Abstract
Inflammatory Bowel Diseases (IBDs), including Ulcerative Colitis (UC) and Crohn's Disease (CD), are chronic gastrointestinal disorders. The gut-brain axis integrates various signals, but its impact on IBD is unclear. Using Mendelian Randomization, we evaluated causal relationships between 13 brain subregions and colon expression quantitative trait loci (eQTLs) with IBDs. Trans-omics analysis, integrating brain, CD and UC intestine single-cell RNA sequencing and genomic eQTLs, identified cellular sources of key genes. Phenome-Wide Association Studies (PheWAS) filtered phenotype associations of leading SNPs. Brain eQTLs showed meaningful associations with IBD susceptibility, with consistent patterns observed across multiple independent cohorts (IIBDGC, UKB, and FinnGen). However, correlation analysis revealed that eQTL sample sizes significantly influence the detection of significant associations (r = 0.53-0.90), indicating that direct quantitative comparisons between tissues should be interpreted cautiously. Multiple brain regions, including the cerebellum, cerebellar hemisphere, and cortex, demonstrated notable associations with IBD. Exploratory analysis identified genes CCDC88B, NAAA and NAGLU showing putative positive causal associations with IBD susceptibility in both brain and colon tissues, whereas CWC15 exhibited an inverse relationship. Stringent Bonferroni correction validated CCDC88B and NAGLU as robust candidates across multiple tissues and IBD subtypes. Single-cell RNA sequencing identified dendritic cells and epithelial cells as sources of NAAA and CWC15, respectively, enriched in inflammatory pathways. PheWAS showed leading SNPs associated with metabolic dysfunction, immune disorders, and brain imaging measures. This study demonstrates meaningful brain-gut axis involvement in IBD pathogenesis while acknowledging methodological limitations in cross-tissue comparisons. The identified candidate genes and cellular mechanisms provide new insights for understanding IBD susceptibility and potential therapeutic targets.