The hidden gut-brain connection in tinnitus: Insight from a cross-sectional and genetic causal mediation study in over 900,000 individuals.

The gut-brain axis has been implicated in various neurological conditions, but its involvement in tinnitus remains unclear. In this study, we investigated whether brain functional connectivity (FC) mediates the relationship between gut microbiota and tinnitus. Using data from the UK Biobank, we identified FC alterations in tinnitus patients, particularly reduced connectivity across the default mode, salience, and central executive networks. Mendelian randomization (MR) analyses revealed that decreased FC in the parietal, temporal, cingulate, and frontal regions (ICA25 edge 87) was causally linked to increased tinnitus risk. Further MR analyses showed that higher abundance of Actinobacteria was associated with reduced FC and increased tinnitus risk, while the chorismate biosynthesis I pathway enhanced FC and reduced tinnitus risk. Mediation analysis confirmed that brain FC partially mediated the effects of both microbial features on tinnitus, with mediation proportions of 31.0% and 17.2%, respectively. Findings were replicated in independent datasets. To enhance transparency and accessibility, we developed an interactive web tool to visualize key associations (https://sysu.nixang.com). Our results provide novel evidence that gut microbiota may contribute to tinnitus via alterations in brain network connectivity, suggesting the gut-brain axis as a potential therapeutic target.