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Original research
Multiple indicators of gut dysbiosis predict all-cause and cause-specific mortality in solid organ transplant recipients
  1. J Casper Swarte1,
  2. Shuyan Zhang1,
  3. Lianne M Nieuwenhuis2,
  4. Ranko Gacesa1,3,
  5. Tim J Knobbe2,
  6. TransplantLines Investigators,
  7. Vincent E De Meijer4,
  8. Kevin Damman2,
  9. Erik A M Verschuuren2,
  10. Tji C Gan2,
  11. Jingyuan Fu5,6,
  12. Alexandra Zhernakova2,
  13. Hermie J M Harmsen7,
  14. Hans Blokzijl2,
  15. Stephan J L Bakker2,
  16. Johannes R Björk1,
  17. Rinse K Weersma1
    1. 1 Gastroenterology and Hepatology, University Medical Centre, Groningen, Netherlands
    2. 2 University Medical Centre, Groningen, Netherlands
    3. 3 Department of Genetics, University of Groningen, University Medical Center, Groningen, Netherlands
    4. 4 Surgery, UMCG, Groningen, Netherlands
    5. 5 Department of Genetics, University Medical Center, Groningen, Netherlands
    6. 6 Department of Pediatrics, University Medical Center, Groningen, Netherlands
    7. 7 Medical Microbiology, University of Groningen, University Medical Center, Groningen, Netherlands
    1. Correspondence to Dr Johannes R Björk, Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, Netherlands; bjork.johannes{at}gmail.com

    Abstract

    Objective Gut microbiome composition is associated with multiple diseases, but relatively little is known about its relationship with long-term outcome measures. While gut dysbiosis has been linked to mortality risk in the general population, the relationship with overall survival in specific diseases has not been extensively studied. In the current study, we present results from an in-depth analysis of the relationship between gut dysbiosis and all-cause and cause-specific mortality in the setting of solid organ transplant recipients (SOTR).

    Design We analysed 1337 metagenomes derived from faecal samples of 766 kidney, 334 liver, 170 lung and 67 heart transplant recipients part of the TransplantLines Biobank and Cohort—a prospective cohort study including extensive phenotype data with 6.5 years of follow-up. To analyze gut dysbiosis, we included an additional 8208 metagenomes from the general population of the same geographical area (northern Netherlands). Multivariable Cox regression and a machine learning algorithm were used to analyse the association between multiple indicators of gut dysbiosis, including individual species abundances, and all-cause and cause-specific mortality.

    Results We identified two patterns representing overall microbiome community variation that were associated with both all-cause and cause-specific mortality. The gut microbiome distance between each transplantation recipient to the average of the general population was associated with all-cause mortality and death from infection, malignancy and cardiovascular disease. A multivariable Cox regression on individual species abundances identified 23 bacterial species that were associated with all-cause mortality, and by applying a machine learning algorithm, we identified a balance (a type of log-ratio) consisting of 19 out of the 23 species that were associated with all-cause mortality.

    Conclusion Gut dysbiosis is consistently associated with mortality in SOTR. Our results support the observations that gut dysbiosis is associated with long-term survival. Since our data do not allow us to infer causality, more preclinical research is needed to understand mechanisms before we can determine whether gut microbiome-directed therapies may be designed to improve long-term outcomes.

    • INTESTINAL MICROBIOLOGY
    • LIVER TRANSPLANTATION

    Data availability statement

    Data are available on reasonable request. The raw microbiome sequencing data and basic phenotypes used in this study are available at the European Genome-Phenome Archive under accession numbers EGAD00001008907 (https://ega-archive.org/datasets/EGAD00001008907), EGAS00001006257 (https://ega-archive.org/studies/EGAS00001006257) and EGAS00001006258 (https://ega-archive.org/studies/EGAS00001006258). Due to patient confidentiality, the clinical datasets associated with the metagenomic datasets are available on request to the University Medical Centre Groningen. Access to this clinical dataset requires a minimal access procedure consisting of a request per email (datarequest.transplantlines@umcg.nl) for a data access form. A response will be provided within two working weeks. This access procedure is to ensure that the data are being requested for research/scientific purposes only and thus comply with the informed consent signed by TransplantLines participants, which specifies that the collected data will not be used for commercial purposes.

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    Data availability statement

    Data are available on reasonable request. The raw microbiome sequencing data and basic phenotypes used in this study are available at the European Genome-Phenome Archive under accession numbers EGAD00001008907 (https://ega-archive.org/datasets/EGAD00001008907), EGAS00001006257 (https://ega-archive.org/studies/EGAS00001006257) and EGAS00001006258 (https://ega-archive.org/studies/EGAS00001006258). Due to patient confidentiality, the clinical datasets associated with the metagenomic datasets are available on request to the University Medical Centre Groningen. Access to this clinical dataset requires a minimal access procedure consisting of a request per email (datarequest.transplantlines@umcg.nl) for a data access form. A response will be provided within two working weeks. This access procedure is to ensure that the data are being requested for research/scientific purposes only and thus comply with the informed consent signed by TransplantLines participants, which specifies that the collected data will not be used for commercial purposes.

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    Footnotes

    • X @CasSwarte, @jingyuan_fu, @HarmsenHermie, @WeersmaLab, @WeersmaLab

    • JRB and RKW contributed equally.

    • Collaborators TransplantLines investigatorsC. Annema, F. A. J. A. Bodewes, M. T. de Boer, K. Damman, A. Diepstra, G. Dijkstra, C. S. E. Doorenbos, M. F. Eisenga, M. E. Erasmus, C. T. Gan, A. W. Gomes Neto, E. Hak, B. G. Hepkema, F. Klont, H. G. D. Leuvenink, W. S. Lexmond, G. J. Nieuwenhuis-Moeke, H. G. M. Niesters, L. J. van Pelt, A. V. Ranchor, J. S. F. Sanders, M. J. Siebelink, R. J. H. J. A. Slart, D. J. Touw, M. C. van den Heuvel, C. van Leer-Buter, M. van Londen, E. A. M. Verschuuren & M. J. Vos.

    • Contributors HB, JCS, SJLB, RKW and JRB conceived and designed the project. JCS, SJLB and RKW obtained funding. TJK, JCS, HB, EAMV, TCG and SJLB collected samples. JCS and JRB analysed and interpreted data. JCS, JRB, SJLB and RKW drafted the manuscript. JCS, RG, RKW and JRB revised the manuscript. SZ, LMN, RG, TJK, VEDM, KD, EAMV, TCG, JF, AZ, HJMH and HB were involved in critically reviewing the manuscript. JCS, SJLB, JRB and RKW accept full responsibility for the work and conduct of the study. All the authors approved the final version of the manuscript.

    • Funding This study was funded by Dutch Ministry of Economic Affairs and Climate Policy(Not Applicable).Seerave Foundation(Not Applicable).Chiesi Farmaceutici(PA-SP/PRJ-2020-9136).Astellas BV(Not Applicable).Dutch NWO/TTW/DSM(project number 14939).EU Horizon Europe Program(miGut-Health 101095470).Netherlands Organization for Scientific Research(Not Applicable).

    • Competing interests The TransplantLines Biobank and Cohort study received funding from Astellas BV (TransplantLines Biobank and Cohort study) and Chiesi Pharmaceuticals BV (PA-SP/PRJ-2020-9136) and was cofinanced by the Dutch Ministry of Economic Affairs and Climate Policy by means of the PPP allowance made available by the Top Sector Life Sciences and Health to stimulate public–private partnerships. Sequencing of the kidney part of the TransplantLines cohort was funded by a grant from the Dutch NWO/TTW/DSM partnership programme Animal Nutrition and Health (project number 14939) to SJLB, RKW is supported by the Seerave Foundation, the Netherlands Organization for Scientific Research (NWO) and the EU Horizon Europe Programme grant miGut-Health: personalised blueprint of intestinal health (101095470). JF is supported by the Dutch Heart Foundation IN-CONTROL (CVON2018-27), the ERC Consolidator grant (grant agreement No. 101001678), NWO-VICI grant VI.C.202.022, the AMMODO Science Award 2023 for Biomedical Sciences from Stichting Ammodo and the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of The Netherlands.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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