Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity.

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.