Abstract
BACKGROUND: Despite the growing evidence of an association between inflammatory bowel disease (IBD) and psychiatric disorders, there has been limited research exploring the underlying mediating role of blood biomarkers on the gut-brain axis. This study aimed to examine the association between IBD and the risk of incident psychiatric disorders and investigate whether and how blood biomarkers mediate this association. METHODS: This prospective cohort study using data from the UK Biobank included participants without psychiatric diagnoses at baseline. The case-cohort consisted of participants with a hospital-based diagnosis of IBD at baseline. The primary outcome was all psychiatric disorders. Secondary outcomes included 11 major psychiatric disorders. Cox regression models estimated adjusted hazard ratios (HRs) for psychiatric outcomes. Causal mediation models investigated the potential mediation effects of blood biomarkers. RESULTS: Among 491 131 participants, patients with IBD exhibited higher risks of overall psychiatric disorders (HR 1.23 [95% CI: 1.13-1.33]), substance misuse (1.23 [1.09-1.38]), depression (1.36 [1.22-1.52]), anxiety (1.15 [1.01-1.30]) and post-traumatic stress disorder (1.87 [1.00-3.51]) compared with non-IBD participants. The association with incident substance misuse was only among patients with Crohn's disease (CD, 1.47 [1.23-1.76]), but not ulcerative colitis (UC, 1.01 [0.84-1.21]). Mediation analysis revealed 16, 14, 15, and 6 biomarkers partially mediated the associations for all psychiatric disorders, substance misuse, depression, and anxiety, respectively. Six blood markers showed the strongest mediating effects: neutrophil count (proportion mediated: 12.04%), C-reactive protein (10.29%), systemic immune-inflammatory index (8.94%), erythrocyte distribution width (16.51%), erythrocyte count (9.76%), and albumin (9.15%). Moreover, several blood mediators of CD identified in association with incident substance misuse may explain the risk discrepancy between IBD subtypes. CONCLUSION: The blood biomarkers of inflammation, blood oxygen-carrying capacity, and metabolism mediate the effect of IBD on the risk of psychiatric outcomes and could be considered as a therapeutic target.