# Metabolism of cancer chemotherapeutics by the human gut microbiome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $573,622

## Abstract

PROJECT SUMMARY
Rigorous data from our lab and others indicate that the gut microbiome may an underappreciated contributor to
inter-individual variations in cancer drug efficacy and side effect profiles; however, we currently lack the
mechanistic insights and data from preclinical mouse models necessary to inform ongoing studies in cancer
patients. We selected fluoropyrimidines, including 5-fluorouracil (5-FU) and its prodrug capecitabine (CAP), as
an initial test case due to their critical role in colorectal cancer (CRC) therapy, increasing oral administration,
highly variable pharmacokinetics, and unexplained differences in efficacy and toxicity. We propose a series of
in vitro and mouse studies to dissect the human gut bacterial species, genes, and enzymes responsible for the
metabolism of 5-FU (Aim 1) and CAP (Aim 2), including their downstream consequences for drug
pharmacokinetics (PK) and pharmacodynamics (PD).
Our overarching hypothesis is that the oral bioavailability and therapeutic effects of fluoropyrimidines
are influenced by pathways for drug metabolism encoded by diverse human gut bacterial species.
In Aim 1, we will identify and characterize the primary gut bacterial taxon responsible for 5-FU inactivation
through a combination of biochemical and cell-based assays coupled to studies in gnotobiotic and xenograft
mouse models. Based on our Preliminary Results, we hypothesize that Anaerostipes is the primary gut
bacterial genus responsible for inter-individual variations in the metabolism of 5-FU.
In Aim 2, we seek to discover the bacterial enzymes responsible for the activation of CAP to 5-FU, motivated
by the surprising finding that E. coli can activate CAP leading to reduced bacterial growth at high
concentrations. We hypothesize that E. coli catalyzes a 3-step metabolic pathway that mirrors the mammalian
conversion of CAP to 5-FU.
Our results in Aim 1 will provide a valuable proof-of-principle for dissecting the conservation and redundancies
in clinically relevant microbial biotransformations, helping to move beyond studies of model gut bacteria to
identify the most translationally relevant species. Aim 2 is potentially paradigm-shifting in that it would provide
definitive evidence for CAP bioactivation outside of hepatocytes and cancer cells, creating new opportunities to
improve treatment outcomes and study the physiological role and broader impacts of this metabolic pathway.
Taken together, this research plan emphasizes the conservation of the pathways for metabolism of
therapeutics across domains of life, highlighting the need to distinguish the relative contributions of human and
microbial cells to drug disposition, efficacy, and side effect profiles. Due to our focus on drugs used as current
standard of care and naturally occurring bacterial species prevalent in the human gut microbiome, this
preclinical research program has clear translational relevance and is highly synergistic with ongoing clinical
studies of cancer pati...

## Key facts

- **NIH application ID:** 10881876
- **Project number:** 5R01CA255116-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Peter James Turnbaugh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $573,622
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881876

## Citation

> US National Institutes of Health, RePORTER application 10881876, Metabolism of cancer chemotherapeutics by the human gut microbiome (5R01CA255116-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10881876. Licensed CC0.

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