The gut microbiome in end-stage lung disease and lung transplantation
Authors: Zhang Shuyan , Swarte J. Casper , Gacesa Ranko , Knobbe Tim J. , Kremer Daan , Jansen Bernadien H. , de Borst Martin H. ,   TransplantLines Investigators, Harmsen Hermie J. M. , Erasmus Michiel E. , Verschuuren Erik A. M. , Bakker Stephan J. L. , Gan C. Tji , Weersma Rinse K. , Björk Johannes R. , Annema Coby , Bakker Stephan J. L. , Berger Stefan P. , Blokzijl Hans , Bodewes Frank A. J. A. , de Boer Marieke T. , Damman Kevin , de Borst Martin H. , Diepstra Arjan , Dijkstra Gerard , Douwes Rianne M. , Doorenbos Caecilia S. E. , Eisenga Michele F. , Erasmus Michiel E. , Gan C. Tji , Hak Eelko , Hepkema Bouke G. , Klont Frank , Knobbe Tim J. , Kremer Daan , Leuvenink Henri G. D. , Lexmond Willem S. , de Meijer Vincent E. , Niesters Hubert G. M. , Nieuwenhuis-Moeke Gertrude J. , van Pelt L. Joost , Pol Robert A. , Porte Robert J. , Ranchor Adelta V. , Siebelink Marion J. , Slart Riemer J. H. J. A. , Swarte J. Casper , Touw Daan J. , van den Heuvel Marius C. , van Leer-Buter Coretta , van Londen Marco , Verschuuren Erik A. M. , Vos Michel J. , Weersma Rinse K. , Gomes Neto Antonio W. , Sanders Jan Stephan F. 
Published: May 2024

ABSTRACT

Gut dysbiosis has been associated with impaired outcomes in liver and kidney transplant recipients, but the gut microbiome of lung transplant recipients has not been extensively explored. We assessed the gut microbiome in 64 fecal samples from end-stage lung disease patients before transplantation and 219 samples from lung transplant recipients after transplantation using metagenomic sequencing. To identify dysbiotic microbial signatures, we analyzed 243 fecal samples from age-, sex-, and BMI-matched healthy controls. By unsupervised clustering, we identified five groups of lung transplant recipients using different combinations of immunosuppressants and antibiotics and analyzed them in relation to the gut microbiome. Finally, we investigated the gut microbiome of lung transplant recipients in different chronic lung allograft dysfunction (CLAD) stages and longitudinal gut microbiome changes after transplantation. We found 108 species (58.1%) in end-stage lung disease patients and 139 species (74.7%) in lung transplant recipients that were differentially abundant compared with healthy controls, with several species exhibiting sharp longitudinal increases from before to after transplantation. Different combinations of immunosuppressants and antibiotics were associated with specific gut microbial signatures. We found that the gut microbiome of lung transplant recipients in CLAD stage 0 was more similar to healthy controls compared to those in CLAD stage 1. Finally, the gut microbial diversity of lung transplant recipients remained lower than the average gut microbial diversity of healthy controls up to more than 20 years post-transplantation. Gut dysbiosis, already present before lung transplantation was exacerbated following lung transplantation.

IMPORTANCE
This study provides extensive insights into the gut microbiome of end-stage lung disease patients and lung transplant recipients, which warrants further investigation before the gut microbiome can be used for microbiome-targeted interventions that could improve the outcome of lung transplantation.