Comparative Analysis of Gut Microbiota in Hormone-Sensitive and Castration-Resistant Prostate Cancer in Japanese Men

The gut microbiome affects various diseases, including irritable bowel syndrome, rheumatoid arthritis, and Alzheimer's disease. It also affects prostate cancer (gut-prostate axis). Short-chain fatty acids (SCFA) derived from gut microbiome stimulate prostate cancer growth via insulin-like growth factor-1.¹ Furthermore, in a cohort of 152 Japanese patients, we identified distinctive gut microbial signatures associated with high-risk prostate cancer, including an enrichment of Rikenellaceae and Clostridiales, known SCFA producers.²

In this study, we investigated how gut microbiota changes during the progression to castration-resistant prostate cancer (CRPC) in human and Pten-deficient (Pten-KO) prostate cancer model mice. We performed 16S rRNA gene sequencing of feces and examined how the microbiota composition varied between hormone-sensitive cancer and castration-resistant cancer. Since gut microbiota composition differs significantly depending on geographic and ethnic factors, the bacteria associated with CRPC in different populations may differ. Previous studies on Caucasian patients have reported that Ruminococcus and Lactobacillus are enriched in CRPC,³ and Ruminococcus is thought to contribute to disease progression by producing androgens.⁴ In contrast, in our analysis of Japanese patients, we found a significant increase in Gemella and Lactobacillus in CRPC cases. Interestingly, our prior studies have shown that Gemella is positively correlated with serum testosterone levels in men without prostate cancer.⁵

Similarly, in our Pten-KO mouse model, we identified an increased abundance of Gemella, Lactobacillus, and Ruminococcus flavefaciens in CRPC. Our results highlight the possibility that regional and ethnic differences influence the gut microbiota composition associated with CRPC. While Ruminococcus may play a key role in CRPC progression among Caucasian populations, Gemella could have a more significant role in Japanese patients. The increase in Gemella observed in Japanese CRPC cases raises the possibility that it contributes to androgen synthesis under androgen-deprived conditions. Interestingly, Lactobacillus are known to produce SCFAs. The increase of Lactobacillus could stimulate prostate cancer progression via SCFAs in CRPC patients. The gut microbiome provides the energy sources or vitamins humans cannot produce. SCFA from the gut microbiome may have originally played a role in the growth of humans by stimulating IGF-1. Androgens are also indispensable in men. The decrease of androgen to undetectable levels would be a critical condition for humans. The gut microbiome might support men's health by increasing androgen-producing bacteria in the gut, while prostate cancer might take over this aid system.

Notably, Japanese populations exhibit unique gut microbiota profiles compared to Western cohorts, likely influenced by genetic, dietary, and environmental factors. Therefore, analyzing gut microbiota in Japanese prostate cancer patients could lead to the identification of novel, population-specific bacterial contributors to prostate cancer progression and uncover previously unrecognized mechanisms of CRPC development.

Despite accumulating evidence linking gut microbiota to prostate cancer, no microbiota-targeted therapeutic approaches for CRPC have been established worldwide. Given the emerging role of gut bacteria in androgen metabolism and immune modulation, our findings may provide a foundation for future microbiota-based interventions in CRPC management.

Written by: Saizo Fujimoto & Kazutoshi Fujita, MD, PhD, Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan

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