, differences in the preparation of the stool and the heterogeneity of the patients. Of particular note is that access to translational FMT research varies due to specific national requirements and regulations, which significantly limits the knowledge gain, but also the implementation and establishment of alternative treatment options.
“It is questionable whether FMT will become established as the exclusive therapy for inflammatory bowel disease. Multifactorial optimisation, for example by combining FMT with special diets and immunomodulating drugs, will certainly be the next generation of trials.”
On the review regarding FMT in C. difficile infection:
“Clostridioides difficile infection (CDI) of the gut is the leading disease of antibiotic-induced dysbiosis of gut bacteria. Considering this very high-quality Cochrane review, with 320 patients treated in six randomised trials, not much seems to have happened since the first publication of a randomised trial of FMT in C. difficile. But this impression can be deceptive.
“The majority of randomised trials of FMT for CDI have been stopped prematurely because of the clear superiority of faecal microbiota transplantation over standard therapy. While the use of statistical tools to assess efficacy in such cases is necessary and the conclusion is clearly positive, this assessment takes the complexity of the situation and co-factors only partially into account.
“FMT has revolutionised the treatment of CDI over the past decade. Virtually all recommendations and guidelines nationally and internationally recommend FMT, with some variations, at the latest after the second relapse. Specialised centres have been established both at European and national levels and FMT is now a routine therapy. For questions about safety or possible long-term effects, registries (EurFMT) have been established that will answer these questions at the European level.
“FMT is a very dynamic field and the search criteria used in the review (until March 2022) are partly outdated for publication in April 2023. For example, a recent study on the efficacy of FMT in first- and second-line CDI was stopped early due to clear superiority of FMT [1].
“Despite this knowledge, it remains a major challenge to inform clinicians in different settings about the availability of FMT for the treatment of CDI in FMT centres, such that their patients can access this highly effective and relatively safe therapy.”
[1] Dahl Baunwall SM et al. (2023): Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial. The Lancet Gastroenterology and Hepatology. DOI: 10.1016/S2468-1253(22)00276-X.
Prof. Dr. Maria Vehreschild, Head of the Infectious Diseases Unit at the Medical Clinic II, Frankfurt University Hospital, Germany:
“The two analyses provide a very good summary of the state of research. The clinical efficacy of fecal microbiota transfer (FMT) for the secondary prevention of recurrent C. difficile infection is already part of all important clinical guidelines for this condition. FMT experts agree that the data support safety and efficacy for this indication. With regard to the use of FMT for the therapy of inflammatory bowel diseases, the results are also consistent with the individual studies. There is insufficient data to assess the situation in Crohn’s disease, and there is probably a clinically relevant effect in the therapy of ulcerative colitis, but it is not as strong as the effect in the indication of recurrent C. difficile infection.
“The effect size of FMT in the secondary prevention of recurrent C. difficile infection is extraordinary. An effect this strong is rarely seen with pharmaceuticals. In the indication of ulcerative colitis, the effect strength is comparatively less distinct in all individual studies. Of course, in such a situation, more patients are needed in order to provide statistically sound evidence of an effect. However, most of the studies conducted in this indication are small to moderate. In my opinion, this does not mean that this form of therapy is not potentially relevant for ulcerative colitis. Even the drugs currently already used in this indication do not have a very pronounced effect. However, since ulcerative colitis can have a very strong impact on quality of life, even a comparatively small effect can represent a relevant improvement in quality of life.
“FMT is only used in guidelines for the secondary prophylaxis of recurrent C. difficile infection, an infectious diarrhoeal disease. Here, the bacteria are obtained from stool donations of healthy donors and encapsulated for oral ingestion or administered endoscopically as part of a colonoscopy. Enemas are also possible.
“Rebyota is an FMT which is administered as an enema. This type of preparation is also already being produced in Germany under similar safety conditions. However, they have not yet been tested and approved in pivotal studies, but are used in the context of individual healing attempts. In my view, if all the prescribed safety precautions are adhered to during production, the risks are limited. However, a new EU directive stipulates that these preparations should be covered by the Transplantation Act in the future. This would significantly simplify making them available.”
Prof. Dr. Andreas Stallmach, Director of the Department of Internal Medicine IV, Jena University Hospital, Germany:
“The two Cochrane reviews confirm previously established knowledge and did not surprise me, as I had already been familiar with the studies examined. Intensive research is currently being conducted on faecal microbiome transfer (FMT) and the importance of microbiota in medicine. Accordingly, there is a lot of available data; in particular, there are many studies on the application of FMT in Clostridioides difficile. So it’s not surprising that Cochrane initiated the reviews on this.
“The results confirm the previous assessment that FMT is highly effective and safe, especially for infection with C. difficile. The main difference between the two diseases studied is that an infection with C. difficile can be understood as an acute disease, usually after antibiotic use, whereas inflammatory bowel disease is a group of chronic diseases. These are mainly ulcerative colitis and Crohn’s disease. For Crohn’s disease, there has been no evidence that FMT is effective, as shown by the summary of controlled trials in the form of this review. For patients with ulcerative colitis, the results were as expected: The review confirms that it is an effective and safe treatment.
“In Germany, FMT is considered to be a drug, but to date there are no approved medicines based on it. If I want to use it as a doctor, this is currently only possible within the framework of an individual healing attempt. This must be done according to the regulations in the German Medicinal Products Act. This means that as a doctor, I have to prepare and use the medication on my own responsibility for a specific patient. So the question arises: Who should pay for the effort and quality control? Since FMT is not listed in the catalogue of benefits of public health insurances, because it is not a recognised treatment but an individual healing attempt, reimbursements are not possible. So patients have to cover the costs themselves.
“The Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte) has commented on the question of how FMT should be conducted as an individual healing attempt (see further research sources). There is a long list of requirements that have to be fulfilled, such as ruling out diseases of the donor. If the requirements are met and the donor is healthy, the donated stool has to be quarantined at minus 80 degree Celsius. After eight weeks, the donor is tested again for infections. If everything is in order, the treatment can be carried out. This is very time-consuming and cost-intensive. The production costs exceed 1000 euros and consist mainly in donor screening costs. So in Germany, the main challenges are not a lack of standardisation or the possible transmission of pathogens, as both can be addressed with a protocol which guarantees the patients’ safety. A high methodological effort simply means spending a lot of money.
“The US Food and Drug Administration (FDA) approved a drug called Rebyota for use in the US in November, as a way to prevent a relapse of intestinal inflammation caused by C. difficile. However, is the process is very inconvenient for patients. The ready-made preparation has to be picked up frozen from a pharmacy and defrosted at home. The liquified stool from carefully selected donors is then administered with an application set. Due to the complex and difficult preparation, as well as the delivery and application conditions, I am not sure whether the drug will be approved in Europe in the short term. Moreover, the effect size in the registration studies was surprisingly low, the difference to the placebo group was only about 15 percent. The effectiveness of a classical FMT proved to be higher in the trials.”
C. diff review: ‘Fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile (Clostridium difficile)’ by Nathan Zev Minkoff et al. was published by Cochrane at 23:59 UK time on Monday 24 April 2023.
DOI: 10.1002/14651858.CD013871.pub2
Inflammatory bowel disease review: ‘Fecal transplantation for treatment of inflammatory bowel disease’ by Aamer Imdad et al. was published by Cochrane at 23:59 UK time on Monday 24 April 2023.
DOI: 10.1002/14651858.CD012774.pub3
Declared interests
Prof. Dr. Alexander Link: “Lecture fee: Janssen, Consulting: Ferring; Microbiome Research with Focus European Union/EFRE; Steering Committee of EurFMT Network.”
Prof. Dr. Maria Vehreschild: “MJGTV has received research grants from 3M, Astellas Pharma, DaVolterra, Gilead Sciences, Glycom, MaaT Pharma, Merck/MSD, Organobalance, Seres Therapeutics; speaker fees from Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance, Pfizer and has been a consultant to Alb Fils Kliniken GmbH, Astellas Pharma, DaVolterra, Ferring, MaaT Pharma, Merck/MSD.”
Prof. Dr. Andreas Stallmach: ”I’m doing research on FMT myself for the treatment of active ulcerative colitis and I’m currently leading the BMBF-funded clinical trial ‘FRESCO’ (NCT03843385).”