Impact of the Intestinal Microbiota on Infections and Survival Following Hematopoietic Stem Cell Transplantation

Highly diverse bacterial populations inhabit the gastrointestinal tract, modulate host inflammation and promote immune tolerance. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the gastrointestinal mucosa is damaged, and colonizing bacteria are impacted, leading to an impaired intestinal microbiota with reduced diversity. Because bacteremia is a frequent complication of allo-HSCT, we examined the microbiota of patients undergoing allo-HSCT and correlated microbial shifts with the risk of bacteremia. Fecal specimens were collected longitudinally from 94 patients undergoing allo-HSCT from pre-transplant until 35 days post-transplantation. The intestinal microbiota was characterized by 454 pyrosequencing of the V1-V3 region of bacterial 16S rRNA genes. Phylogenetic classification was obtained using the Ribosomal Database Project (RDP) classifier. Associations of the microbiota with clinical predictors and outcomes were evaluated. 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 three-fold by metronidazole administration, while domination by Proteobacteria was reduced ten-fold by fluoroquinolone administration. As a predictor of outcomes, enterococcal domination increased the risk of vancomycin resistant enterococcus bacteremia nine-fold, and proteobacterial domination increased the risk of gram negative rod bacteremia five-fold. We also examined whether intestinal diversity was predictive of clinical outcomes following transplantation. Subjects were classified into high, intermediate, and low bacterial diversity groups, and assessed for up to three years for differences in overall survival and transplant-related mortality. Overall survival was worse in subjects with low intestinal diversity, compared with intermediate or high diversity (at three years, 36%, 60%, and 67%, respectively; log-rank P=0.019); similar results were observed for transplant-related mortality. Multivariate Cox hazards analysis demonstrated a persistent association after adjusting for other clinical covariates. In conclusion, 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. Diversity of the intestinal microbiota is also an independent predictor of mortality in allo-HSCT recipients following engraftment. These results indicate that the intestinal microbiota is an important factor in the success or failure in allo-HSCT.