ABSTRACT Age‐related hearing loss (ARHL) is a prevalent sensory disorder lacking disease‐modifying interventions. The biological drivers, particularly the contribution of the gut microbiota and gut–inner ear crosstalk, remain poorly defined. Here, we utilize germ‐free (GF) mice and fecal microbiota transplantation (FMT) to isolate microbiota‐dependent effects on ARHL progression. Through integrated metagenomic, metabolomic, and proteomic profiling, we map molecular signatures of auditory aging and uncover functional gut‐inner ear network, prioritizing 5‐hydroxytryptophan (5‐HTP) as a key intermediate metabolite within this network. Furthermore, in an aging‐like House Ear Institute–Organ of Corti 1 (HEI‐OC1) model, 5‐HTP exhibits protective effects, potentially mediated through the PI3K/Akt–antioxidant signaling axis. Collectively, this study provides a valuable multi‐omics resource and highlights microbiota‐derived metabolic regulation as a promising avenue for biomarker discovery and therapeutic development in ARHL.
Yang et al. (2026) studied this question.