目标:迄今为止,目前尚不清楚环境因素如何影响克罗恩病(CD)风险以及它们如何与生物过程相互作用。这项研究调查了环境暴露与CD风险之间的关联,并评估了它们与疾病前生物标志物的关联。
方法:我们研究了来自加拿大克罗恩病和结肠炎的4,289名健康的一级亲属(FDRs)的CD患者-遗传,Environmental,微生物(CCC-GEM)项目。回归模型确定了与未来CD发病相关的环境因素及其与疾病前生物学因素的关联。包括通过乳果糖与甘露醇比率(LMR)的尿排泄分数测量的肠道通透性改变;通过粪便钙卫蛋白(FCP)水平引起的肠道炎症;以及通过16SrRNA测序的粪便微生物组组成。
结果:经过5.62年的中位随访,86FDRs开发了CD。与5-15岁的狗一起生活(HR=0.62;95%CI=0.40-0.96;P=0.034),并且在出生后第一年生活在一个大家庭中(HR=0.43;95%CI=0.21-0.85;P=.016)与降低CD风险相关;而在招募时养鸟(HR=2.78;CI=1.36-5.68;P=.005)与增加CD风险相关。此外,和狗一起生活与LMR降低有关,改变了多个细菌属的相对丰度,并增加了Chao1多样性;而鸟类所有者的FCP水平较高。参与者生命第一年的大家庭与微生物群组成改变有关,而不影响FCP或LMR。
结论:本研究确定了与CD风险相关的环境变量。这些变量也与屏障功能的改变有关,亚临床炎症,和肠道微生物组组成变化,提示在CD发病机制中的潜在作用。
OBJECTIVE: To date, it is unclear how environmental factors influence Crohn\'s disease (CD) risk and how they interact with biological processes. This study investigates the association between environmental exposures and CD risk and evaluates their association with pre-disease biomarkers.
METHODS: We studied 4289 healthy first-degree relatives (FDRs) of patients with CD from the Crohn\'s and Colitis Canada - Genetic, Environmental, Microbial (CCC-GEM) project. Regression models identified environmental factors associated with future CD onset and their association with pre-disease biological factors, including altered intestinal permeability measured by urinary fractional excretion of lactulose to mannitol ratio (LMR); gut inflammation via fecal calprotectin (FCP) levels; and fecal microbiome composition through 16S rRNA sequencing.
RESULTS: Over a 5.62-year median follow-up, 86 FDRs developed CD. Living with a dog between ages 5 and 15 (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40-0.96; P = .034), and living with a large family size in the first year of life (HR, 0.43; 95% CI, 0.21-0.85; P = .016) were associated with decreased CD risk, whereas having a bird at the time of recruitment (HR, 2.78; 95% CI, 1.36-5.68; P = .005) was associated with an increased CD risk. Furthermore, living with a dog was associated with reduced LMR, altered relative abundance of multiple bacterial genera, and increased Chao1 diversity, whereas bird owners had higher FCP levels. Large family during participants\' first year of life was associated with altered microbiota composition without affecting FCP or LMR.
CONCLUSIONS: This study identifies environmental variables associated with CD risk. These variables were also associated with altered barrier function, subclinical inflammation, and gut microbiome composition shifts, suggesting potential roles in CD pathogenesis.