Exploring bidirectional causal relationships between ulcerative colitis and depression via the gut-brain axis: A Mendelian randomization study with plasma protein mediator analysis.

Ulcerative colitis (UC) and depression are highly comorbid with significant bidirectional effects, posing great challenges to clinical management of inflammatory bowel disease (IBD). Though their epidemiological associations are well-documented, the bidirectional causal nature and underlying molecular mediators remain unclear. This study combined Mendelian randomization (MR) and plasma proteomics to explore UC-depression causal interactions, identify key gut-brain axis (GBA) mediating proteins, and offer mechanistic insights and potential therapeutic targets. Bidirectional MR confirmed their significant bidirectional causal effects; a two-step MR framework was applied to screen differential mediating proteins using Icelandic cohort plasma proteomic data, identifying 108 depression-associated proteins linked to UC and 17 UC-associated proteins tied to depression. Key candidates were refined via proteomic profiles of UCD (UC with depression) and UCN (UC without depression) clinical cohorts, with validation including colonic immunohistochemistry and retrospective serum analysis. Two core UC → depression mediators were identified: Ezrin (EZR, OR = 0.96, 95% CI: 0.93-1.00, P = 0.031) and albumin (ALB, OR = 1.05, 95% CI: 1.01-1.09, P = 0.0062). Immunohistochemistry showed reduced EZR in UCD colonic mucosa vs. UCN (P < 0.05); serum analyses revealed elevated ALB in UCD (P < 0.01), positively correlated with depressive severity (Pearson's r = 0.372, P = 0.00181). This integrative approach clarifies UC-depression bidirectional causality, highlights putative protein-mediated pathways, and systematically constructs a protein-level evidence chain of potential targets for bidirectional GBA crosstalk, providing supplementary experimental evidence and novel research hypotheses to further elucidate the molecular mechanisms driving UC-depression comorbidity. EZR and ALB are candidate biomarkers for comorbidity risk stratification and potential "gut-brain cotherapy" targets.