High-resolution analyses of associations between medications, microbiome, and mortality in cancer patients.

Discerning the effect of pharmacological exposures on intestinal bacterial communities in cancer patients is challenging. Here, we deconvoluted the relationship between drug exposures and changes in microbial composition by developing and applying a new computational method, PARADIGM (parameters associated with dynamics of gut microbiota), to a large set of longitudinal fecal microbiome profiles with detailed medication-administration records from patients undergoing allogeneic hematopoietic cell transplantation. We observed that several non-antibiotic drugs, including laxatives, antiemetics, and opioids, are associated with increased Enterococcus relative abundance and decreased alpha diversity. Shotgun metagenomic sequencing further demonstrated subspecies competition, leading to increased dominant-strain genetic convergence during allo-HCT that is significantly associated with antibiotic exposures. We integrated drug-microbiome associations to predict clinical outcomes in two validation cohorts on the basis of drug exposures alone, suggesting that this approach can generate biologically and clinically relevant insights into how pharmacological exposures can perturb or preserve microbiota composition. The application of a computational method called PARADIGM to a large dataset of cancer patients' longitudinal fecal specimens and detailed daily medication records reveals associations between drug exposures and the intestinal microbiota that recapitulate in vitro findings and are also predictive of clinical outcomes.

Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation.

PURPOSE: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. EXPERIMENTAL DESIGN: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. RESULTS: We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)-thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine-cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. CONCLUSIONS: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.

The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD.

Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.

Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation.

BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).