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Certain bacterial species in colorectal cancer can resist the toxicity of 5-fluorouracil and reduce drug efficacy

Colorectal cancer (CRC) cells have intimate associations with the bacterial microbiota. Bacterial members of the intratumoral microbiota exhibit metabolic activity in CRC and, together with malignant cells, interact with the chemotherapeutic agents. In this study, the authors from the United States investigated the complex interactions between CRC microbiota and the chemotherapeutic agents. 

A growing body of evidence demonstrated that the composition of the microbiota plays a significant role (both directly and indirectly) in the chemotherapeutic efficacy of numerous drugs in a wide variety of cancers. Fusobacterium nucleatum (Fn) is a dominant bacterial species found in CRC tissue. Numerous studies have demonstrated that Fn is associated with cancer recurrence and outcomes, contributing to tumorigenesis, accelerated cancer cell growth, resistance to chemotherapy, disease recurrence, metastasis, and reduced survival. Post-chemotherapeutic studies revealed the persistence of Fn in distant CRC metastases. Furthermore, a high load of Fn in primary CRC tissue positively correlated with a higher risk of disease recurrence.

The same research group has demonstrated before that treatment of Fn-positive human CRC xenografts with the antibiotic metronidazole in mice significantly reduced tumor growth and cancer cell proliferation. This shows that Fn targeting may be a therapeutic option for a subset of patients with CRC. 





About the study

The researchers screened a random selection of 1,846 small molecules from the Broad Institute’s “Bioactive Compound” library. They identified 34 compounds that inhibit Fn growth, and approximately half (56%) are well-known antimicrobial compounds. However, 15% of inhibitors are classified as antineoplastic agents that act upon thymidylate synthase, estrogen receptors, or topoisomerase II.

The scientists then monitored Fn growth in the presence of 24 chemotherapeutic agents using eight-point dose-response curves ranging from 0.23 to 30 μM. The mainstay CRC chemotherapeutic drug tegafur and its active metabolite, 5-fluorouracil (5-FU), have been identified as potent inhibitors of Fn CRC strain growth. Capecitabine, another prodrug of 5-FU, did not affect Fn growth in vitro under these conditions. The authors speculated that the difference in inhibition of Fn growth in vitro between 5-FU prodrugs might be due to different enzymatic pathways required for prodrug activation.

The authors then investigated the sensitivity of CRC Fn clinical isolates to 5-FU. They evaluated the half-maximal inhibitory concentration (IC50) of 5-FU in 14 strains of Fn from CRC tumor tissue (n= 11), the oral cavity (n= 2), and inflamed irritable bowel disease tissue (n= 1). The results showed that 5-FU exhibited potent growth inhibition properties on CRC Fn isolates.

In addition, the 5-FU toxicity was evaluated towards other dominant CRC-associated bacterial species that frequently co-occur with Fn. The members of the intratumoral microbiota, Escherichia coli, Bacteroides fragilis, Bifidobacterium breve, and Parvimonas micra were resistant to physiologically relevant concentrations of 5-FU (2.5–10μM). According to the authors, these strains might have mechanisms capable of detoxifying 5-FU. To investigate this possibility, they inoculated Escherichia coli and Fna, the most prevalent subspecies found in CRC, together with 5-FU. Importantly, this resulted in the protection of Fna from 5-FU toxicity, with a viability of 74% after 48 hours.

Original illustration from the article by LaCourse KD. Cell Reports 2022.


To assess whether E.coli can alter the chemotherapeutic efficacy of 5-FU towards CRC cells, researchers cultured a human CRC epithelial cell line sensitive to 5-FU with 5-FU previously exposed to E.coli and monitored cell growth over 72 h. Remarkably, prior exposure of 5-FU to E.coli completely abrogated 5-FU toxicity against human CRC epithelial cells. These results show that 5-FU depletion mediated by bacteria reduced drug efficacy against human CRC tumor epithelial cells.

Since certain members of the microbiota can detoxify 5-FU, scientists then examined whether exposure to 5-FU facilitates the expansion of 5-FU-resistant bacterial species and impacts the structure of CRC microbiota. Metagenomic analyses of treatment-naive CRC tissue from six patients showed that 5-FU exposure altered the relative abundance of community members and allowed the expansion of 5-FU-resistant bacterial species. These findings demonstrate that some bacterial community members can resist 5-FU toxicity and potentially decrease drug bioavailability, thereby protecting both CRC tumor cells and sensitive bacterial strains. However, other bacterial species, in addition to Fn, may also be sensitive to 5-FU.



The findings revealed that bacterial community members seem to fit into three distinct categories concerning a first-line CRC chemotherapeutic agent, 5-FU: highly sensitive, resistant, and resistant and depleting. These findings support the hypothesis that in some patients with CRC, certain bacterial species are capable of metabolizing and detoxifying 5-FU. The reduced efficacy of 5-FU would protect tumor-supporting bacteria such as Fn and resident cancer cells from the drug’s toxicity, and promote CRC recurrence.

The authors emphasized a need for clinical studies about the co-occurrence of intratumoral Fn and microbiota, like E. coli, that modify 5-FU


This article was published in Cell Reports.


Journal Reference

LaCourse KD, Zepeda-Rivera M, Kempchinsky AG et al. The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota. Cell Reports 2022; 41, 111625



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