Diet-Microbiome Relationships in Prostate Cancer Survivors with Prior Androgen Deprivation Therapy Exposure and Previously Enrolled in Exercise Intervention

(1) Background: 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. (2) Methods: We conducted a comprehensive analysis of diet-microbiome associations in 79 prostate cancer survivors (ages 62-81) enrolled in a randomized exercise intervention trial. 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, LASSO), were used. Statistical analyses included beta regression for alpha diversity, PERMANOVA for beta diversity (both Bray-Curtis and Sørensen metrics), and MaAsLin2 with negative binomial regression for taxa-level associations. All models tested interactions with exercise intervention, APOE genotype, and testosterone levels; (3) Results: There was an interaction between MEDAS and exercise type on gut alpha diversity (Shannon: p = 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 p = 0.002; MIND p = 0.025; MEDAS p = 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 MoCA scores after FDR correction (p = 0.0009, q = 0.014) through direct pathways rather than gut microbiome modulation; (4) Conclusions: In cancer survivors, dietary recommendations should be tailored to exercise habits, genetic background, and hormonal status.