Beyond association: Causal evidence and translational limits of phytochemical–microbiome interactions in cancer prevention

Cancer remains a leading cause of illness and death, highlighting the urgent need for safe, scalable, and affordable dietary prevention strategies. Phytochemicals in fruits, vegetables, whole grains, legumes, teas, and herbs interact with the gut microbiota through fermentation, biotransformation, and changes in microbial composition and activity. This review examines phytochemicals such as polyphenols, dietary fibers, glucosinolates, carotenoids, omega-3 fatty acids, and other metabolites, focusing on how their interactions with the gut microbiota as a dynamic, diet-responsive ecosystem may impact inflammation, immunity, genomic stability, metabolic reprogramming, angiogenesis, and cancer-related outcomes. Direct effects on host cells are distinguished from microbial conversion of dietary substrates and experimentally supported microbiome-dependent mechanisms. Particular attention is given to short-chain fatty acids and urolithins, as well as potentially harmful microbial products such as certain secondary bile acids and N-nitroso compounds, recognizing that their effects depend on exposure and biological context. Mechanistic and animal studies support selected pathways, whereas human interventions mainly demonstrate changes in microbial communities, metabolites, and host biomarkers rather than established microbiome-mediated cancer prevention. Challenges involving individual microbiome variability, food-matrix interactions, bioavailability, delivery-system stability, and safety are discussed. Plant-based dietary strategies therefore offer promising research opportunities, but their preventive applications require further validation through well-designed human studies with clinically relevant outcomes.