Diet–Microbiome Relationships in Prostate-Cancer Survivors with Prior Androgen Deprivation-Therapy Exposure and Previous Exercise Intervention Enrollment

The gut microbiome is a modifiable factor in cancer survivorship. Diet represents the most practical intervention for modulating the gut microbiome. However, diet-microbiome relationships in prostate-cancer survivors remain poorly characterized. We conducted a comprehensive analysis of diet-microbiome associations in 79 prostate-cancer survivors (ages 62-81) enrolled in a randomized exercise intervention trial, 59.5% of whom still have active metastatic disease. Dietary intake was assessed using the Diet History Questionnaire (201 variables) and analyzed using three validated dietary pattern scores: Mediterranean Diet Adherence Score (MEDAS), Healthy Eating Index-2015 (HEI-2015), and the Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet score. Gut microbiome composition was characterized via 16S rRNA sequencing. Dimensionality reduction strategies, including theory-driven diet scores and data-driven machine learning (Random Forest, and Least Absolute Shrinkage and Selection Operator (LASSO)), were used. Statistical analyses included beta regression for alpha diversity, Permutational Multivariate Analysis of Variance (PERMANOVA) for beta diversity (both Bray-Curtis and Sørensen metrics), and Microbiome Multivariable Associations with Linear Models (MaAsLin2) with negative binomial regression for taxa-level associations. All models tested interactions with exercise intervention, <i>APOLIPOPROTEIN E</i> (<i>APOE</i>) genotype, and testosterone levels. There was an interaction between MEDAS and exercise type on gut alpha diversity (Shannon: <i>p</i> = 0.0022), with stronger diet-diversity associations in strength training and Tai Chi groups than flexibility controls. All three diet-quality scores predicted beta diversity (HEI <i>p</i> = 0.002; MIND <i>p</i> = 0.025; MEDAS <i>p</i> = 0.034) but not Bray-Curtis (abundance-weighted) distance, suggesting diet shapes community membership rather than relative abundances. Taxa-level analysis revealed 129 genera with diet associations or diet × host factor interactions. Among 297 dietary variables tested for cognitive outcomes, only caffeine significantly predicted Montreal Cognitive Assessment (MoCA) scores after False Discovery Rate (FDR) correction (<i>p</i> = 0.0009, <i>q</i> = 0.014) through direct pathways beneficial to cognitive performance without notable gut microbiome modulation. In cancer survivors, dietary recommendations should be tailored to exercise habits, genetic background, and hormonal status.