Abstract IA22: The role of the intestinal microbiome in allogeneic hematopoietic cell transplantation

Abstract

Abstract Relationships between microbiota composition and clinical outcomes of patients following allogeneic hematopoietic cell transplantation (allo-HCT) 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. Therefore, we studied 8,767 fecal samples from 1,362 allo-HCT patients at four centers on three continents by 16S ribosomal sequencing. In an observational study, we examined associations between microbiota diversity and overall survival during two years of follow-up after allo-HCT with proportional-hazards analysis. We observed reproducible patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Low diversity in the peri-neutrophil engraftment period was reproducibly associated with increased risk of death (multivariate-adjusted HR 0.48, 95% CI 0.30-0.77, p = 0.002 in the largest cohort). Subset analysis suggested that these reductions in overall survival were in part due to an increased risk of transplant-related mortality and graft-versus-host disease. Baseline pre-HCT samples already bore evidence of microbiome disruption, and low diversity prior to transplantation was associated with poor survival. In addition, we found that Enterococcus faecium dominates the intestinal microbiota of up to 65% allo-HCT patients early after transplant at all four transplant centers. Enterococcus domination was associated with an increased incidence of acute graft-versus-host disease (GVHD), increased GVHD-related mortality, and reduced overall survival. Post-transplant expansion of Enterococci was also observed in mouse models of GVHD in the absence of antibiotic treatment. Spiking a minimal flora with Enterococci in gnotobiotic mice exacerbated lethal GVHD. Metagenomic sequencing of human and murine Enterococcus-dominated fecal samples revealed an enrichment of lactose and galactose degradation genes, a pathway necessary for Enterococcus growth in vitro. A lactose-free chow attenuated the intestinal outgrowth of Enterococcus and reduced the severity of lethal GVHD in mice. In patients, a lactose-nonabsorber genotype was associated with an increased Enterococcus abundance after cessation of antibiotic treatment after allo-HCT. In conclusion, the concordance of microbiota disruption patterns and their associations with clinical outcomes suggest that approaches to manipulate the intestinal microbiota with the aim of improving allo-HCT clinical outcomes may be generalizable. Citation Format: Marcel van den Brink. The role of the intestinal microbiome in allogeneic hematopoietic cell transplantation [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA22.