Microbiota Injury in Auto-HCT Is Frequent, Occurs across Geography, and Is Comparable to That Observed in Allo-HCT

Intestinal microbiota injuries in allo-HCT patients are characterized by loss of a-diversity and domination of microbial communities by single organisms. These injury patterns are associated with poor survival after allo-HCT and are likely attributable to antibiotic exposure, nutritional alterations, and regimen-related mucosal injury. As recipients of auto-HCT patients have similar exposures, we hypothesized that similar patterns of dysbiosis occur in auto-HCT patients. We present the first analysis of intestinal microbiota composition in auto-HCT patients at two independent institutions. From a prospectively collected cohort, we retrospectively identified 365 patients (median age 60) who received auto-HCT (May 2009 to Feb. 2018) at two transplant centers (MSK n = 316; Duke n = 49) with heterogeneous conditioning regimens, pre-HCT remission status, and diagnoses: 179 (49%) myeloma, 153 (42%) lymphoma, and 33 (9%) other diseases. 857 samples collected approximately weekly peri-transplant were 16S sequenced (V4-V5 region, Illumina platform) at a central laboratory. Stool samples from 17 volunteers at MSK and a publicly available dataset of 313 subjects from the Human Microbiome Project (HMP) served as healthy-control cohorts. The median pre-auto-HCT a-diversity during day -10 to 0 (as measured by Simpson reciprocal index, S ) at both centers was significantly lower than healthy controls ( Fig A ) (HMP vs MSK auto-HCT, S =12.05 vs. 9.19, p S =12.05 vs 6.91, p S  = 12.05 vs 8.74, p=0.53). Overall (days -10 to +30) diversity decreased comparably after auto-HCT and allo-HST across both centers, while auto-HCT patients demonstrated a slightly more rapid recovery at day +30 compared to allo-HCT patients ( Fig 1B ). Monodomination was observed in the samples ( Fig 1C ), with Streptococcus and Enterococcus as the most common genus, as defined by any single taxon comprising >30% of bacterial abundance. The cumulative incidence of intestinal domination by any organism was >50% by day 0 and was >75% by day +14. Microbial diversity is reduced prior to transplant in both auto-HCT and allo-HCT patients compared with healthy volunteers. Loss of diversity after auto-HCT occurs across transplant centers and the degree of injury is comparable to the dysbiosis observed in allo-HCT patients. We previously reported that intestinal monodomination increases the risk of bacteremia with corresponding organisms in allo-HCT patients. We now report these events are a common occurrence after auto-HCT, which suggests prevention or repair of microbiota injury as a strategy to reduce the toxicity of auto-HCT.