Systemic Signatures Differentiating Varicocele‐Associated Semen Quality Heterogeneity: An Exploratory Multi‐Omics Pilot Study

BACKGROUND: Significant semen-quality heterogeneity exists among varicocele (VC) patients with similar macro-anatomical backgrounds. OBJECTIVES: This exploratory pilot study characterized and compared fecal microbial configurations and relative serum metabolomic signatures associated with individual phenotypic divergence in left-sided clinical VC. MATERIALS AND METHODS: Twenty-five young males with left-sided VC were stratified into low semen quality (VC_L, n = 17) and normal semen quality (VC_N, n = 8) groups. Multi-omics profiling was performed via fecal 16S rRNA sequencing and serum untargeted LC-MS/MS metabolomics. RESULTS: Fecal microbiota alpha and beta diversity metrics were comparable between groups. LEfSe analysis revealed taxonomic differentiation: the VC_N group showed enrichment of Fusobacteriota lineages and Faecalimonas, whereas the VC_L group showed higher discriminative abundance of the Ruminococcus gauvreauii group and UCG_003. Cross-domain integrative profiling revealed distinct modular patterns: a cluster dominated by Bacteroides and Blautia aligned positively with circulating carbohydrate-related metabolites (inositol and D-ribose), whereas potential opportunistic taxa such as Escherichia_Shigella showed inverse associations with these metabolites and positive associations with lipid-related features (palmitoylcarnitine). Serum untargeted metabolomics further showed distinct relative ion intensities: VC_L exhibited higher signals of lipid-, amino acid-, and TCA cycle-related features (oleoyl ethanolamide, palmitoylcarnitine, taurine, and L-malate), whereas VC_N showed higher intensities of arachidonic acid, citric acid, choline, and D-ribose. DISCUSSION AND CONCLUSION: Semen-quality-defined subgroups of left-sided VC patients exhibit distinct gut microbial taxonomic distributions and relative serum metabolic profiles. These preliminary, associative findings provide a descriptive multi-omics landscape of individual phenotypic heterogeneity and generate hypotheses regarding the gut-testis axis.