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.