Protective Factors in the Intestinal Microbiome Against Clostridium difficile Infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Background: Clostridium difficile infection (CDI) is a frequent complication in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), who receive intensive treatments that significantly disrupt the intestinal microbiota. In this study, we examined the microbiota composition of allo-HSCT recipients to identify bacterial colonizers that confer protection against CDI after engraftment.

Methods: Feces collected from adult recipients allo-HSCT at engraftment were analyzed; 16S ribosomal RNA genes were sequenced and analyzed from each sample. Bacterial taxa with protective effects against development of CDI were identified by means of linear discriminant analysis effect size analysis and then further assessed with clinical predictors of CDI using survival analysis.

Results: A total of 234 allo-HSCT recipients were studied; postengraftment CDI developed in 53 (22.6%). Within the composition of the microbiota, the presence of 3 distinct bacterial taxa was correlated with protection against CDI: Bacteroidetes, Lachnospiraceae, and Ruminococcaceae. Colonization with these groups at engraftment was associated with a 60% lower risk of CDI, independent of clinical factors.

Conclusions: Colonization with these 3 bacterial groups is associated with a lower risk of CDI. These groups have been shown to be vital components of the intestinal microbiota. Targeted efforts to maintain them may help minimize the risk of CDI in this at-risk population.

Keywords: Bacteroidetes; Clostridium difficile; Lachnospiraceae; Ruminococcaceae.; microbiome.

Figure 1.

Identification of bacterial taxa associated with increased or decreased risk of Clostridium difficile infection (CDI), by linear discriminant analysis (LDA) effect size. A, Cladogram depicting all observed bacterial taxa (1010 nodes total). Five bacterial taxa (open colored triangles) were associated with reduced risk of subsequent CDI, and 5 ( open gray circles) were associated with increased risk of CDI. All other taxa (small black circles) were not significantly associated. B, Relative abundances (circles) are shown for each of the 5 taxonomic groups associated with protection against CDI (colored triangles corresponding to cladogram), grouped by whether or not CDI occurred. Data are accompanied by box plots showing median and interquartile range (IQR); whiskers represent 1.5 times IQR. Note that Bacteroidia (class) and Bacteroidales (order) are equivalent taxonomic designations.

Figure 2.

Impact of colonization by protective bacterial taxa on risk of subsequent Clostridium difficile infection (CDI). Kaplan-Meier estimates of CDI are plotted for colonization by each of the 3 protective taxonomic groups. Presence or absence within the microbiome was defined as a relative abundance of ≥0.001 in the postengraftment sample. (P values determined with log-rank test).

Figure 3.

Microbial composition breakdown within the protective groups, by genus level. A heat map shows relative abundances of bacteria at the genus level (rows) for each subject (columns); shading represents relative abundance. Bottom strip shows whether or not Clostridium difficile infection (CDI) developed.