Supplementary Tables.xlsx

<b>Background: </b>The gut-brain axis has been implicated in various neurological conditions, but its involvement in tinnitus remains underexplored. This study aims to prioritize brain functional connectivity (FC) traits and their underlying mechanisms linking gut microbiota, metabolic pathways to tinnitus.<b>Methods:</b> A cross-sectional study was performed in the UK Biobank (UKB) to investigate brain regions and FC changes associated with tinnitus. A two-sample Mendelian randomization (MR) analysis was then conducted to prioritize brain imaging-derived phenotypes (IDPs) linked to tinnitus risk. Additional MR analyses assessed causal relationships between gut microbiota, metabolic pathways, identified IDPs, and tinnitus. A two-step MR approach evaluated whether brain FC mediates these relationships. Putative results were validated using data from alternative cohorts.<b>Results:</b> Tinnitus patients exhibited widespread FC abnormalities across the default mode network (DMN), central executive network (CEN), and salience network (SN) compared to controls. Weaker FC in parietal, temporal, cingulate, and frontal regions (ICA25 edge 87) was causally linked to increased tinnitus risk. Additionally, <i>Actinobacteria[c] </i>and <i>Actinobacteria[p]</i>, as well as the<i> chorismate biosynthesis I</i> pathway, were found to influence both brain FC and tinnitus risk. <i>Actinobacteria[c]</i> mediated 31.0% of tinnitus risk via ICA25 edge 87 (95% CI, 8.1% to 54.0%; P = 0.008), with similar effect for <i>Actinobacteria[p]</i>. The <i>chorismate biosynthesis I </i>pathway mediated 17.2% (95% CI, 0.2% to 34.2%; P = 0.048).<b>Conclusion: </b>Our findings provided evidence to support gut microbiota influence tinnitus by modulating brain FC, highlighting the potential role of the gut-brain axis in tinnitu