# Gut–Metabolome–Proteome Interactions in Age‐Related Hearing Loss: Insights from Fecal Microbiota Transplantation and Multi‐Omics Analyses

## TL;DR

This study explores how gut microbes and their metabolites influence age-related hearing loss, identifying a key compound that may help develop new treatments.

## Contribution

The study identifies 5-hydroxytryptophan as a microbiota-linked metabolic hub in age-related hearing loss using multi-omics and FMT in mice.

## Key findings

- Fecal microbiota transplantation in germ-free mice reveals microbiota-dependent effects on auditory aging.
- 5-hydroxytryptophan (5-HTP) is a key intermediate metabolite in the gut-inner ear network linked to ARHL.
- 5-HTP protects against aging-like stress via the PI3K/Akt–antioxidant signaling axis in cellular models.

## 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.

Germ‐free (GF) mice receiving fecal microbiota transplantation (FMT) reveal microbiota‐dependent effects on auditory aging. Integrated metagenomic, metabolomic and proteomic profiling maps gut–inner ear network and highlights 5‐hydroxytryptophan (5‐HTP) as a microbiota‐linked metabolic hub in age‐related hearing loss (ARHL). Cellular validation shows that 5‐HTP attenuates aging‐like stress through the PI3K/Akt–antioxidant signaling axis, supporting microbiome‐based diagnostic and therapeutic strategies as promising avenues for ARHL.