Background Inflammation and metabolic dysregulation are associated with increased risk of colorectal cancer (CRC); the underlying mechanisms are not fully understood. We characterized metabolomic signatures of inflammation and metabolic dysregulation and evaluated the association of the signatures and individual metabolites with CRC risk. Methods Among 684 incident CRC cases and 684 age-matched controls in the Nurses’ Health Study (n = 818 women) and Health Professionals Follow-up Study (n = 550 men), we applied reduced rank and elastic net regression to 277 metabolites for markers of inflammation (CRP, IL6, TNFRSF1B, and GDF15) or metabolic dysregulation (body mass index, waist circumference, C-peptide, and adiponectin) to derive metabolomic signatures. We evaluated the association of the signatures and individual metabolites with CRC using multivariable conditional logistic regression. All statistical tests were 2-sided. Results We derived a signature of 100 metabolites that explained 24% of variation in markers of inflammation and a signature of 73 metabolites that explained 27% of variation in markers of metabolic dysregulation. Among men, both signatures were associated with CRC (odds ratio per 1-standard deviation increase, inflammation = 1.34, 95% confidence interval 1.07 to 1.68; metabolic dysregulation = 1.25, 1.00 to 1.55); neither signature was associated with CRC in women. Eleven metabolites were individually associated with CRC and biomarkers of inflammation or metabolic dysregulation among either men or women. Conclusion We derived metabolomic signatures and identified individual metabolites associated with inflammation, metabolic dysregulation, and CRC, highlighting several metabolites as promising candidates involved in the inflammatory and metabolic dysregulation pathways for CRC incidence.

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与结直肠癌风险相关的炎症和代谢失调的代谢组学特征

背景炎症和代谢失调与结直肠癌 (CRC) 风险增加相关；其根本机制尚不完全清楚。我们表征了炎症和代谢失调的代谢组学特征，并评估了这些特征和个体代谢物与 CRC 风险的关联。方法 在护士健康研究（n = 818 名女性）和卫生专业人员随访研究（n = 550 名男性）中的 684 例 CRC 病例和 684 例年龄匹配对照中，我们对 277 种代谢物应用降序排序和弹性网络回归炎症标志物（CRP、IL6、TNFRSF1B 和 GDF15）或代谢失调（体重指数、腰围、C 肽和脂联素）以获得代谢组学特征。我们使用多变量条件逻辑回归评估了特征和个体代谢物与 CRC 的关联。所有统计检验都是双面的。结果 我们得出了 100 种代谢物的特征，解释了炎症标志物中 24% 的变异，以及 73 种代谢物的特征，解释了代谢失调标志物中 27% 的变异。在男性中，这两种特征均与 CRC 相关（每增加 1 个标准差，比值比 = 1.34，炎症 = 1.34，95% 置信区间 1.07 至 1.68；代谢失调 = 1.25、1.00 至 1.55）；这两种特征均与女性 CRC 无关。十一种代谢物分别与男性或女性的结直肠癌和炎症或代谢失调的生物标志物相关。结论 我们得出了代谢组学特征，并鉴定了与炎症、代谢失调和 CRC 相关的单个代谢物，强调了几种代谢物作为参与 CRC 发病的炎症和代谢失调途径的有希望的候选物。