Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity

Zachariah DeFilipp, Jonathan U Peled, Shuli Li, Jasmin Mahabamunuge, Zeina Dagher, Ann E Slingerland, Candice Del Rio, Betsy Valles, Maria E Kempner, Melissa Smith, Jami Brown, Bimalangshu R Dey, Areej El-Jawahri, Steven L McAfee, Thomas R Spitzer, Karen K Ballen, Anthony D Sung, Tara E Dalton, Julia A Messina, Katja Dettmer, Gerhard Liebisch, Peter Oefner, Ying Taur, Eric G Pamer, Ernst Holler, Michael K Mansour, Marcel R M van den Brink, Elizabeth Hohmann, Robert R Jenq, Yi-Bin Chen, Zachariah DeFilipp, Jonathan U Peled, Shuli Li, Jasmin Mahabamunuge, Zeina Dagher, Ann E Slingerland, Candice Del Rio, Betsy Valles, Maria E Kempner, Melissa Smith, Jami Brown, Bimalangshu R Dey, Areej El-Jawahri, Steven L McAfee, Thomas R Spitzer, Karen K Ballen, Anthony D Sung, Tara E Dalton, Julia A Messina, Katja Dettmer, Gerhard Liebisch, Peter Oefner, Ying Taur, Eric G Pamer, Ernst Holler, Michael K Mansour, Marcel R M van den Brink, Elizabeth Hohmann, Robert R Jenq, Yi-Bin Chen

Abstract

We hypothesized that third-party fecal microbiota transplantation (FMT) may restore intestinal microbiome diversity after allogeneic hematopoietic cell transplantation (allo-HCT). In this open-label single-group pilot study, 18 subjects were enrolled before allo-HCT and planned to receive third-party FMT capsules. FMT capsules were administered no later than 4 weeks after neutrophil engraftment, and antibiotics were not allowed within 48 hours before FMT. Five patients did not receive FMT because of the development of early acute gastrointestinal (GI) graft-versus-host disease (GVHD) before FMT (n = 3), persistent HCT-associated GI toxicity (n = 1), or patient decision (n = 1). Thirteen patients received FMT at a median of 27 days (range, 19-45 days) after HCT. Participants were able to swallow and tolerate all FMT capsules, meeting the primary study endpoint of feasibility. FMT was tolerated well, with 1 treatment-related significant adverse event (abdominal pain). Two patients subsequently developed acute GI GVHD, with 1 patient also having concurrent bacteremia. No additional cases of bacteremia occurred. Median follow-up for survivors is 15 months (range, 13-20 months). The Kaplan-Meier estimates for 12-month overall survival and progression-free survival after FMT were 85% (95% confidence interval, 51%-96%) and 85% (95% confidence interval, 51%-96%), respectively. There was 1 nonrelapse death resulting from acute GI GVHD (12-month nonrelapse mortality, 8%; 95% confidence interval, 0%-30%). Analysis of stool composition and urine 3-indoxyl sulfate concentration indicated improvement in intestinal microbiome diversity after FMT that was associated with expansion of stool-donor taxa. These results indicate that empiric third-party FMT after allo-HCT appears to be feasible, safe, and associated with expansion of recipient microbiome diversity. This trial was registered at www.clinicaltrials.gov as #NCT02733744.

Conflict of interest statement

Conflict-of-interest disclosure: E. Hohmann receives research support from Seres Therapeutics, Inc. J.U.P. holds patents with or receives royalties from Seres Therapeutics, Inc. R.R.J. is on the board of directors or an advisory committee for Seres Therapeutics, Inc., has consulted for Ziopharm Oncology, and holds patents with or receives royalties from Seres Therapeutics, Inc. M.R.M.v.d.B. is on the board of directors or an advisory committee for Seres Therapeutics, Inc. and holds patents with or receives royalties from Seres Therapeutics, Inc. E.G.P. is on the board of directors or an advisory committee for Seres Therapeutics, Inc. and holds patents with or receives royalties from Seres Therapeutics, Inc. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Study schema.
Figure 2.
Figure 2.
Study flow diagram. IBD, inflammatory bowel disease.
Figure 3.
Figure 3.
Longitudinal changes in urinary 3-IS levels before allo-HCT and after FMT administration in the early posttransplant period.
Figure 4.
Figure 4.
Evaluation of the microbiome prior to and following administration of FMT. Longitudinal changes in (A) inverse Simpson index, (B) Clostridiales abundance, and (C) UniFrac distance before allo-HCT and after FMT administration in the early posttransplant period, as determined from 16S rRNA sequencing of stool specimens. (D) Longitudinal changes in the origin of operational taxonomic units. Four selected patients shown.
Figure 5.
Figure 5.
Microbiome assessment under conditions that highlight the potential benefit of FMT as part of an exploratory analysis in a subset of 8 patients. Eligibility criteria for inclusion in this subset analysis received microbiome-disrupting antibiotics (ceftazidime, cefepime, piperacillin-tazobactam, meropenem, oral vancomycin, or metronidazole) before FMT, and did not receive microbiome-disrupting antibiotics in the 60 days after FMT.
Figure 6.
Figure 6.
Microbiome diversity after FMT compared with a post hoc comparison cohort of patients with allo-HCT who did not receive FMT. The inverse Simpson scores of 8 FMT recipients from Figure 5 are compared with those of patients who underwent allo-HCT at 2 other institutions and had stool specimens collected and 16S sequenced in a manner identical to those from FMT recipients.

Source: PubMed

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