Comprehensive multi-omics analyses elucidate the mechanism of male sexual dysfunction induced by chronic prostatitis/chronic pelvic pain syndrome in the experimental autoimmune prostatitis rat model.

BACKGROUND

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), characterized by persistent pain, is significantly associated with sexual dysfunction, yet the underlying mechanisms remain poorly understood.

AIM: This study sought to elucidate the underlying central mechanisms linking autoimmune prostatitis to sexual dysfunction by employing an integrated multi-omics approach in a well-established rodent model.

METHODS

An experimental autoimmune prostatitis (EAP) model was induced by injecting a mixture of rat prostate protein and Freund's adjuvant. Comprehensive assessments were conducted, including histopathological evaluation of prostate and penile tissues via H&E and Masson's trichrome staining, quantification of serum cytokines and neurochemicals using ELISA, functional assessment of erectile capability by measuring intracavernous pressure/mean arterial pressure (ICP/MAP) ratio, and detailed mating behavior analysis. Brain tissues from rats were collected for comprehensive transcriptomic profiling and non-targeted metabolomic analyses.

OUTCOMES: Primary outcomes included brain transcriptomic and metabolomic alterations, mating behavior parameters, erectile function assessed by ICP/MAP measurement, histological changes in prostate and penile tissues, and serum inflammatory cytokine and neurochemical levels.

RESULTS

The EAP model demonstrated significant prostatic inflammation, elevated serum pro-inflammatory cytokines (TNF-α, IL-8, IL-6, IL-1β), impaired erectile function (reduced ICP/MAP ratio), increased penile fibrosis, and disturbed ejaculatory behavior with shorter ejaculation latency. Serum analyses revealed altered neurochemical levels, including reduced 5-HT and elevated norepinephrine and leptin. Transcriptomic analysis identified 557 differentially expressed genes with enrichment in cGMP-PKG, calcium, oxytocin, RAP1, and MAPK signaling pathways. Besides, metabolomic analysis detected 45 differentially abundant metabolites, including key molecules such as N-acetyl-DL-aspartic acid, aspartic acid, threonine, and the nitric oxide pathway intermediate argininosuccinic acid. Integrated pathway analysis highlighted significant alterations in neuroactive ligand-receptor interaction, GABAergic synapse, and glutathione metabolism pathways. Immunofluorescence validation confirmed substantial downregulation of GABAergic proteins (GABRA5, GAD65, VGAT) in the paraventricular nucleus. Furthermore, integrated multi-omics analysis revealed coordinated alterations between gene expression and metabolic profiles.

CLINICAL IMPLICATIONS: The identified central GABAergic dysregulation presents a promising therapeutic target for managing CP/CPPS-related sexual dysfunction.

STRENGTHS & LIMITATIONS: The novel application of integrated brain multi-omics represents a key strength, while limited translational applicability to humans remains a constraint.

CONCLUSION

Autoimmune prostatitis induces significant central genetic and metabolic alterations that contribute to sexual dysfunction, providing new mechanistic insights and potential therapeutic avenues for this challenging condition.