Exercise, APOE Genotype, and Testosterone Modulate Gut Microbiome-Cognition Associations in Prostate Cancer Survivors

Background: Men treated with androgen deprivation therapy (ADT) for prostate cancer are at risk for cognitive decline. Patient genetics and endocrine state may shape gut microbiome features that relate to cognition. Methods: We studied a subsample of 79 prostate cancer survivors with prior ADT exposure previously enrolled in a randomized controlled exercise trial comparing three training modalities (strength training, Tai Chi training, or stretching control) who completed an additional food-frequency questionnaire and remote Montreal Cognitive Assessment (MoCA) and provided saliva and stool for APOE genotyping, salivary testosterone, and 16S rRNA sequencing. We used beta regression for MoCA (scaled 0-1), linear models for testosterone, alpha diversity regressions, PERMANOVA for beta diversity, and DESeq2 for genus-level differential abundance, with false-discovery correction. Results: Compared to post-stretching control, post-strength training testing was associated with higher MoCA scores whereas post-Tai Chi testing was not. APOE epsilon4 carriers exhibited a greater testosterone increase with strength training than non-carriers. Testosterone, and its interactions with exercise modality and APOE epsilon4 status, was related to presence/absence-based community structure; APOE epsilon4 interacted with exercise intervention to influence alpha diversity. At the genus level, exercise was linked to lower levels of Bacteroidota taxa (including Muribaculaceae) and higher levels of Enterobacteriaceae; APOE epsilon4 status was linked to higher Megamonas and lower Rikenellaceae RC9 levels; and higher salivary testosterone levels were linked to higher Prevotellaceae taxa and Succinivibrio levels. Higher MoCA scores were associated with lower abundances of several Firmicutes genera. Conclusions: Endocrine state and APOE genotype may condition the gut microbiome's response to exercise intervention in ADT-treated prostate cancer survivors, with downstream associations with cognition. These findings could inform precision survivorship strategies pairing strength training with genotype- and hormone-informed microbiome monitoring to optimize cognitive performance.

研究背景：因前列腺癌接受雄激素剥夺治疗（androgen deprivation therapy, ADT）的男性患者存在认知衰退风险。患者的遗传学特征与内分泌状态或可塑造与认知功能相关的肠道微生物组特征。
研究方法：本研究纳入79名既往接受过ADT治疗的前列腺癌幸存者亚队列，这些受试者此前已参与一项比较三种训练模式（抗阻训练、太极训练与拉伸对照）的随机对照运动试验，且额外完成了食物频率问卷、远程蒙特利尔认知评估（Montreal Cognitive Assessment, MoCA），并提供唾液与粪便样本，用于APOE基因分型、唾液睾酮检测及16S rRNA测序。本研究针对标准化至0~1区间的MoCA评分采用β回归分析，针对睾酮水平采用线性模型分析，针对α多样性进行回归分析，针对β多样性采用置换多元方差分析（PERMANOVA），针对属水平差异丰度采用DESeq2分析，并进行错误发现率校正。
研究结果：与拉伸对照组干预后相比，抗阻训练干预后的MoCA评分显著更高，而太极训练干预后未出现此差异。APOE ε4携带者在接受抗阻训练后，睾酮水平的提升幅度显著高于非携带者。睾酮水平及其与运动模式、APOE ε4状态的交互作用与菌群群落的存在-缺失结构相关；APOE ε4状态与运动干预共同影响肠道菌群的α多样性。在属水平上，运动干预与拟杆菌门（Bacteroidota）类群（包括Muribaculaceae）丰度降低相关，同时与肠杆菌科（Enterobacteriaceae）丰度升高相关；APOE ε4状态与巨单胞菌属（Megamonas）丰度升高、理研菌科RC9群（Rikenellaceae RC9）丰度降低相关；唾液睾酮水平升高则与普雷沃氏菌科（Prevotellaceae）类群及琥珀酸弧菌属（Succinivibrio）丰度升高相关。较高的MoCA评分与多种厚壁菌门（Firmicutes）属类群的丰度降低存在关联。
研究结论：内分泌状态与APOE基因型或可调控接受ADT治疗的前列腺癌幸存者的肠道微生物组对运动干预的应答反应，并与认知功能存在下游关联。本研究结果可为精准生存策略提供参考，即联合抗阻训练与基于基因型及激素水平的微生物组监测，以优化认知表现。