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

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

Authors:	Nguyen, C. L.; Markey, K. A.; Miltiadous, O.; Dai, A.; Waters, N.; Sadeghi, K.; Fei, T.; Shouval, R.; Taylor, B. P.; Liao, C.; Slingerland, J. B.; Slingerland, A. E.; Clurman, A. G.; Maloy, M. A.; Bohannon, L.; Giardina, P. A.; Brereton, D. G.; Armijo, G. K.; Fontana, E.; Gradissimo, A.; Gyurkocza, B.; Sung, A. D.; Chao, N. J.; Devlin, S. M.; Taur, Y.; Giralt, S. A.; Perales, M. A.; Xavier, J. B.; Pamer, E. G.; Peled, J. U.; Gomes, A. L. C.; van den Brink, M. R. M.
Article Title:	High-resolution analyses of associations between medications, microbiome, and mortality in cancer patients
Abstract:	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. © 2023 Elsevier Inc.
Keywords:	adult; cancer chemotherapy; controlled study; middle aged; antibiotic agent; major clinical study; sequence analysis; nonhuman; validation process; cancer patient; methotrexate; disease association; in vitro study; retrospective study; prediction; cancer mortality; hydralazine; medical record; metoprolol; allogeneic hematopoietic stem cell transplantation; enterococcus; observational study; intestine flora; computer model; estradiol; metronidazole; cyclosporine; drug exposure; longitudinal study; thymocyte antibody; fentanyl; gabapentin; hematopoietic cell transplantation; palifermin; antibacterial activity; docusate sodium; zolpidem; clinical outcome; ursodeoxycholic acid; meropenem; microbiota; microbial diversity; hydroxyzine; famotidine; atropine plus diphenoxylate; levetiracetam; feces microflora; computational modeling; metagenomics; human; male; female; article; population abundance; macrogol 3350; cotrifamole; 16s sequencing; subspecies; temporal analysis; pharmacological exposures; microbial competition
Journal Title:	Cell
Volume:	186
Issue:	12
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2023-06-08
Start Page:	2705
End Page:	2718.e17
Language:	English
DOI:	10.1016/j.cell.2023.05.007
PROVIDER:	scopus
PUBMED:	37295406
PMCID:	PMC10390075
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85160701452&doi=10.1016%2fj.cell.2023.05.007&partnerID=40&md5=acb8f02787dcb5586569882b8949e57b
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Marcel R.M. van den Brink -- Source: Scopus