Journal of Crohn's and Colitis, 2016, 375–376 doi:10.1093/ecco-jcc/jjw005 Advance Access publication January 7, 2016 Editorial
Editorial Toward Rational Donor Selection in Faecal Microbiota Transplantation for IBD Harry Sokol Avenir Team Gut Microbiota and Immunity, UMR 7203, Saint-Antoine Hospital, Paris, France, INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France, and Department of Gastroenterology, Saint Antoine Hospital, AP-HP, UPMC Univ Paris 06, France; French Group of Faecal Microbiota Transplantation [GFTF] Corresponding author: Harry Sokol, Service de Gastroentérologie et Nutrition, Hôpital Saint-Antoine, 184 rue du faubourg St Antoine, 75571 Paris cedex 12, France. Tel: +33 149 283 162; fax: +33 149 283 188; email: [email protected]
Inflammatory bowel disease [IBD] pathogenesis involves a disturbed cross-talk between host immune cells and intestinal microbiota. Moreover, an imbalanced microbiota [named dysbiosis] has been repeatedly pointed out in IBD and is now recognised as an actor in the gut inflammatory process. Targeting the microbiota is thus an attractive therapeutic strategy in IBD, but it has been mostly disappointing until now. Probiotics have shown some efficacy in mild-to-moderate ulcerative colitis [UC] only. Although antibiotics have shown some efficacy in inducing remission in Crohn’s disease [CD] and UC, as well as preventing postoperative relapse in CD, their use is limited by long-term tolerance and ecological issues.1 Faecal microbiota transplantation [FMT] is a more radical approach that has been shown to be efficient in recurrent Clostridium difficile infection2 and has been proposed to treat patients with refractory IBD. However, inconstant results have been reported in case reports and case series, and precise indication as well as effectiveness remain to be determined. In a recently published randomised controlled trial in patients with active UC, FMT [one enema once weekly for 6 weeks] was statistically superior to placebo to induce remission at week 7.3 However, one of the donors was associated with better clinical outcome, suggesting that donor characteristics are, logically, drivers of the potential beneficial effect of FMT in IBD. In this issue of the Journal of Crohns and Colitis,4 Vermeire and colleagues investigated the impact of FMT in patients with IBD and looked for predictors of clinical response in donors’ microbiota characteristics. In all, 14 patients [6 with CD and 8 with UC] with refractory disease underwent FMT. Two UC patients only went into remission and one UC patient experienced transient improvement. None of the patients with CD improved after FMT. In term of safety, four patients developed fever [> 38.5°C] within a few hours after FMT and one of them required antibiotics. One patient vomited after upper route FMT and had aspiration pneumonia that was treated with broad-spectrum antibiotics. Following this severe adverse event, all the subsequent FMTs were performed by enema route. The authors then
analysed the microbiota composition and diversity of donors to look for factors associated with clinical response. They observed that donors from whom the stools resulted in a successful FMT were characterised by a significantly higher bacterial richness. Importantly, richness of the faecal microbiota of the recipient at baseline was not predictive of FMT efficacy, showing that this parameter was independent of recipient status. At Week 8 after FMT, responders tended to have a higher bacterial richness than non-responders [p = 0.058]. FMT is a complex therapeutic procedure involving a high number of parameters to take into account. Route of administration [upper vs lower gastrointestinal tract], fresh or frozen status, preparation with antibiotics or colon cleansing, amount of material, volume of dilution, and nature of the diluent are the most obvious and can be easily controlled. Timing of the FMT is another important factor, but it has been poorly studied until now. Indeed, the effect of FMT in a recipient who achieved remission after conventional treatment might be associated with fewer side effects and different clinical outcome than that in patient with active inflammation. Furthermore, donor’s characteristics represent major factors potentially influencing FMT effects, as already suggested in the study by Moayyedi and colleagues.3 Identifying the features of a ‘good’ donor’s microbiota is thus a major objective in FMT field, that can be solved only by performing clinical trials and looking for predictors. In addition, it cannot be ruled out that characteristics of the recipient’s microbiota are also important. This would add another layer of complexity and require identifying a kind of matching process between donor and recipient. Although the study by Vermeire and colleagues is of limited size, it opens the first doors to rationally selecting donors in the context of FMT for IBD. These results need to be confirmed in larger and independent studies, but richness of the donor’s microbiota is an attractive parameter to consider. Moreover, the fact that high richness of both donor’s microbiota and the post-FMT recipient’s microbiota was associated with response suggests that this parameter could be involved in the clinical effect of FMT itself. Other features
Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
375
H. Sokol
376 of the donor’s microbiota might be relevant to investigate, such as abundance of anti-inflammatory taxa like Faecalibacterium prausnitzii5 or in butyrate producers; but an unbiased approach should be preferred to identify relevant parameters. Ongoing and future randomised control trials evaluating FMT in IBD should be considered as important opportunities to confirm the results of Vermeire and colleagues, to identify new markers of efficacy, and finally to define successful procedures.
Conflict of Interest HS received consultancy fees from Enterome, Maat Pharma, Astellas, Danone, MSD, Ferring, and Roche, and speaker’s fees from Takeda, Abbvie, Astellas, and Biocodex.
References 1. Sokol H. Probiotics and antibiotics in IBD. Dig Dis 2014;32[Suppl 1]:10–7. 2. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407–15. 3. Moayyedi P, Surette MG, Kim PT, et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology 2015;149:102–9 e6. 4. Vermeire S, Joossens M, Verbeke K, et al. Donor species richness determines faecal microbiota transplantation success in inflammatory bowel disease. J Crohns Colitis 2015. 5. Sokol H, Pigneur B, Watterlot L, et al. Fecalibacterium prausnitzii is an antiinflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 2008;105:16731–6.
Editorial Toward Rational Donor Selection in Faecal Microbiota Transplantation for IBD Harry Sokol Avenir Team Gut Microbiota and Immunity, UMR 7203, Saint-Antoine Hospital, Paris, France, INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France, and Department of Gastroenterology, Saint Antoine Hospital, AP-HP, UPMC Univ Paris 06, France; French Group of Faecal Microbiota Transplantation [GFTF] Corresponding author: Harry Sokol, Service de Gastroentérologie et Nutrition, Hôpital Saint-Antoine, 184 rue du faubourg St Antoine, 75571 Paris cedex 12, France. Tel: +33 149 283 162; fax: +33 149 283 188; email: [email protected]
Inflammatory bowel disease [IBD] pathogenesis involves a disturbed cross-talk between host immune cells and intestinal microbiota. Moreover, an imbalanced microbiota [named dysbiosis] has been repeatedly pointed out in IBD and is now recognised as an actor in the gut inflammatory process. Targeting the microbiota is thus an attractive therapeutic strategy in IBD, but it has been mostly disappointing until now. Probiotics have shown some efficacy in mild-to-moderate ulcerative colitis [UC] only. Although antibiotics have shown some efficacy in inducing remission in Crohn’s disease [CD] and UC, as well as preventing postoperative relapse in CD, their use is limited by long-term tolerance and ecological issues.1 Faecal microbiota transplantation [FMT] is a more radical approach that has been shown to be efficient in recurrent Clostridium difficile infection2 and has been proposed to treat patients with refractory IBD. However, inconstant results have been reported in case reports and case series, and precise indication as well as effectiveness remain to be determined. In a recently published randomised controlled trial in patients with active UC, FMT [one enema once weekly for 6 weeks] was statistically superior to placebo to induce remission at week 7.3 However, one of the donors was associated with better clinical outcome, suggesting that donor characteristics are, logically, drivers of the potential beneficial effect of FMT in IBD. In this issue of the Journal of Crohns and Colitis,4 Vermeire and colleagues investigated the impact of FMT in patients with IBD and looked for predictors of clinical response in donors’ microbiota characteristics. In all, 14 patients [6 with CD and 8 with UC] with refractory disease underwent FMT. Two UC patients only went into remission and one UC patient experienced transient improvement. None of the patients with CD improved after FMT. In term of safety, four patients developed fever [> 38.5°C] within a few hours after FMT and one of them required antibiotics. One patient vomited after upper route FMT and had aspiration pneumonia that was treated with broad-spectrum antibiotics. Following this severe adverse event, all the subsequent FMTs were performed by enema route. The authors then
analysed the microbiota composition and diversity of donors to look for factors associated with clinical response. They observed that donors from whom the stools resulted in a successful FMT were characterised by a significantly higher bacterial richness. Importantly, richness of the faecal microbiota of the recipient at baseline was not predictive of FMT efficacy, showing that this parameter was independent of recipient status. At Week 8 after FMT, responders tended to have a higher bacterial richness than non-responders [p = 0.058]. FMT is a complex therapeutic procedure involving a high number of parameters to take into account. Route of administration [upper vs lower gastrointestinal tract], fresh or frozen status, preparation with antibiotics or colon cleansing, amount of material, volume of dilution, and nature of the diluent are the most obvious and can be easily controlled. Timing of the FMT is another important factor, but it has been poorly studied until now. Indeed, the effect of FMT in a recipient who achieved remission after conventional treatment might be associated with fewer side effects and different clinical outcome than that in patient with active inflammation. Furthermore, donor’s characteristics represent major factors potentially influencing FMT effects, as already suggested in the study by Moayyedi and colleagues.3 Identifying the features of a ‘good’ donor’s microbiota is thus a major objective in FMT field, that can be solved only by performing clinical trials and looking for predictors. In addition, it cannot be ruled out that characteristics of the recipient’s microbiota are also important. This would add another layer of complexity and require identifying a kind of matching process between donor and recipient. Although the study by Vermeire and colleagues is of limited size, it opens the first doors to rationally selecting donors in the context of FMT for IBD. These results need to be confirmed in larger and independent studies, but richness of the donor’s microbiota is an attractive parameter to consider. Moreover, the fact that high richness of both donor’s microbiota and the post-FMT recipient’s microbiota was associated with response suggests that this parameter could be involved in the clinical effect of FMT itself. Other features
Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
375
H. Sokol
376 of the donor’s microbiota might be relevant to investigate, such as abundance of anti-inflammatory taxa like Faecalibacterium prausnitzii5 or in butyrate producers; but an unbiased approach should be preferred to identify relevant parameters. Ongoing and future randomised control trials evaluating FMT in IBD should be considered as important opportunities to confirm the results of Vermeire and colleagues, to identify new markers of efficacy, and finally to define successful procedures.
Conflict of Interest HS received consultancy fees from Enterome, Maat Pharma, Astellas, Danone, MSD, Ferring, and Roche, and speaker’s fees from Takeda, Abbvie, Astellas, and Biocodex.
References 1. Sokol H. Probiotics and antibiotics in IBD. Dig Dis 2014;32[Suppl 1]:10–7. 2. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407–15. 3. Moayyedi P, Surette MG, Kim PT, et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology 2015;149:102–9 e6. 4. Vermeire S, Joossens M, Verbeke K, et al. Donor species richness determines faecal microbiota transplantation success in inflammatory bowel disease. J Crohns Colitis 2015. 5. Sokol H, Pigneur B, Watterlot L, et al. Fecalibacterium prausnitzii is an antiinflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 2008;105:16731–6.
