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Haematopoietic cell transplantation outcomes are linked to intestinal mycobiota dynamics and an expansion of Candida parapsilosis complex species

Nature Microbiology volume 6, pages 1505–1515 (2021)Cite this article

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Abstract

Allogeneic haematopoietic cell transplantation (allo-HCT) induces profound shifts in the intestinal bacterial microbiota. The dynamics of intestinal fungi and their impact on clinical outcomes during allo-HCT are not fully understood. Here we combined parallel high-throughput fungal ITS1 amplicon sequencing, bacterial 16S amplicon sequencing and fungal cultures of 1,279 faecal samples from a cohort of 156 patients undergoing allo-HCT to reveal potential trans-kingdom dynamics and their association with patient outcomes. We saw that the overall density and the biodiversity of intestinal fungi were stable during allo-HCT but the species composition changed drastically from day to day. We identified a subset of patients with fungal dysbiosis defined by culture positivity (n = 53) and stable expansion of Candida parapsilosis complex species (n = 19). They presented with distinct trans-kingdom microbiota profiles, characterized by a decreased intestinal bacterial biomass. These patients had worse overall survival and higher transplant-related mortality independent of candidaemia. This expands our understanding of the clinical significance of the mycobiota and suggests that targeting fungal dysbiosis may help to improve long-term patient survival.

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Fig. 1: Dynamics of the fungal and bacterial microbiota during allo-HCT.
Fig. 2: Distinct characteristics of fungal culture-positive and culture-negative faecal samples.
Fig. 3: Fungal composition in faecal samples during allo-HCT.
Fig. 4: Trans-kingdom bacterial and fungal interactions during allo-HCT.
Fig. 5: The intestinal fungal mycobiota and clinical outcomes.

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Data availability

Fungal ITS1 and bacterial 16S amplicon sequences specific to this paper are deposited in NCBI SRA under Bioproject PRJNA746305. Samples, sequences and their accession numbers are provided in the Supplementary Data. Clinical and laboratory data used for the analyses in this manuscript are listed in the Supplementary Data. Additional requests for clinical data and materials will be reviewed by MSKCC to determine if they are subject to intellectual property or confidentiality obligations. Data and materials that can be shared will be released via a material transfer or data-sharing agreements and can be requested from the corresponding author.

Code availability

Denoising and taxonomic annotation pipelines were customized as reported49. All analyses were performed in R using base R and publicly available packages. Analysis code can be requested from T.R. (e-mail: rollingt@mskcc.org).

Change history

  • 30 March 2022

    In the version of the Supplementary Data initially published in this article, decimals were missing in the second column of the “qpcr_results” tab, and have now been restored.

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Acknowledgements

This work was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant no. RO-5328/1-2 (to T.R.), National Institutes of Health (NIH) grant nos. R01 AI093808 (T.M.H.), R21 AI105617 (T.M.H.), R21 AI156157 (T.M.H.), U01 AI124275 (J.B.X.), R01 AI137269 (J.B.X. and Y.T.), K08 HL143189 (J.U.P.), R01 CA228358 (M.R.M.v.d.B.), R01 CA228308 (M.R.M.v.d.B.), P01 CA023766 (M.R.M.v.d.B.), R01 HL125571 (M.R.M.v.d.B.), R01 HL123340 (M.R.M.v.d.B.), P01 AG052359 (Project 2, M.R.M.v.d.B.), a Takeda Science Foundation-Fellowship (K.Y.M.), an Investigator in the Pathogenesis of Infectious Diseases Award from the Burroughs Wellcome Fund (T.M.H.), the Ludwig Center for Cancer Immunotherapy (T.M.H.), a Tri-Institutional Stem Cell Initiative award no. 2016-013 (M.R.M.v.d.B.), the Lymphoma Foundation (M.R.M.v.d.B.), the Parker Institute for Cancer Immunotherapy at MSKCC (M.R.M.v.d.B., K.A.M. and J.U.P.), the Susan and Peter Solomon Divisional Genomics Program (T.M.H. and M.R.M.v.d.B.) and the DKMS (K.A.M.). All authors were supported by NIH P30 CA008748 (Cancer Center Core Grant).

Author information

Author notes

  1. Bing Zhai

    Present address: CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

  2. These authors contributed equally: Thierry Rolling, Bing Zhai.

Authors and Affiliations

  1. Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Thierry Rolling, Bing Zhai, Mergim Gjonbalaj, Nicholas Tosini, Keiko Yasuma-Mitobe, Emily Fontana, Luigi A. Amoretti, Roberta J. Wright, Ying Taur & Tobias M. Hohl

  2. Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Thierry Rolling, Bing Zhai, Mergim Gjonbalaj, Nicholas Tosini, Keiko Yasuma-Mitobe, Marcel R. M. van den Brink & Tobias M. Hohl

  3. Division of Infectious Diseases, First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Thierry Rolling

  4. Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Doris M. Ponce, Miguel A. Perales, Marcel R. M. van den Brink, Kate A. Markey & Jonathan U. Peled

  5. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Doris M. Ponce, Miguel A. Perales, Marcel R. M. van den Brink, Kate A. Markey, Jonathan U. Peled, Ying Taur & Tobias M. Hohl

  6. Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Joao B. Xavier

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Contributions

The study was conceived by T.R., B.Z. and T.M.H. Clinical data were collected by D.M.P., M.A.P., M.R.M.v.d.B., K.A.M., J.U.P., Y.T. and T.M.H. Data analysis and visualization were conducted by T.R., with assistance from B.Z., J.B.X., Y.T. and J.U.P. Sample processing was done by T.R., B.Z., M.G., N.T., K.Y.M., E.F., L.A.A. and R.J.W. The manuscript was written by T.R. and T.M.H. All co-authors reviewed and edited the manuscript.

Corresponding author

Correspondence to Tobias M. Hohl.

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Competing interests

J.U.P. reports research funding, intellectual property fees and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra, CSL Behring and from Maat Pharma. He has filed intellectual property applications related to the microbiome (reference nos. 62/843,849, 62/977,908 and 15/756,845). M.R.M.v.d.B. has received research support from Seres Therapeutics; he has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, WindMIL Therapeutics, Rheos, Frazier Healthcare Partners, Nektar Therapeutics, Notch Therapeutics, Forty Seven Inc., Priothera, Ceramedix, Lygenesis, Pluto Immunotherapeutics, Magenta Therapeutics, Merck & Co., Inc. and DKMS Medical Council (Board); and he has IP Licensing with Seres Therapeutics, Juno Therapeutics and stock options from Seres and Notch Therapeutics. T.M.H. has participated in a scientific advisory board for Boehringer-Ingelheim Inc.

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Peer review information Nature Microbiology thanks Scott Filler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Table 1 Patient Characteristics
Full size table
Extended Data Table 2 Cox proportional hazard model of overall survival
Full size table

Extended Data Fig. 1 Impact of culture positivity and TPN administration on fungal and bacterial microbiota dynamics during allo-HCT, related to Fig. 1.

(a) Comparison of fungal density per gram of stool (n = 246 pre-transplant samples and n = 978 post-transplant samples) and (b) fungal diversity (n = 251 pre-transplant samples and n = 1028 post-transplant samples) between the pre- (days -10 to -1) and the post-transplant period (days 0 to 30). (c) Comparison of bacterial density per gram of stool (n = 241 pre-transplant samples and n = 976 post-transplant samples) and (d) diversity (n = 245 pre-transplant samples and n = 939 post-transplant samples) between the pre- and post-transplant period. Statistical tests (a–d): Two-sided P-values issued from generalized estimating equations with patient ID as cluster variable are shown. The upper whisker represents the maximum value or the 75th percentile value plus 1.5 times the IQR, whichever is larger. The lower whisker represents the minimum value or the 25th percentile value minus 1.5 times the IQR.

Extended Data Fig. 2 Taxonomic composition and relation to culture positivity, related to Fig. 3.

(a) Taxonomic composition of culture-positive samples by ITS (top ribbon) and species cultured from the respective samples (bottom ribbon). (b) Comparison of fungal similarity (1 − Chao–Jaccard index) according to presence of fungal domination status of the earliest sample. Each dot represents a sample pair of an individual patient collected one day apart (n = 516 sample pairs). (c) Comparison of fungal similarity (1 − Chao–Jaccard index) according to the taxa responsible for fungal domination in the earliest samples. Each dot represents a sample pair of an individual patient collected one day apart (n = 88 sample pairs). (b–c) Two-sided p-values issued from generalized estimating equations with patient ID as cluster variable without accounting for multiple comparisons are shown. The upper whisker represents the maximum value or the 75th percentile value plus 1.5 times the IQR, whichever is larger. The lower whisker represents the minimum value or the 25th percentile value minus 1.5 times the IQR.

Extended Data Fig. 3 Supplementary data for clinical outcomes and the fungal intestinal mycobiota, related to Fig. 5.

(a) Overall survival and (b) transplant-related mortality in relation to a relative abundance of C. parapsilosis complex ≥ 82% within the pre-engraftment period (days 0 to the first day of an absolute neutrophil count > 500/mm3). (a) Kaplan–Meier curves tested by two-sided log-rank test. (b) Cumulative incidence curves with relapse and progression of primary disease as competing interest. Differences tested by two-sided Gray’s test. (c) Overall survival and (d) transplant-related mortality in relation to domination by C. albicans within the pre-engraftment period (days 0 to the first day of an absolute neutrophil count > 500/mm3). (c) Kaplan–Meier curves tested by two-sided log-rank test. (d) Cumulative incidence curves with relapse and progression of primary disease as competing interest. Differences tested by two-sided Gray’s test. (a–d) Numbers below the graphs correspond to the number of patients (still) at risk at the specific time point.

Supplementary information

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Supplementary Data

Source data of patients and samples including accession numbers.

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Rolling, T., Zhai, B., Gjonbalaj, M. et al. Haematopoietic cell transplantation outcomes are linked to intestinal mycobiota dynamics and an expansion of Candida parapsilosis complex species. Nat Microbiol 6, 1505–1515 (2021). https://doi.org/10.1038/s41564-021-00989-7

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