Luo Chenyu, Tian Bowen, Zhou Yueyang, Luo Jiahui, Shang Qing, Yu Si, Dai Min, Li Yue, Chen Hongda
Center for Prevention and Early Intervention, National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China.
Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Mediators Inflamm. 2025 Mar 8;2025:4967641. doi: 10.1155/mi/4967641. eCollection 2025.
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. 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. 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 , and decreased and , which in turn affected CRP, neutrophils, and lymphocytes. Notably, IBD decreased the abundance of after Bonferroni correction ( = -9.463, =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. IBD alters the microbial abundance of , , and , 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.
炎症性肠病（IBD）患者患结直肠癌（CRC）的风险升高，但其病因尚不清楚。本研究旨在阐明IBD、肠道微生物群（GM）、炎症生物标志物和CRC风险之间的相互作用。首先，我们采用队列分析，利用英国生物银行（UKB）、连锁不平衡评分回归（LDSC）和孟德尔随机化（MR）分析来研究IBD与CRC之间的关联。其次，使用中介分析评估炎症生物标志物的间接效应。第三，利用MR评估IBD对GM以及GM对炎症生物标志物的因果效应。最后，我们构建了一个疾病严重程度生物标志物评分，并评估其CRC风险分层性能。在441,321名参与者中，IBD与CRC风险增加1.78倍（95%置信区间（CI）：1.45 - 2.18）相关。虽然LDSC和MR分析显示IBD与CRC之间无遗传相关性，但中介分析表明，C反应蛋白（CRP）和中性粒细胞与淋巴细胞比值（NLR）分别显著介导了IBD - CRC关联的10.41%和9.97%。IBD增加了 的GM丰度，降低了 和 的GM丰度，这反过来又影响了CRP、中性粒细胞和淋巴细胞。值得注意的是，经Bonferroni校正后，IBD降低了 的丰度（ = -9.463， = 0.0002）。构建了一个由CRP、血小板、血小板与淋巴细胞比值（PLR）、NLR、血红蛋白（Hgb）和白蛋白组成的疾病严重程度生物标志物评分。得分最高的IBD患者患CRC的风险是得分最低者的3.07倍（95% CI：1.35 - 7.00）。IBD改变了 、 和 的微生物丰度，从而影响包括CRP、中性粒细胞和淋巴细胞在内的炎症生物标志物，这些生物标志物介导了IBD患者CRC风险的增加。构建的生物标志物评分能够对IBD患者进行个体化的CRC风险分层。
