PARADIGM Identifies Associations between Drugs, the Microbiome, and Mortality

Environmental factors, including antibiotic use, have been associated with changes to the gut microbiota, but these effects are difficult to discern in patients with cancer. Nguyen and colleagues sought to investigate the relationship between medications, microbiome composition, and clinical outcomes from serially collected fecal samples obtained from patients who had undergone allogeneic hematopoietic cell transplantation (allo-HCT) through the use of the newly developed PARADIGM computational method. Results showed that several nonantibiotic drugs, including laxatives, antiemetics, and opioids, are associated with microbiome perturbations, including an induction in the relative abundance of potentially pathogenic Enterococcus as well as overall reduced alpha diversity, with these results from real-world patient data being confirmed against published in vitro observations. Dominant-strain convergence was observed, which supports a reduction in species variability and the rise of a dominant subtype, and antibiotic exposure was demonstrated as a significant predictor of dominant-strain genetic convergence within the species Enterococcus faecium. Conversely, this process did not occur with nonantibiotic exposure, suggesting antibiotic exposure is a strong predictor of subspecies dynamics. Investigation into if drug exposure–micro­biome associations could predict clinical outcome was conducted in two independent cohorts by defining patient-specific response scores as metrics that quantify the net response of microbiome features to drug exposure profiles. This revealed an enhanced risk of all-cause and transplant-related mortality following allo-HCT in patients whose drug exposure profiles predicted higher Enterococcus expansion, while those drug exposure profiles that predicted preservation of alpha diversity had a reduced risk of mortality, indicating that the association between drug exposures and clinical outcome is, in part, dependent on drug interactions with the gut microbiota. In summary, this study demonstrates that the computational method PARADIGM can be used to evaluate the associations between drug exposure and intestinal microbiome dynamics. Together, these results indicate a relationship between nonantibiotic drugs and microbial dynamics in patients following allo-HCT that can be used to predict future microbial changes as well as clinical outcomes in patients.

Nguyen CL, Markey KA, Miltiadous O, Dai A, Waters N, Sadeghi K, et al. High-resolution analyses of associations between medications, microbiome, and mortality in cancer patients. Cell 2023;186:2705–18.e17.

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