SRA

Diet and microbiota affect the health of the host. A growing body of evidence shows that the diet, the microbiota, and the interaction between the two, also modulate the efficacy and toxicity of therapeutic drugs. However, a mechanistic understanding of how diet, drugs and microbiota interact in vivo to influence host health is lacking. Here, using the genetically tractable nematode C. elegans as the host and four E. coli strains as the microbiota, we unravel the mechanisms by which the diet and intraspecies variation in the microbiota define the toxicity of the chemotherapeutic agent 5’-fluorodeoxyuridine. We show that the sole supplementation of serine shifts the microbe’s response to the drug, reshapes the response pathways the host engages, and ultimately redefines the outcome of the drug-microbiota-host interaction. Thus, this study presents the first mechanistic in vivo dissection of a four-way diet-drug-microbiota-host interaction, revealing the astonishing complexity and sensitivity of microbe-host co-metabolism, and highlighting the potential as well as the challenges we face to fully exploit the therapeutic potential of the microbiota.