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Abstract

We thank Cui et al for their comments regarding our randomized controlled trial of fecal microbiota transplantation (FMT) for patients with ulcerative colitis (NCT01650038).1Rossen N.G. et al.Gastroenterology. 2015; 149: 110-118.e4Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar The authors are concerned by the in their view unexpectedly high placebo response rate of 25% in our trial as opposed to the 5% response rate in the trial by Moayyedi et al,2Moayyedi P. et al.Gastroenterology. 2015; 149: 102-109.e6Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar which was published in the same issue of Gastroenterology. They suggest that this difference is owing to the choice of placebo (autologous feces vs water enemas), and suspect that the median lag time between production and reinfusion of feces of 6 hours with exposure to aerobic conditions might have influenced the function or viability of certain kinds of microbiota. First, the 20% and 25% placebo response in the intention-to-treat and per protocol analysis, respectively, in our trial concurs with what was anticipated from observed placebo rates of 15%-30% in earlier trials using probiotics in ulcerative colitis. Conversely, the placebo rate in the Canadian trial was exceptionally low, even when taking into account their strict co-primary endpoint requiring a Mayo 0 endoscopic score at 7 weeks.2Moayyedi P. et al.Gastroenterology. 2015; 149: 102-109.e6Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar Second, we acknowledge and agree that the preparation and procedure of FMT may influence its treatment effect. From the randomized trial of FMT for Clostridium difficile infection from our center, we know that the microbiota composition of the donor feces before and after dilution and filtration shows high similarity.3van Nood E. et al.N Engl J Med. 2013; 368: 407-415Crossref PubMed Scopus (2458) Google Scholar, 4Fuentes S. et al.ISME J. 2014; 8: 1621-1623Crossref PubMed Scopus (129) Google Scholar This, however, does not guarantee equal viability and capacity to outgrow of all constituents. Whether the rapid GenFMTer automated processing system mentioned by Cui et al is able to improve overall viability is an interesting suggestion, but remains to be demonstrated. We have to keep in mind that with FMT one does not transplant an entire microbiota, but the microbial building blocks to construct a new microbiota, together with the residual microbes that escaped evacuation. To accommodate for such potentially confounding factors was the main reason why we chose for autologous fecal infusion as placebo instead of water. Furthermore, we do not think the adverse event rate in the placebo group may be caused by a change in the microbiota before infusion, because the proportions of—mostly mild—adverse events were 78.3% and 64% in the donor and autologous feces recipients, respectively, which is more indicative of a procedure-related phenomenon. In addition, we feel the microbiota shift in placebo patients is not suggestive of this either, because this was only observed in 25% of the autologous FMT recipients.There may be other confounding factors influencing FMT such as bowel preparation. Jalanka et al5Jalanka J. et al.Gut. 2015; 64: 1562-1568Crossref PubMed Scopus (136) Google Scholar recently showed that bowel cleansing persé in healthy individuals is associated with an increase in Proteobacteria at least up to 28 days, which we also observed in those placebo patients who met the primary outcome criteria at 12 weeks. Why this is associated with improvement whereas in autologous and donor feces recipients who were nonresponders no microbiata signature shifts were observed remains elusive. One explanation might be that the level of purging plays a role here. On average, total bacterial load is reduced by 31-fold after bowel cleansing, but this can vary and may impact the chance that a new microbiota may successfully hatch and induce an altered signature.5Jalanka J. et al.Gut. 2015; 64: 1562-1568Crossref PubMed Scopus (136) Google ScholarWe agree with Cui et al that the source of donor feces may be key in determining its efficacy. FMT recipients that attained the primary endpoint all shifted to a microbiota signature similar to their respective donor. This shift was mainly explained by a regain of Clostridium clusters IV, XIVa, and XVIII, and reduction in Bacteroidetes. In a follow-up assessment of our trial sustained response was highly associated with successful engraftment from a Clostridium clusters IV/XIVa rich donor (unpublished data). This is in accordance with the finding that the treatment effect in the Canadian trial was almost exclusively driven by 1 donor, who was especially rich in Lachnospiraceae and ruminococci.2Moayyedi P. et al.Gastroenterology. 2015; 149: 102-109.e6Abstract Full Text Full Text PDF PubMed Scopus (934) Google ScholarWe believe that with regard to improving methodology of FMT the focus must lie on selecting the right donors and the right susceptible patients, as well as on the proper dosing and route(s) of administration, for example, combined nasojejunal tube and enemas. We thank Cui et al for their comments regarding our randomized controlled trial of fecal microbiota transplantation (FMT) for patients with ulcerative colitis (NCT01650038).1Rossen N.G. et al.Gastroenterology. 2015; 149: 110-118.e4Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar The authors are concerned by the in their view unexpectedly high placebo response rate of 25% in our trial as opposed to the 5% response rate in the trial by Moayyedi et al,2Moayyedi P. et al.Gastroenterology. 2015; 149: 102-109.e6Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar which was published in the same issue of Gastroenterology. They suggest that this difference is owing to the choice of placebo (autologous feces vs water enemas), and suspect that the median lag time between production and reinfusion of feces of 6 hours with exposure to aerobic conditions might have influenced the function or viability of certain kinds of microbiota. First, the 20% and 25% placebo response in the intention-to-treat and per protocol analysis, respectively, in our trial concurs with what was anticipated from observed placebo rates of 15%-30% in earlier trials using probiotics in ulcerative colitis. Conversely, the placebo rate in the Canadian trial was exceptionally low, even when taking into account their strict co-primary endpoint requiring a Mayo 0 endoscopic score at 7 weeks.2Moayyedi P. et al.Gastroenterology. 2015; 149: 102-109.e6Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar Second, we acknowledge and agree that the preparation and procedure of FMT may influence its treatment effect. From the randomized trial of FMT for Clostridium difficile infection from our center, we know that the microbiota composition of the donor feces before and after dilution and filtration shows high similarity.3van Nood E. et al.N Engl J Med. 2013; 368: 407-415Crossref PubMed Scopus (2458) Google Scholar, 4Fuentes S. et al.ISME J. 2014; 8: 1621-1623Crossref PubMed Scopus (129) Google Scholar This, however, does not guarantee equal viability and capacity to outgrow of all constituents. Whether the rapid GenFMTer automated processing system mentioned by Cui et al is able to improve overall viability is an interesting suggestion, but remains to be demonstrated. We have to keep in mind that with FMT one does not transplant an entire microbiota, but the microbial building blocks to construct a new microbiota, together with the residual microbes that escaped evacuation. To accommodate for such potentially confounding factors was the main reason why we chose for autologous fecal infusion as placebo instead of water. Furthermore, we do not think the adverse event rate in the placebo group may be caused by a change in the microbiota before infusion, because the proportions of—mostly mild—adverse events were 78.3% and 64% in the donor and autologous feces recipients, respectively, which is more indicative of a procedure-related phenomenon. In addition, we feel the microbiota shift in placebo patients is not suggestive of this either, because this was only observed in 25% of the autologous FMT recipients. There may be other confounding factors influencing FMT such as bowel preparation. Jalanka et al5Jalanka J. et al.Gut. 2015; 64: 1562-1568Crossref PubMed Scopus (136) Google Scholar recently showed that bowel cleansing persé in healthy individuals is associated with an increase in Proteobacteria at least up to 28 days, which we also observed in those placebo patients who met the primary outcome criteria at 12 weeks. Why this is associated with improvement whereas in autologous and donor feces recipients who were nonresponders no microbiata signature shifts were observed remains elusive. One explanation might be that the level of purging plays a role here. On average, total bacterial load is reduced by 31-fold after bowel cleansing, but this can vary and may impact the chance that a new microbiota may successfully hatch and induce an altered signature.5Jalanka J. et al.Gut. 2015; 64: 1562-1568Crossref PubMed Scopus (136) Google Scholar We agree with Cui et al that the source of donor feces may be key in determining its efficacy. FMT recipients that attained the primary endpoint all shifted to a microbiota signature similar to their respective donor. This shift was mainly explained by a regain of Clostridium clusters IV, XIVa, and XVIII, and reduction in Bacteroidetes. In a follow-up assessment of our trial sustained response was highly associated with successful engraftment from a Clostridium clusters IV/XIVa rich donor (unpublished data). This is in accordance with the finding that the treatment effect in the Canadian trial was almost exclusively driven by 1 donor, who was especially rich in Lachnospiraceae and ruminococci.2Moayyedi P. et al.Gastroenterology. 2015; 149: 102-109.e6Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar We believe that with regard to improving methodology of FMT the focus must lie on selecting the right donors and the right susceptible patients, as well as on the proper dosing and route(s) of administration, for example, combined nasojejunal tube and enemas. Methodology, Not Concept of Fecal Microbiota Transplantation, Affects Clinical FindingsGastroenterologyVol. 150Issue 1PreviewTwo recent randomized controlled trials published in Gastroenterology indicated inconsistent results in the treatment of ulcerative colitis by fecal microbiota transplantation (FMT).1,2 Moayyedi et al1 reported a significant efficacy of FMT in inducing the remission of ulcerative colitis activity, with the 24% in FMT group compared with 5% in placebo group, whereas Rossen et al2 reported that there was no difference in clinical and endoscopic remission between the patients who received FMT with feces from healthy donor and patients who received FMT with autologous feces. Full-Text PDF