Multi-omics and mendelian randomization uncover microbial-metabolite-gene interactions in age-related hearing loss

Age-related hearing loss (ARHL), as one of the most common sensory impairments among the elderly, has a complex etiology and lacks effective targeted intervention strategies. Through integrated multiomics analysis, we identified 38 ARHL core-associated candidate genes that are predominantly enriched in pathways such as NF-κB signaling, antigen presentation, and oxidative phosphorylation. These findings suggest potential metabolic dysregulation and features consistent with "inflammatory aging" in the cochlea. Mendelian randomization analysis further highlighted UROS, C1QB, and GLIPR1 as potential biomarkers with high predictive value (AUC 0.948–0.970) within our dataset. Analysis of immune infiltration revealed a positive association between GLIPR1 and Th2 and neutrophil expression. Through correlation analysis and GutMgene database screening, we observed that FPR2 and GLIPR1 are significantly co-expressed. Molecular docking and molecular dynamics simulations further suggested that FPR2 can bind to taurodeoxycholic acid with high stability. Based on these findings, we hypothesize the existence of a "Roseburia–FPR2–taurodeoxycholic acid" regulatory network that may contribute to ARHL. This speculative model provides a novel framework for future investigations into the potential role of the gut–inner ear axis in ARHL.