Dietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion

Area of Science:

• Microbiology
• Pharmacology
• Toxicology

Background:

• The gut microbiota plays a crucial role in drug metabolism, influencing efficacy and toxicity.
• Diet is known to modulate both host and microbial metabolism, but its impact on diet-microbiota-drug interactions remains underexplored.

Purpose of the Study:

• To investigate how dietary components, through microbial mechanisms, alter host responses to drugs.
• To elucidate the distinct pathways by which dietary thymidine and serine modify the toxicity of 5-fluoro-2'-deoxyuridine (FUdR).

Main Methods:

• Utilized the model organism C. elegans to study diet-microbe-drug interactions.
• Analyzed the metabolic conversion of FUdR by gut microbes under different dietary conditions (thymidine, serine).
• Assessed host toxicity, mitochondrial function, and autophagy activation in response to FUdR and dietary interventions.

Main Results:

• Dietary thymidine enhanced FUdR toxicity by promoting microbial conversion to 5-fluorouridine-5'-monophosphate (FUMP), causing mitochondrial damage and lethal autophagy.
• Dietary serine did not alter FUdR metabolism but impacted microbial 1C-metabolism, reducing host nucleotide supply and exacerbating DNA toxicity.
• Autophagy inhibition was lethal with thymidine, while it promoted survival in the serine-induced toxicity condition.

Conclusions:

• Diet-microbe interactions can significantly alter host drug responses independently of changes to the drug or host genetics.
• Dietary thymidine and serine exert distinct, microbe-mediated mechanisms to modulate FUdR toxicity, highlighting the complexity of nutritional influences on pharmacology.
• These findings underscore the importance of considering diet and the gut microbiome in drug efficacy and toxicity assessments.