Despite the fact that we still do not know all the secrets and mysteries about the gut microbiota, a lot of hope is put on treating GI diseases with intestinal microbiota. Fecal microbiota transplantation seems to be the Holy Grale. But is it? At 2018’s UEGW in Vienna numerous lectures were dedicated to it. An overview.
THE IDEAL DONOR
Despite the fact that up until now nobody really knew how to precisely define the normal gut microbiota (“eubiosis”), we do know that high microbial diversity and gene richness are of key importance in the host-microbiota equilibrium. Therefore, the ideal fecal donor should be screened for bacterial richness. A surrogate marker for this property was proposed by Marie Joossen (Leuven, Belgium) who pointed out that the presence of Blastocystis hominis correlates with a higher microbial richness . This finding – if confirmed by others – may change our current practice to avoid carriers of this commensal as fecal donors. Enriching the donor’s microbiota by prebiotics or using multiple donors may also ensure (theoretically) a higher baseline diversity of the donated material. This was also observed by Karakan et al. (Ankara, Turkey) who performed an open trial in ulcerative colitis with an overall complete response rate of 32% which was particularly influenced by a high bacterial diversity in the donated fecal material.
THE NEW BROWN GOLD
Strict adherence to current guidelines for selection of donors for fecal material necessitates the rejection of most donors. Terveer et al. (Leiden, the Netherlands) report that only 3,5% of possible donors are suitable at the end of the line . The main reasons for not being accepted as a donor are: age above 50, high BMI and carrier status of non-pathogenic germs (Blastocystis hominis, Dientamoeba fragilis) and MDROs (multidrug resistant organisms) .
The main indication for fecal microbiota transplantation remains refractory infection with Clostridium difficile (C. difficile). Ianiro et al. (Rome, Italy) showed, in a retrospective series of 282 C. difficile patients comparing antibiotic treatment and fecal transplant, that this latter treatment resulted in significant shorter hospital stay, significantly lower mortality and specifically less sepsis-related mortality.
Antonio Gasbarrini (Rome, Italy) therefore suggests that the time has come to promote fecal microbiota transplantation as the first line therapy in C. difficile infection.
EXPANDING THE SCOPE OF FMT
Antonio Gasbarrini gave a nice overview of promising indications for fecal micro- biota transplantation. It has been shown that fecal transplants restore the human microbiota better than probiotics after antibiotic-induced dysbiosis in humans. This was also the case following combined chemotherapy and antibiotic induced dysbiosis in the setting of hematological stem cell therapy and in patients with liver cirrhosis receiving antibiotics. Mice models even show evidence for restoration of immune function and intestinal integrity after chemotherapy induced intestinal damage. Therefore, Antonio Gasbarrini makes the case for pre-emptive stool conservation for subsequent autologous fecal microbiota transplantation, e.g. following antibiotic treatment or bone marrow transplantation. In vivo evidence from clinical trials must be awaited before this futuristic but not unrealistic strategy can be implemented. Anyhow, it seems quite logical that collecting one’s own stool for autologous transplantation later in life, is the way to go.
In 3 out of 4 published randomized controlled trials fecal microbiota transplantation was superior to placebo in refractory ulcerative colitis (UC) patients . Mean remission rate in these studies, however, was only 25-30 % and Rainer et al. (Graz, Austria) presented a study with similar complete remission rates, showing no added value of administering fresh stool in these patients. Nevertheless, up until now there was no standardized stool transplantation protocol in UC. Remission rates of 30% seem low but to put things in perspective: this is also the remission rate that is achieved with the expensive and widely used biologicals [...]. The importance of colonic microbiota in UC was demonstrated by Herrera-de Guise et al. (Barcelona, Spain) who showed that patients in long-term stable remission (more than 5 years) present with an abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii, similar to healthy controls. These authors even suggest that we should think of a paradigm shift in treating UC: our therapeutic endpoint should perhaps no longer be immune suppression, but we should aim to reach eubiotic microbiota characteristics.
IRRITABLE BOWEL SYNDROME
Irritable bowel syndrome (IBS) is certainly the condition for which the expectations of a cure by fecal microbiota transplantation are very high in both patients and health care practitioners. Still, conflicting results from randomized controlled trials [4, 5] do not currently support a widespread use of this treatment in IBS. Intestinal dysbiosis is present in IBS but a clear causality between these microbial changes and symptoms are lacking. Halkjaer et al. (Copenhagen, Denmark) performed a randomized controlled trial in 52 adult IBS patients; an increase in biodiversity (comparable to the donors) was observed in the patients being actively transplanted (5). Unfortunately, the placebo group had a significantly better clinical outcome at 3 and 6 months than the patients receiving fecal capsules . In a small cohort of 16 IBS patients, Holster et al. (Orebro, Sweden) were also unable to demonstrate efficacy for fecal microbiota transplant vs. placebo. They also studied rectal sensitivity by means of a barostat and showed no difference between the active and control groups, concluding that changing the microbiota does not contribute to the visceral hypersensitivity in IBS.
Ianiro et al. performed an open label trial in C. difficile infection with a synthetic microbiota suspension (10 patients only) demonstrating efficacy. Khanna et al. (Rochester, USA) have also demonstrated efficacy in prevention of C. difficile infection’s relapse with a non-frozen, lyophilized, orally administrated microbiota restoring drug (RBX7455) in an open-label phase 1 trial. These are promising results that need to be confirmed in large scale randomized trials.
The UEGW 2018 added more insight into the desired eubiotic characteristics of fecal material and the promising new indications for fecal microbiota transplantation that may arise the upcoming years. Up until now C. difficile infection remains the only clear-cut indication for this treatment which is currently not ready for prime time in other conditions.
1. Tito RY, Chaffron S, Caenepeel C, et al. Population-level analysis of Blastocystis subtype prevalence and variation in the human gutmicrobiota. Gut 2018 [Publication en ligne avant l’impression].
2. Terveer EM. How to establish and run a stool bank. Clin Microbiol Infect 2017 ; 23 : 924-30.
3. Imdad A, Nicholson MR, Tanner-Smith EE, et al. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev 2018 ; 11:CD012774.
4. Johnsen PH, Hilpüsch F, Cavanagh JP, et al. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, pa- rallel-group, single-centre trial. Lancet Gastroenterol Hepatol 2018 ; 3 : 17-24.
5. Halkjær SI, Christensen AH, Lo BZS, et al. Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo-controlled study. Gut 2018 ; 67 : 2107-15.