Circulating microbial metabolites and the gut–prostate axis in prostate cancer: Implications for laboratory biomarkers and therapeutic response

Prostate cancer progression and treatment response are influenced not only by tumor genomics and androgen receptor signaling but also by systemic host–microbiome interactions along the gut–prostate axis. Increasing evidence indicates that gut microbial metabolism produces bioactive compounds that circulate in human body fluids and can influence immune regulation, hormone metabolism, and therapeutic outcomes. This review synthesizes current evidence on microbiome-derived metabolites that may serve as measurable biomarkers relevant to prostate cancer biology and clinical laboratory diagnostics. Microbial metabolism of dietary substrates generates circulating molecules—including short-chain fatty acids, secondary bile acids, indole derivatives, polyamines, and endotoxin-associated signals—that can modulate inflammation, epithelial barrier integrity, and systemic immune responses involved in tumor progression. In addition, intestinal microbes participate in steroid transformation and enterohepatic cycling of hormones, potentially influencing circulating androgen and estrogen levels that contribute to androgen-driven prostate cancer development and adaptation under androgen deprivation therapy. Importantly, many of these microbial metabolites are detectable in serum or plasma using validated analytical platforms such as liquid chromatography–mass spectrometry and gas chromatography–mass spectrometry, supporting their potential integration into laboratory biomarker panels. Emerging multi-omics approaches combining metagenomics, metabolomics, host transcriptomics, and immune profiling are beginning to clarify mechanistic links between microbial activity and therapy response, including variability in outcomes with androgen-targeted agents, chemotherapy, radiotherapy, and immune checkpoint inhibitors. From a clinical chemistry perspective, characterization of circulating microbiome-derived metabolites may enhance the diagnostic and prognostic performance of established biomarkers such as prostate-specific antigen while providing new opportunities for non-invasive monitoring of disease progression and treatment response. Establishing reproducible microbial metabolic signatures across diverse patient populations will be essential to translate microbiome-informed biomarkers into next-generation diagnostic and prognostic tools in prostate cancer management.