Rediscovering the Gut–Mito–Ear Axis: A Systems-Biology Framework for Ototoxic Vulnerability and Microbiome-Targeted Prevention

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–Mito–Ear axis in which gut ecosystem function influences circulating mediator modules that converge on two cochlear mediator nodes: blood–labyrinth 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. Framed in this way, the Gut–Mito–Ear axis is presented not as an established mechanism but as an operational, falsifiable systems-biology model that defines minimum and ideal standards for A-tier evidence, interpretable criteria for boundary-setting A− evidence, and testable predictions for causal validation.