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TY - JOUR

T1 - Profiling the Fungal Microbiome after Fecal Microbiota Transplantation for Graft-versus-Host Disease

T2 - Insights from a Phase 1 Interventional Study

AU - van Lier, Yannouck F.

AU - Rolling, Thierry

AU - Armijo, Gabriel K.

AU - Zhai, Bing

AU - Haverkate, Nienke J. E.

AU - Meijer, Ellen

AU - Nur, Erfan

AU - Blom, Bianca

AU - Peled, Jonathan U.

AU - van den Brink, Marcel R. M.

AU - Hohl, Tobias M.

AU - Hazenberg, Mette D.

AU - Markey, Kate A.

N1 - Funding Information: Financial disclosure: Y.F.v.L. was supported by a work visit grant from the Amsterdam Institute for Infection & Immunity, a research mobility grant from the European Hematology Association, an anonymous donation via the AMC Foundation, and an intramural grant from the Academic Medical Center. T.R. was supported by a Deutsche Forschungsgemeinschaft fellowship grant (RO 5328/1-2). J.U.P. received funding from the national Heart, Lung, and Blood Institute (Grant K08 HL143189), the Memorial Sloan Kettering Cancer Center (Core Grant NCI P30 CA008748), and the Parker Institute for Cancer Immunotherapy at the Memorial Sloan Kettering Cancer Center. M.R.M.v.d.B. was supported by the National Cancer Institute, Memorial Sloan Kettering Cancer Center (Core Grants P30 CA008748, R01 CA228358, R01 CA228308, and P01 CA023766), the National Heart, Lung, and Blood Institute (Grants R01 HL125571 and R01 HL123340), the National Institute of Aging (Award Project 2 P01 AG052359), the National Institute of Allergy and Infectious Diseases (Grant U01 AI124275), the Tri-Institutional Stem Cell Initiative (Award 2016-013), the Lymphoma Foundation, the Susan and Peter Solomon Divisional Genomics Program, and the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center. T.M.H. was supported by the National Institutes of Health (Grants R21 AI 156157 and P30 CA008748 [to Memorial Sloan Kettering]), a Burroughs Wellcome Investigator in the Pathogenesis of Infectious Diseases Award, the Susan and Peter Solomon Divisional Genomics Program, and a Ludwig Center for Cancer Immunotherapy Award. K.A.M. is supported by the DKMS and the Parker Institute for Cancer Immunotherapy. M.D.H. is supported by the Dutch Research Council (Vidi Grant NWO ZonMW 91715362) and the Landsteiner Foundation for Blood Research (Fellowship 1438F). Funding Information: Financial disclosure: Y.F.v.L. was supported by a work visit grant from the Amsterdam Institute for Infection & Immunity, a research mobility grant from the European Hematology Association, an anonymous donation via the AMC Foundation, and an intramural grant from the Academic Medical Center. T.R. was supported by a Deutsche Forschungsgemeinschaft fellowship grant (RO 5328/1-2). J.U.P. received funding from the national Heart, Lung, and Blood Institute (Grant K08 HL143189), the Memorial Sloan Kettering Cancer Center (Core Grant NCI P30 CA008748), and the Parker Institute for Cancer Immunotherapy at the Memorial Sloan Kettering Cancer Center. M.R.M.v.d.B. was supported by the National Cancer Institute, Memorial Sloan Kettering Cancer Center (Core Grants P30 CA008748, R01 CA228358, R01 CA228308, and P01 CA023766), the National Heart, Lung, and Blood Institute (Grants R01 HL125571 and R01 HL123340), the National Institute of Aging (Award Project 2 P01 AG052359), the National Institute of Allergy and Infectious Diseases (Grant U01 AI124275), the Tri-Institutional Stem Cell Initiative (Award 2016-013), the Lymphoma Foundation, the Susan and Peter Solomon Divisional Genomics Program, and the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center. T.M.H. was supported by the National Institutes of Health (Grants R21 AI 156157 and P30 CA008748 [to Memorial Sloan Kettering]), a Burroughs Wellcome Investigator in the Pathogenesis of Infectious Diseases Award, the Susan and Peter Solomon Divisional Genomics Program, and a Ludwig Center for Cancer Immunotherapy Award. K.A.M. is supported by the DKMS and the Parker Institute for Cancer Immunotherapy. M.D.H. is supported by the Dutch Research Council (Vidi Grant NWO ZonMW 91715362) and the Landsteiner Foundation for Blood Research (Fellowship 1438F). Conflict of interest statement: J.U.P. reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra and Maat Pharma. He has filed intellectual property applications related to the microbiome (reference numbers 62/843,849, 62/977,908, and 15/756,845). M.R.M.v.d.B. has received research support from Seres Therapeutics; has consulted, received honorarium from, or participated on advisory boards for Seres Therapeutics, WindMIL Therapeutics, Rheos, Frazier Healthcare Partners, Nektar Therapeutics, Notch Therapeutics, Forty Seven, Priothera, Ceramedix, Lygenesis, Pluto Immunotherapeutics, Magenta Therapeutics, Merck & Co, and the DKMS Medical Council (Board); has IP licensing with Seres Therapeutics and Juno Therapeutics; and holds stock options from Seres and Notch Therapeutics. K.A.M. is on the advisory board of and holds equity in PostBiotics Plus Research and has served on an advisory board for Incyte. T.R. is currently an employee of BioNTech US. Authorship statement: Y.F.v.L. designed the study, collected clinical data, and wrote the manuscript; T.R. analyzed and interpreted the sequencing data and contributed to figure preparation; B.Z. performed research and contributed to critical data analysis and interpretation; G.K.A. performed the DNA extraction and prepared the amplicon libraries for sequencing; N.J.E.H. performed sample preparation; E.M. and E.N. enrolled study participants; B.B. J.U.P. M.R.M.v.d.B. and T.M.H. contributed to the conception and editing of the manuscript; and K.A.M. and M.D.H. designed the study, were major contributors to data interpretation and edited the manuscript. All authors had access to the study data and reviewed and approved the final manuscript. Y.F.v.L. and T.R. contributed equally as co-first authors. M.D.H. and K.A.M. contributed equally as co-last authors. Financial disclosure: See Acknowledgments on page 63.e4. Publisher Copyright: © 2022 The American Society for Transplantation and Cellular Therapy

PY - 2023/1

Y1 - 2023/1

N2 - Disruption of the intestinal bacterial microbiota is frequently observed in the context of allogeneic hematopoietic cell transplantation (HCT) and is particularly pronounced in patients who develop graft-versus-host disease (GVHD). Donor fecal microbiota transplantation (FMT) restores gut microbial diversity and reduces GVHD in HCT recipients. The composition of the intestinal fungal community in patients with GVHD, and whether fungal taxa are transferred during FMT are currently unknown. We performed a secondary analysis of our clinical trial of FMT in patients with steroid-refractory GVHD with a focus on the mycobiota. We characterized the fecal mycobiota of 17 patients and healthy FMT donors using internal transcribed spacer amplicon sequencing. The donor who provided the majority of FMT material in our study represents an n-of-one study of the intestinal flora over time. In this donor, mycobiota composition fluctuated over time while the bacterial microbiota remained stable over 16 months. Fungal DNA was detected more frequently in baseline stool samples from patients with steroid-refractory GVHD than in patients with steroid-dependent GVHD. We could detect fungal taxa in the majority of samples but did not see evidence of mycobiota transfer from donor to recipient. Our study demonstrates the feasibility of profiling the mycobiota alongside the more traditional bacterial microbiota, establishes the methodology, and provides a first insight into the mycobiota composition of patients with GVHD.

AB - Disruption of the intestinal bacterial microbiota is frequently observed in the context of allogeneic hematopoietic cell transplantation (HCT) and is particularly pronounced in patients who develop graft-versus-host disease (GVHD). Donor fecal microbiota transplantation (FMT) restores gut microbial diversity and reduces GVHD in HCT recipients. The composition of the intestinal fungal community in patients with GVHD, and whether fungal taxa are transferred during FMT are currently unknown. We performed a secondary analysis of our clinical trial of FMT in patients with steroid-refractory GVHD with a focus on the mycobiota. We characterized the fecal mycobiota of 17 patients and healthy FMT donors using internal transcribed spacer amplicon sequencing. The donor who provided the majority of FMT material in our study represents an n-of-one study of the intestinal flora over time. In this donor, mycobiota composition fluctuated over time while the bacterial microbiota remained stable over 16 months. Fungal DNA was detected more frequently in baseline stool samples from patients with steroid-refractory GVHD than in patients with steroid-dependent GVHD. We could detect fungal taxa in the majority of samples but did not see evidence of mycobiota transfer from donor to recipient. Our study demonstrates the feasibility of profiling the mycobiota alongside the more traditional bacterial microbiota, establishes the methodology, and provides a first insight into the mycobiota composition of patients with GVHD.

KW - Acute graft-versus-host disease

KW - Allogeneic hematopoietic cell transplantation

KW - Fecal microbiota transplantation

KW - Mycobiota

UR - http://www.scopus.com/inward/record.url?scp=85142883904&partnerID=8YFLogxK

U2 - 10.1016/j.jtct.2022.10.011

DO - 10.1016/j.jtct.2022.10.011

M3 - Article

C2 - 36280104

VL - 29

SP - 63.e1-63.e5

JO - Transplantation and Cellular Therapy

JF - Transplantation and Cellular Therapy

SN - 2666-6367

IS - 1

ER -