Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent genitourinary disease that has gradually become recognized as a potential autoimmune disease. Our previous research revealed that a high-glucose diet exacerbated experimental autoimmune prostatitis (EAP), a widely used animal model of CP/CPPS. However, its effects on the metabolism of EAP mice remain unknown. Here, we applied non-targeted metabolomics analysis of feces and enzyme-linked immunosorbent assays to identify differential metabolites in EAP mice with and without high-glucose feeding. Metabolomics analysis demonstrated significant enrichment of the vitamin digestion and absorption pathway. Glucose-fed EAP mice exhibited increased fecal excretion and reduced absorption of 1,25-dihydroxyvitamin D3 (DHVD3) into the bloodstream, accompanied by decreased expression of the vitamin D receptor (VDR) in prostate tissue. In vitro experiments, proteomic sequencing, western blot, and flow cytometry analyses demonstrated that DHVD3 suppressed T helper 17 (Th17) cell differentiation by activating the VDR/extracellular signal-regulated kinase (ERK) pathway. DHVD3 supplementation ameliorated Th17 responses and EAP severity in glucose-fed mice, whereas the administration of the VDR antagonist MeTC7 reversed these effects. We concluded that high-glucose feeding aggravates EAP through DHVD3/VDR/ERK axis-mediated Th17 differentiation. VD3 supplementation may benefit CP/CPPS patients consuming a high-sugar diet.

Keywords: chronic prostatitis/chronic pelvic pain syndrome; experimental autoimmune prostatitis; high glucose; Th17; vitamin D3