Chemotherapy modulation by a cancer-associated microbiota metabolite
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.
Authors
- Bernard T. Golding (ORCID: https://orcid.org/0000-0001-6291-9344)
- Christian Frezza (ORCID: https://orcid.org/0000-0002-3293-7397)
- Susumu Hirabayashi (ORCID: https://orcid.org/0000-0002-5096-4241)
- Daniel Martínez‐Martínez (ORCID: https://orcid.org/0000-0001-8468-1357)
- Lena Best (ORCID: https://orcid.org/0000-0003-2772-153X)
- Julian Roberto Marchesi (ORCID: https://orcid.org/0000-0002-7994-5239)
- Despoina Chrysostomou (ORCID: https://orcid.org/0000-0001-8150-7142)
- Tanara V. Peres (ORCID: https://orcid.org/0000-0003-0199-8653)
- Γεώργιος Μαρίνος (ORCID: https://orcid.org/0000-0002-6443-7696)
- Filipe Cabreiro (ORCID: https://orcid.org/0000-0002-3696-4843)
- Cecilia Cabrera (ORCID: https://orcid.org/0000-0002-9941-6828)
- Timothy A. Scott (ORCID: https://orcid.org/0000-0001-7042-8609)
- Stephen J. Cutty (ORCID: https://orcid.org/0000-0002-2750-0932)
- João Benhur Mokochinski (ORCID: https://orcid.org/0000-0002-9364-0386)
- Helena M. Cochemé (ORCID: https://orcid.org/0000-0001-8637-0042)
- Susanne Brodesser (ORCID: https://orcid.org/0000-0001-5631-0663)
- Alex Montoya (ORCID: https://orcid.org/0000-0002-6501-883X)
- Holger Kramer (ORCID: https://orcid.org/0000-0002-6400-0945)
- Michalina Zatorska
- Ivan Andrew (ORCID: https://orcid.org/0000-0003-3310-9937)
- Alexis R. Barr (ORCID: https://orcid.org/0000-0002-6684-8114)
- Ayesha Safoor
- Christoph Kaleta (ORCID: https://orcid.org/0000-0001-8004-9514)
- Leonor M. Quintaneiro
- Kristin Gehling
- Maksym Cherevatenko (ORCID: https://orcid.org/0009-0003-0938-1233)
- Bian Zhang
- Masuma Begum
- Johannes Zimmerman
Institutions
- University of Cologne (DE)
- Hammersmith Hospital (GB)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- MRC London Institute of Medical Sciences (GB)
Publication Details
- Journal
- Cell Systems
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1016/j.cels.2025.101397
- Citations
- 1
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.81