{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:35:13Z","timestamp":1785429313669,"version":"3.56.0"},"reference-count":89,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002583","name":"Gyeongsang National University Hospital","doi-asserted-by":"crossref","award":["GNUHBRIF\u20112024\u20110001"],"award-info":[{"award-number":["GNUHBRIF\u20112024\u20110001"]}],"id":[{"id":"10.13039\/501100002583","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002583","name":"Gyeongsang National University Hospital","doi-asserted-by":"crossref","award":["GNUHBRIF-2023-0001"],"award-info":[{"award-number":["GNUHBRIF-2023-0001"]}],"id":[{"id":"10.13039\/501100002583","id-type":"DOI","asserted-by":"crossref"}]},{"award":["GNUHBRIF\u20112024\u20110001"],"award-info":[{"award-number":["GNUHBRIF\u20112024\u20110001"]}],"id":[{"id":"https:\/\/ror.org\/00gbcc509","id-type":"ROR","asserted-by":"publisher"}]},{"award":["GNUHBRIF-2023-0001"],"award-info":[{"award-number":["GNUHBRIF-2023-0001"]}],"id":[{"id":"https:\/\/ror.org\/00gbcc509","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Ototoxicity is traditionally viewed as a local cochlear adverse effect of indispensable therapies such as cisplatin and aminoglycosides. However, emerging evidence suggests that cochlear vulnerability is shaped by systemic physiology, including inflammatory tone, vascular barrier integrity, and metabolic state. In this Review, we propose a Gut\u2013Mito\u2013Ear axis in which gut ecosystem function influences circulating mediator modules that converge on two cochlear mediator nodes: blood\u2013labyrinth barrier (BLB) gating and mitochondrial stress tolerance. We synthesize evidence showing that gut perturbation can alter cochlear outcomes in vivo, that at least one microbiota-derived metabolite signal can directly protect hearing in experimental settings, and that BLB dysfunction and inflammatory trafficking are mechanistically relevant to cisplatin- and aminoglycoside-induced injury. We further organize the literature using an evidence-weighted framework that distinguishes direct cochlear causality from mechanistic plausibility and explicitly retains negative studies as boundary-setting evidence. Finally, we outline a translational roadmap in which microbiome-targeted prevention is pursued through mediator-anchored, non-interference-aware strategies and evaluated across linked state variables spanning exposure context, gut function, defined mediator modules, BLB gating, mitochondrial stress tolerance, and auditory phenotype. The Gut\u2013Mito\u2013Ear axis is not considered an established mechanism. We present it as a falsifiable systems-biology model that organizes the current evidence. Within this model, we define the minimum and ideal standards for A-tier causal evidence, explicit criteria for interpreting boundary-setting negative (A\u2212) studies, and a set of testable predictions for causal validation.<\/jats:p>","DOI":"10.3390\/cells15090769","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T17:26:18Z","timestamp":1777051578000},"page":"769","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rediscovering the Gut\u2013Mito\u2013Ear Axis: A Systems-Biology Framework for Ototoxic Vulnerability and Microbiome-Targeted Prevention"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2110-1092","authenticated-orcid":false,"given":"Chae Dong","family":"Yim","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea"},{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52725, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7582-4990","authenticated-orcid":false,"given":"Hayeong","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea"},{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52725, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6325-0398","authenticated-orcid":false,"given":"Jung Je","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea"},{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52725, Republic of Korea"},{"name":"Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-7505","authenticated-orcid":false,"given":"Seung-Jun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Convergence Medical Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hyun","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52725, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8571-2722","authenticated-orcid":false,"given":"Young-Sool","family":"Hah","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52725, Republic of Korea"},{"name":"Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Ki","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea"},{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52725, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114045","DOI":"10.1016\/j.biopha.2022.114045","article-title":"Cisplatin-induced ototoxicity: From signaling network to therapeutic targets","volume":"157","author":"Wang","year":"2023","journal-title":"Biomed. 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