Abstract
Gut dysbiosis has been associated with worse allogeneic hematopoietic cell transplantation (allo-HCT) outcomes. We reported an association between intrinsically vancomycin-resistant enterococci (iVRE: E. gallinarum and E. casseliflavus) gut colonization and lower post-transplant mortality. In this study, using an expanded cohort, we evaluated whether our previously observed association is species-specific. We included allo-HCT recipients with ≥1 positive rectal swab or stool culture for iVRE between days -14 and +14 of transplant. To investigate whether iVRE modulate the gut microbiota, we performed agar diffusion assays. To investigate whether iVRE differ in their ability to activate the aryl hydrocarbon receptor, we analyzed iVRE genomes for enzymes in the shikimate and tryptophan pathways. Sixty six (23 E. casseliflavus and 43 E. gallinarum) of the 908 allograft recipients (2011–2017) met our inclusion criteria. Overall survival was significantly higher in patients with E. casseliflavus (91% vs. 62% at 3 years, P = 0.04). In multivariable analysis, E. casseliflavus gut colonization was significantly associated with reduced all-cause mortality (hazard ratio 0.20, 95% confidence interval 0.04–0.91, P = 0.04). While agar assays were largely unremarkable, genome mining predicted that E. casseliflavus encodes a larger number of enzymes in the tryptophan metabolism pathway. In conclusion, E. casseliflavus gut colonization is associated with reduced post-HCT morality. Further research is needed to understand the mechanisms for this association.
Highlights
The importance of gut microbiota as a predictor of allogeneic hematopoietic cell transplantation (HCT) outcomes has become apparent in recent years [1]
We recently reported an unexpected association between pre-HCT gut colonization with intrinsically vancomycin-resistant enterococci and improved overall survival (OS) due to decreased non-relapse mortality (NRM) [2]. iVRE are characterized by susceptibility to teicoplanin and constitutive low-level vancomycin resistance through the chromosomally encoded vanC genotype [3,4]
Nine (39%) patients colonized with E. casseliflavus and 34 (79%) of those colonized with E. gallinarum had at least one other sample colonized with the same species between days -14 and +14
Summary
The importance of gut microbiota as a predictor of allogeneic hematopoietic cell transplantation (HCT) outcomes has become apparent in recent years [1]. We recently reported an unexpected association between pre-HCT gut colonization with intrinsically vancomycin-resistant enterococci (iVRE: E. gallinarum and E. casseliflavus) and improved overall survival (OS) due to decreased non-relapse mortality (NRM) [2]. The objective of the present study was to determine whether our reported association between pre-HCT iVRE gut colonization and improved outcomes is species-specific (i.e., E. gallinarum vs E. casseliflavus). Including patients who were iVRE colonized early after HCT, we demonstrate that this association with improved survival is specific to E. casseliflavus. Using in vitro agar diffusion assays and bioinformatic analysis of iVRE genomes, we explored two potential mechanisms for an E. casseliflavus-mediated effect: (i) a direct effect on the host and (ii) an indirect effect on the host via modulation of the gut microbiota
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