Drug-microbiome interactions: What we know and why predictive translation remains elusive

Medication-induced alterations of the gut microbiome influence drug efficacy, toxicity, and long-term outcomes. Despite extensive evidence for drug-microbe interactions, predictive translation into clinical practice remains limited. Generalization from shifts in taxonomic profiles, mechanistic studies or isolated enzymatic assays is challenging because microbial activity is highly context-dependent. Drug-microbiome interactions are shaped by host factors including pH, transit time, nutrient and cofactor availability, and spatial organization along the gastrointestinal tract. Here, we argue that predictive translation requires measuring functional outputs, site-specific activity, ecological interactions, and host-contextual modulation, rather than static microbial properties.