Speakers: Anne Vrieze (Netherlands), Lawrence Brandt (USA)
Dr Vrieze’s talk focused on faecal microbiota transplantation (FMT) as a therapy for metabolic syndrome and C. difficile inflammation (CDI), under the guiding question whether the lacking diversity of the gut microbiota, which is assumed to play a major role in the disease onset, can be restored by the infusion of donor faeces.
After having pointed to the long history of FMT, which dates back to the 4th century BC, Dr Vrieze started with a description of the FMT procedure at the Academic Medical Center (AMC) Amsterdam. A crucial step is the prior screening of the donors in order to avoid the transmission of diseases. This examination includes a questionnaire about, among others, bowel habits, travel history and medication use, as well as a screening of donors’ blood and faeces, and a checklist, which is to be filled in by the donor one day before treatment, to make sure that no significant changes have occurred since the last screening. Donors are excluded if they are immunocompromised, have a family history of autoimmune diseases, use medication – antibiotics in particular – or suffer from systemic or unexplained conditions. For the actual procedure, fresh faeces, to be applied within six hours after donation, are being used. The faeces are diluted by sterile saline, and after filtering, the transplant is administered by a naso-duodenal tube. Dr Vrieze and her colleagues feel that this route provides a better access than the colon. However, as Dr Vrieze made clear that there currently is no thorough study that tested the efficiency of the different modes.
Dr Vrieze then moved on to present two studies, carried out at her hospital, on the effect of FMT on metabolic syndrome and CDI, respectively. The metabolic syndrome study was a double blind randomised control trial; its 18 participants were obese males between 21 and 65 years of age, with a body mass index ≥ 30 kg/m2, a fasting plasma glucose ≥ 5.6 mmol/l, and without medication use. Half of the patients received faecal transplants from lean male volunteers, while the other half received their own faeces. Measurements of the peripheral and hepatic insulin sensitivity, the gut microbiota composition and the faecal short-chain fatty acids at baseline and after six weeks showed no changes in the subjects who had received their own faeces, while in the test subjects of the other group, the transplants coming from the lean donors had improved the peripheral insulin sensitivity and, although only slightly, the hepatic insulin sensitivity. The donor faeces of the lean donors had also boosted these patients’ gut microbial diversity with an increase of sixteen bacterial groups, nine of which are involved in the butyrate production (an energy source for cells of the small and the large intestine that is also involved in insulin sensitivity).
The second study Dr Vrieze presented was a randomised control trial aiming to detect the effect of donor faeces in patients with recurrent C. difficile inflammation (RCDI), a condition which is assumed to be caused initially by certain antibiotic treatments that disturb the gut microbiota balance, thus inducing an overflow of C. difficile bacteria. This fosters the production of toxins and causes the disease. The recurrent form of C. difficile inflammation develops since the conventional antibiotic treatments often fail. Accordingly, the study was designed to compare the effects of FMT with the outcome of the intake of vancomycin, which is the conventionally prescribed drug. The trial, which ran over a period of 14 days, included 41 patients over eighteen years old who had had a relapse of CDI after at least one course of adequate antibiotic treatment. 16 subjects received a four-day treatment of vancomycin, followed by bowel lavage and infusion of donor faeces, 12 subjects received only vancomycin, and 13 received vancomycin together with a bowel lavage on the fourth or fifth day. Dr Vrieze reported impressive results: 94% of the patients who had received donor faeces were cured, compared to 31% of the vancomycin group and 23% of the vancomycin and bowel lavage group. Immediately after the faecal infusion, most patients had diarrhoea and abdominal cramps, but these symptoms dissolved within a couple of hours. After the infusion, the microbiota of these patients showed an increase of diversity comparable to that of healthy donors.
Dr Vrieze concluded by setting out a research agenda consisting of a precise definition of the causative role of the gut microbiota in diseases such as DCI and obesity, the need of further double blind randomised control trials in order to establish the efficacy of FMT, and the development of novel treatments that might replace FMT in the long run. One way might be the culturing of beneficial microorganisms that could be used for novel probiotics.
Prof. Brandt’s talk provided the audience with further information on the potential of FMT in RCDI patients. He started with an epidemiological overview, pointing out that 15-20% of patients with initial CDI suffer from recurrence. The recurrence may be due to the same bacterial strain (“relapse”), or a different strain (“re-infection”) or it may be an irritable bowel syndrome (IBS) developed in the aftermath of CDI (“post-CDI IBS”). In patients who have one recurrence, the chance of a second one is up to 45%, and of those patients who have a second recurrence, the chance of a third recurrence is up to 65%. Prof. Brandt indicated that, although the number of treatment failures is increasing, so far there is no standardised treatment that has been agreed upon by all experts. As regards the conventional treatment of RCDI, doctors usually resort to additional courses of metronidazole in milder cases and to vancomycin in more severe cases. Normally, on second and third recurrence, the medication is applied in a pulsed fashion, with a progressively diminishing dose each day. With respect to probiotics, there is very limited evidence for their effect.
According to Prof. Brandt, FMT could be considered as a treatment option when a third recurrence of CDI is occurring. He underlined the benefits of this treatment: it avoids the long-term use of antibiotics, and it allows to re-establish normal diversity of the intestinal microbiota. In modern times, the first use of FMT for treatment of RCDI dates back around 30 years. Meanwhile, a variety of methods have been developed for the faecal infusion, including colonoscopy, naso-duodenal infusion and enemas. One of the latest developments is the self-administration of enemas, which Prof. Brandt regarded as a suitable form of therapy for certain patients. As regards the selection of appropriate donors, Prof. Brandt stressed that the formerly held belief that healthy intimate partners are preferable to strangers because they already share bacteria, cannot be maintained. The donor exclusion criteria that Prof. Brandt named resembled those that Dr Vrieze had listed.
Prof. Brandt said that he has his patients stop their intake of antibiotics two or three days before the transplantation, but that doctors proceed differently, because there are no studies to determine which is the right way. As Prof. Brandt normally prefers the lower route for infusion, his patients are given a large-volume colonoscopy preparation the evening before the procedure to clean out the colon. Immediately before the transplantation, patients take some Loperamide, so that they can retain their stool for at least four hours. The donor takes a gentle laxative the night before the procedure in order to produce soft stool, which makes it easier to prepare the transplant. The freshly passed stool, which does not need to be refrigerated and should not be frozen, is brought by donors in a plastic container and is used within six to eight hours.
The stool is suspended in non-bacteriostatic saline by blender and filtered through gauze into a canister and then into a 60cc catheter-tip syringe to deliver the product. Prof. Brandt said that he puts a volume of 300cc of diluent, containing about 60g of stool, into the ascending colon. As there are no established standards concerning the appropriate amount of stool, Prof. Brandt reported from general experience that “more is better.” Providing an overview of the development of FMT, Prof. Brandt referred to 434 FMTs that have been performed since the 1950s, the majority of them through the colon, the others mostly by the naso-gastric route, with a total cure rate of 93%. He pointed out that treatment rates are generally better for infusions from below than from above. The cure rate after one administration of FMT is about 85% from above and about 91% from below. With a second administration, the response rate is about 98%, regardless of the route.
Prof. Brandt then presented the audience with a follow-up study, carried out in 2011 and covering a period of more than three months after FMT. Included were 77 patients from five medical centres across the US. The mean duration of the patients’ illness had been 11 months, and their response to FMT was very fast, despite the long duration of illness: 74% responded in less than three days, the mean response time being six days. The primary cure rate – patients responding to the first transplant – was 91%. The secondary cure rate – patients not responding to a first FMT, but then responding either to a second transplant or to antibiotic treatment – was 98.7%. 97% of the patients said they would have another FMT if necessary, and 58.3% said they would prefer FMT to antibiotics in the future.
Prof. Brandt put the potential drawbacks of FMT – possible transmission of infectious or allergic reactions – in contrast with the benefits: FMT re-establishes the a “normal” microbiota, it is inexpensive and effective very rapidly, and antibiotic-resistant bacteria do not emerge due to the avoidance of antibiotics. Although, according to Prof. Brandt, RCDI therapy is the major field of FMT application to date, it has also been used successfully to treat IBD, IBS, obesity and chronic constipation. Even in a number of non-gastrointestinal diseases, such as Parkinson’s, chronic fatigue syndrome and autism, FMT has shown to be helpful.
Prof. Brandt concluded by emphasising that using stool is but the first step in exploiting the potential of this therapeutic field. If the critically important question as to which bacteria exactly are involved in the healing process will be answered, it might soon be possible to assign different bacteria to corresponding diseases and thus to design more precisely tailored treatments. In Prof. Brandt’s opinion, the number of bacteria that finally will be found to be causally effective will probably turn out to be relatively small.
This concept of Transplantation of Gut Microbiota confirms in a way the importance of that organ, the gut microbiota. Transplantations are done for very important organ only.
Written by Wolfgang Krischke, impressum health & science communication