The DiAMonD project generated results that go beyond the current state of the art by uncovering new mechanisms through which chemotherapy drugs, particularly 5-fluorouracil (5FU), interact with and reshape bacterial communities. Previous studies had suggested that microbiome alterations could influence chemotherapy outcomes, but the underlying processes were largely unknown. Through a combination of metagenomics, strain isolation, and experimental evolution, the project revealed that 5FU can directly trigger prophage induction in bacterial genomes, leading to lytic activation and bacterial death. Crucially, these effects were demonstrated across multiple Staphylococcus species and strains, including S. epidermidis, S. hominis, and S. pasteuri, each showing distinct responses depending on their prophage complement and genetic background. Strains carrying pseudogenized or non-functional prophages did not undergo activation, highlighting the evolutionary consequences of prophage decay and mutational inactivation within staphylococcal genomes.
Beyond individual strain responses, the project demonstrated that 5FU exposure reshapes microbial community structure and interactions, driving shifts toward disbiotic configurations characterized by altered phage–bacteria dynamics and competitive imbalances. By integrating genomic and ecological perspectives, DiAMonD established a conceptual and experimental framework for understanding microbiome resilience and adaptation under drug pressure. This approach, bridging evolutionary microbiology and biomedicine, represents a significant advancement in how microbiome–drug interactions are studied and interpreted.
The potential impact of these findings extends to clinical, scientific, and societal domains. From a clinical standpoint, identifying microbial and phage factors that modulate 5FU toxicity opens opportunities for predictive diagnostics and microbiome-informed interventions to reduce adverse effects such as Hand–Foot Syndrome. Scientifically, the project contributes new data and hypotheses to the emerging field of chemotherapeutic–microbiome interactions, with implications for oncology, microbiology, and microbial ecology. On a broader level, by elucidating how microbial ecosystems respond to human-introduced chemical stressors, the project supports European priorities on health, innovation, and sustainable biomedical research. Its outcomes promote safer and more personalized therapeutic approaches while advancing our understanding of microbial adaptation in the context of human health and environmental change.
