Characterising and preventing the gut microbiota’s inactivation of trifluridine, a colorectal cancer drug

The gut microbiome, home to trillions of bacteria, plays a vital role not only in digestion and immunity but also in drug metabolism, influencing how medications work in the body. In this study, we explored how gut bacteria affect trifluridine, a drug used to treat colorectal cancer. Since most gut bacteria reside in the colon, drugs reaching this area are especially vulnerable to microbial breakdown.

Using high-performance liquid chromatography and mass spectrometry, we examined how fecal microbiota from six healthy individuals metabolized trifluridine. The drug underwent multiple transformations, with metabolism levels varying significantly between samples. Notably, we identified four previously unknown microbial metabolites.

To understand these differences, we used metagenomic sequencing to analyze the bacterial composition of each sample. We found a strong correlation between the presence of Clostridium perfringens and the rate of trifluridine breakdown, with a correlation coefficient of R² = 0.8966.

To counter this, we tested uridine, a naturally occurring compound. Uridine competitively inhibited the bacterial enzymes responsible for metabolizing trifluridine and also supported gut health through its prebiotic effects.

These findings contribute to the growing field of pharmacobiomics, helping us design drug delivery strategies that consider microbiome interactions and improve treatment outcomes.

Explore the full study here.