Chemotherapy modulation by a cancer-associated microbiota metabolite
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Understanding how the microbiota produces regulatory metabolites is of significance for cancer and cancer therapy. Using a host-microbe-drug-nutrient 4-way screening approach, we evaluated the role of nutrition at the molecular level in the context of 5-fluorouracil toxicity. Notably, our screens identified the metabolite 2-methylisocitrate, which was found to be produced and enriched in human tumor-associated microbiota. 2-methylisocitrate exhibits anti-proliferative properties across genetically and tissue-diverse cancer cell lines, three-dimensional (3D) spheroids, and an in vivo Drosophila gut tumor model, where it reduced tumor dissemination and increased survival. Chemical landscape interaction screens identified drug-metabolite signatures and highlighted the synergy between 5-fluorouracil and 2-methylisocitrate. Multi-omic analyses revealed that 2-methylisocitrate acts via multiple cellular pathways linking metabolism and DNA damage to regulate chemotherapy. Finally, we converted 2-methylisocitrate into its trimethyl ester, thereby enhancing its potency. This work highlights the great impact of microbiome-derived metabolites on tumor proliferation and their potential as promising co-adjuvants for cancer treatment.
Date Issued
2025-09-17
Date Acceptance
2025-08-18
Citation
Cell Systems, 2025, 16 (9)
ISSN
2405-4720
Publisher
Elsevier (Cell Press)
Journal / Book Title
Cell Systems
Volume
16
Issue
9
Copyright Statement
© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40934913
Subjects
Animals
Antineoplastic Agents
Cell Line, Tumor
Cell Proliferation
Fluorouracil
Gastrointestinal Microbiome
Humans
Microbiota
Neoplasms
cancer metabolism
cancer-associated microbiota
chemotherapy
host-microbe interactions
methylcitrate cycle
microbial metabolism
Publication Status
Published
Coverage Spatial
United States
Article Number
101397
Date Publish Online
2025-09-10