Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation

Abstract

Background: Bacteremia is a frequent complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unclear whether changes in the intestinal microbiota during allo-HSCT contribute to the development of bacteremia. We examined the microbiota of patients undergoing allo-HSCT, and correlated microbial shifts with the risk of bacteremia.

Methods: Fecal specimens were collected longitudinally from 94 patients undergoing allo-HSCT, from before transplant until 35 days after transplant. The intestinal microbiota was characterized by 454 pyrosequencing of the V1-V3 region of bacterial 16S ribosomal RNA genes. Microbial diversity was estimated by grouping sequences into operational taxonomic units and calculating the Shannon diversity index. Phylogenetic classification was obtained using the Ribosomal Database Project classifier. Associations of the microbiota with clinical predictors and outcomes were evaluated.

Results: During allo-HSCT, patients developed reduced diversity, with marked shifts in bacterial populations inhabiting the gut. Intestinal domination, defined as occupation of at least 30% of the microbiota by a single predominating bacterial taxon, occurred frequently. Commonly encountered dominating organisms included Enterococcus, Streptococcus, and various Proteobacteria. Enterococcal domination was increased 3-fold by metronidazole administration, whereas domination by Proteobacteria was reduced 10-fold by fluoroquinolone administration. As a predictor of outcomes, enterococcal domination increased the risk of Vancomycin-resistant Enterococcus bacteremia 9-fold, and proteobacterial domination increased the risk of gram-negative rod bacteremia 5-fold.

Conclusions: During allo-HSCT, the diversity and stability of the intestinal flora are disrupted, resulting in domination by bacteria associated with subsequent bacteremia. Assessment of fecal microbiota identifies patients at highest risk for bloodstream infection during allo-HCST.

Figures

Figure 1.

Changes in microbial diversity within the intestinal tract during allogeneic hematopoietic stem cell transplantation. Microbial diversity, quantified by the Shannon diversity index, was calculated for each fecal specimen of each patient and plotted over day of transplant (circles). A diversity trend (solid black line; 95% confidence intervals shown in gray) was constructed using moving average filtering.

Figure 2.

Characterization of the intestinal microbiota during allogeneic hematopoietic stem cell transplantation. A, Genus-level taxonomy of 12 selected patients, plotted over day of transplant. Each stacked bar represents the microbial composition of a single fecal specimen, based on taxonomic classification. Shading between specimens are provided for interpolation and visualization of changes in relative abundances. Concurrent antibiotic administration (vancomycin, fluoroquinolones, metronidazole, and beta-lactams) and detected bacteremias are shown for each patient. Patients in the first row generally maintained diversity with few changes in composition; patients in the second row developed intestinal domination by Enterococcus; patients in the third row developed intestinal domination by Streptococcus; and patients in the fourth row developed domination with Proteobacteria. Note that patient 58 in the top row maintained diversity but developed Enterococcus domination shortly after metronidazole administration. (Plots of all 94 patients can be found in Supplementary Figure 3.) B, Kaplan-Meier plot of intestinal domination as a survival event. Crosshairs represent censored observations. Intestinal domination by Enterococcus, Streptococcus, and Proteobacteria was common and occurred at various times throughout the observation period.

Figure 3.

Microbiota states and their transitions. A, Hierarchical clustering of all fecal specimens according to microbiota state based on phylogenetic classification. There was wide variation in phylogenetic composition; some specimens showed a relatively biodiverse membership, whereas others were largely dominated by a single bacterial taxon. B, Circos plots representing microbiota state transitions between consecutive specimens within the observation period. Subplots of transitions during specific transplant periods are shown in C–E. C, Pre-transplant transitions revealing that patients in the “biodiverse microbiota” state tend to remain in that state; resilience of the “biodiverse” state, measured as the percentage of consecutive specimens that remain in that state, is 77%. D, Resilience of “biodiverse” state decreasing to 35% during the intra-transplant period (consecutive specimens straddling the day of stem cell infusion). E, Post-transplant transitions with the “biodiverse” state resilience staying low at 48%.