دورية أكاديمية
Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity.
| العنوان: | Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity. |
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| المؤلفون: | Trepka KR; Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA., Kidder WA; Department of Medicine, Division of Hematology and Oncology, University of California San Francisco; San Francisco, USA.; UCSF Helen Diller Family Comprehensive Cancer Center; San Francisco, USA., Kyaw TS; Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA., Olson CA; Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA., Upadhyay V; Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA., Noecker C; Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA., Stanfield D; UCSF Helen Diller Family Comprehensive Cancer Center; San Francisco, USA., Steiding P; UCSF Helen Diller Family Comprehensive Cancer Center; San Francisco, USA., Spanogiannopoulos P; Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA., Dumlao D; Department of Gastroenterology, University of California San Francisco; San Francisco, USA., Turnbaugh JA; Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA., Stachler MD; Department of Pathology, University of California San Francisco; San Francisco, USA., Van Blarigan EL; UCSF Helen Diller Family Comprehensive Cancer Center; San Francisco, USA.; Department of Epidemiology and Biostatistics, University of California San Francisco; San Francisco, USA.; Department of Urology, University of California San Francisco; San Francisco, USA., Venook AP; Department of Medicine, Division of Hematology and Oncology, University of California San Francisco; San Francisco, USA.; UCSF Helen Diller Family Comprehensive Cancer Center; San Francisco, USA., Atreya CE; Department of Medicine, Division of Hematology and Oncology, University of California San Francisco; San Francisco, USA.; UCSF Helen Diller Family Comprehensive Cancer Center; San Francisco, USA., Turnbaugh PJ; Department of Microbiology and Immunology, University of California San Francisco; San Francisco, USA.; Chan Zuckerberg Biohub-San Francisco; San Francisco, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 06. Date of Electronic Publication: 2024 Jun 06. |
| نوع المنشور: | Journal Article; Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. 16S rRNA gene and metagenomic sequencing revealed significant shifts in gut microbial community structure during treatment with oral fluoropyrimidines, which was validated in an independent cohort. Gene abundance was also markedly changed by oral fluoropyrimidines, including an enrichment for the preTA operon, which is sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). Higher levels of preTA led to increased 5-FU depletion by the gut microbiota grown ex vivo . Germ-free and antibiotic-treated mice had increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA + E. coli , or CRC patient stool with high preTA levels. preTA abundance was negatively associated with patient toxicities. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach is generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease. Competing Interests: W.A.K. has received research funding (institution) from Pfizer; there is no direct overlap with the current study. P.J.T. is on the scientific advisory boards of Pendulum, Seed and SNIPRbiome; there is no direct overlap between the current study and these consulting duties. C.E.A served on the scientific advisory board of Pionyr Immunotherapeutics and has received research funding (institution) from Bristol Meyer Squibb, Erasca, Gossamer Bio, Guardant Health, Kura Oncology, Merck and Novartis; there is no direct overlap with the current study. E.V.B. is on the medical advisory board for Fight CRC; there is no direct overlap with the current study.All other authors declare no competing interests. |
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| معلومات مُعتمدة: | F30 CA257378 United States CA NCI NIH HHS; R01 CA255116 United States CA NCI NIH HHS; R01 HL122593 United States HL NHLBI NIH HHS |
| تواريخ الأحداث: | Date Created: 20240619 Latest Revision: 20240624 |
| رمز التحديث: | 20240624 |
| مُعرف محوري في PubMed: | PMC11185696 |
| DOI: | 10.1101/2024.06.04.597471 |
| PMID: | 38895199 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.06.04.597471 |
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