Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation

Peled, Jonathan U. ; Gomes, Antonio L. C.

; Devlin, Sean M. ; Littmann, Eric R. ; Taur, Ying ; Sung, Anthony D. ; Weber, Daniela ; Hashimoto, Daigo ; Slingerland, Ann E. ; Slingerland, John B. ; Maloy, Molly ; Clurman, Annelie G. ; Stein-Thoeringer, Christoph K. ; Markey, Kate A. ; Docampo, Melissa D. ; Burgos da Silva, Marina ; Khan, Niloufer

; Gessner, André ; Messina, Julia A. ; Romero, Kristi ; Lew, Meagan V. ; Bush, Amy ; Bohannon, Lauren ; Brereton, Daniel G.

; Fontana, Emily ; Amoretti, Luigi A. ; Wright, Roberta J. ; Armijo, Gabriel K. ; Shono, Yusuke ; Sanchez-Escamilla, Míriam ; Castillo Flores, Nerea ; Alarcon Tomas, Ana ; Lin, Richard J.

; Yáñez San Segundo, Lucrecia ; Shah, Gunjan L. ; Cho, Christina ; Scordo, Michael ; Politikos, Ioannis ; Hayasaka, Kasumi ; Hasegawa, Yuta ; Gyurkocza, Boglarka ; Ponce, Doris M. ; Barker, Juliet N. ; Perales, Miguel-Angel ; Giralt, Sergio A. ; Jenq, Robert R. ; Teshima, Takanori ; Chao, Nelson J. ; Holler, Ernst ; Xavier, Joao B. ; Pamer, Eric G. ; van den Brink, Marcel R. M.

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In this study, the gastrointestinal microbiome was serially monitored in patients undergoing allogeneic hematopoietic-cell transplantation at four centers. Lower microbial diversity was associated with poorer outcomes after HCT. Background Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. Methods The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. Results We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. Conclusions Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.)

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