Intestinal Microbiota Injury during Allo-Hct is Generalizable across Transplantation Centers and is Associated with Increased Mortality, Broad-Spectrum Antibiotics, and Decreased Calorie Intake

Intestinal microbiota composition is associated with important outcomes after allo-HCT including survival, relapse, GVHD, and infections. Loss of diversity after allo-HCT and domination by single organisms is common. Low diversity is associated with poor overall survival from transplant-related mortality, including death after GVHD. These observations were all made in single-center cohorts. Here we compare—for the first time—the kinetics of microbiota diversity in allo-HSCT patients (pts) from three independent international institutions. We also explore the role of nutrition as well as antibiotics (abx) and recovery from microbiota injury after discharge. Weekly stool samples from adult allo-HCT inpatients and ~monthly post-discharge samples were collected. Samples from all three centers were V4-V5 16S sequenced at MSKCC. 5, 823 samples from 1, 118 pts were compared: 5, 508 from 947 MSKCC pts, 108 from 40 Duke pts, and 152 samples from 109 Regensburg pts. The pts varied in diagnosis, graft source, conditioning, and GVHD prophylaxis. Samples from all three centers spread throughout tSNE space, revealing no transplant-center-specific effect (A). Enterococcus domination, a low-diversity state we previously associated with enterococcal bacteremia was observed in all centers. Diversity decreased comparably at all centers (B), validating our prior findings in this larger, international multicenter cohort. In a separate cohort at MSKCC, we explored the relative contributions of abx and nutrition using a multivariate linear regression model of diversity dynamics. Exposure to piperacillin-tazobactam (pip-tazo) and calorie intake were significant predictors (P < .01 and P < .05, respectively). Samples collected on days of pip-tazo administration had lower diversity as compared to pip-tazo-free days (Simpson reciprocal, S: 4.15 ± .35 vs 7.75 ± .21, p = 1.6−12). Calorie intake correlated with diversity in the absence of pip-tazo (r = .22, p = 2.95 × 10−5). Recovery from microbiota injury after allo-HCT in 37 samples from a separate cohort of 21 outpatients showed gradual recovery of diversity at a rate in S of 2.17 per 100 days (C; P = .004). Finally, we validate our prior association of low diversity around the time of neutrophil engraftment with poor overall survival in a cohort from MSKCC (n = 651, P = .006 for below- vs. above-median S) and in a cohort from Regensburg (n = 59, P = .015; D). Microbiota injuries after allo-HCT occur generally across geographic regions. Nutritional perturbations and abx exposure are both associated with injury, and recovery from the injured state occurs over several months post-discharge. Diversity at the time of neutrophil engraftment is associated reproducibly with overall survival. Ongoing work seeks to develop strategies to prevent or repair microbiota injury to improve allo-HCT outcomes.