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The biological drivers, particularly the contribution of the gut microbiota and gut\u2013inner ear crosstalk, remain poorly defined. Here, we utilize germ\u2010free (GF) mice and fecal microbiota transplantation (FMT) to isolate microbiota\u2010dependent effects on ARHL progression. Through integrated metagenomic, metabolomic, and proteomic profiling, we map molecular signatures of auditory aging and uncover functional gut\u2010inner ear network, prioritizing 5\u2010hydroxytryptophan (5\u2010HTP) as a key intermediate metabolite within this\u00a0network. Furthermore, in an aging\u2010like House Ear Institute\u2013Organ of Corti 1 (HEI\u2010OC1) model, 5\u2010HTP exhibits protective effects, potentially mediated through the PI3K\/Akt\u2013antioxidant signaling axis. Collectively, this study provides a valuable multi\u2010omics resource and highlights microbiota\u2010derived metabolic regulation as a promising avenue for biomarker discovery and therapeutic development in ARHL.<\/jats:p>","DOI":"10.1002\/advs.202514269","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T12:37:21Z","timestamp":1769863041000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Gut\u2013Metabolome\u2013Proteome Interactions in Age\u2010Related Hearing Loss: Insights from Fecal Microbiota Transplantation and Multi\u2010Omics Analyses"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7835-3899","authenticated-orcid":false,"given":"Ting","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery Chongqing General Hospital Chongqing University  Chongqing 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