Abstract
Background: Patients with inflammatory bowel disease (IBD) have an elevated colorectal cancer (CRC) risk, though the etiology remains unclear. This study aimed to elucidate the interplay among IBD, gut microbiota (GM), inflammatory biomarkers, and CRC risk. Methods: First, we employed cohort analysis using the UK Biobank (UKB), linkage disequilibrium score regression (LDSC), and Mendelian randomization (MR) analyses to investigate the association between IBD and CRC. Second, inflammatory biomarkers' indirect effect was assessed using mediation analysis. Third, the causal effects of IBD on GM and GM on inflammatory biomarkers were evaluated using MR. Finally, we constructed a disease severity biomarker score and evaluated its CRC risk stratification performance. Results: Among 441,321 participants, IBD was associated with a 1.78-fold (95% confidence interval (CI): 1.45-2.18) increased risk of CRC. While LDSC and MR analyses showed no genetic correlation between IBD and CRC, mediation analyses revealed that C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) significantly mediated 10.41% and 9.97% of the IBD-CRC association, respectively. IBD increased the GM abundance of Rikenellaceae RC9 gut group, and decreased Lactobacillaceae and Ruminococcus 2, which in turn affected CRP, neutrophils, and lymphocytes. Notably, IBD decreased the abundance of Ruminococcus 2 after Bonferroni correction (β = -9.463, p=0.0002). A disease severity biomarker score comprising of CRP, platelets, platelet-to-lymphocyte ratio (PLR), NLR, hemoglobin (Hgb), and albumin was constructed. IBD patients with the highest scores had a 3.07-fold (95% CI: 1.35-7.00) higher CRC risk compared to those with the lowest scores. Conclusions: IBD alters the microbial abundance of Rikenellaceae RC9 gut group, Lactobacillaceae, and Ruminococcus 2, thereby, influencing inflammatory biomarkers including CRP, neutrophils, and lymphocytes, which mediate the increased risk of CRC in IBD patients. The constructed biomarker score enables individualized CRC risk stratification in IBD patients.