Department of Big Data in Health Science School of Public Health, Centre of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Cancer Epidemiol Biomarkers Prev. 2023 Jun 1;32(6):809-817. doi: 10.1158/1055-9965.EPI-22-0724.
Human gut microbiome has complex relationships with the host, contributing to metabolism, immunity, and carcinogenesis.
Summary-level data for gut microbiota and metabolites were obtained from MiBioGen, FINRISK and human metabolome consortia. Summary-level data for colorectal cancer were derived from a genome-wide association study meta-analysis. In forward Mendelian randomization (MR), we employed genetic instrumental variables (IV) for 24 gut microbiota taxa and six bacterial metabolites to examine their causal relationship with colorectal cancer. We also used a lenient threshold for nine apriori gut microbiota taxa as secondary analyses. In reverse MR, we explored association between genetic liability to colorectal neoplasia and abundance of microbiota studied above using 95, 19, and 7 IVs for colorectal cancer, adenoma, and polyps, respectively.
Forward MR did not find evidence indicating causal relationship between any of the gut microbiota taxa or six bacterial metabolites tested and colorectal cancer risk. However, reverse MR supported genetic liability to colorectal adenomas was causally related with increased abundance of two taxa: Gammaproteobacteria (β = 0.027, which represents a 0.027 increase in log-transformed relative abundance values of Gammaproteobacteria for per one-unit increase in log OR of adenoma risk; P = 7.06×10-8), Enterobacteriaceae (β = 0.023, P = 1.29×10-5).
We find genetic liability to colorectal neoplasia may be associated with abundance of certain microbiota taxa. It is more likely that subset of colorectal cancer genetic liability variants changes gut biology by influencing both gut microbiota and colorectal cancer risk.
This study highlights the need of future complementary studies to explore causal mechanisms linking both host genetic variation with gut microbiome and colorectal cancer susceptibility.
人类肠道微生物组与宿主之间存在复杂的关系，有助于代谢、免疫和癌变。
从 MiBioGen、FINRISK 和人类代谢组联盟获得了肠道微生物群和代谢物的汇总水平数据。从全基因组关联研究荟萃分析中获得了结直肠癌的汇总水平数据。在正向孟德尔随机化（MR）中，我们使用 24 种肠道微生物群分类群和 6 种细菌代谢物的遗传工具变量（IV）来检查它们与结直肠癌的因果关系。我们还使用了宽松的阈值来作为二次分析的 9 种先验肠道微生物群分类群。在反向 MR 中，我们使用 95、19 和 7 个 IV 分别用于结直肠癌、腺瘤和息肉，探索了结直肠肿瘤遗传易感性与上述研究的微生物群丰度之间的关联。
正向 MR 没有发现任何证据表明所测试的肠道微生物群分类群或 6 种细菌代谢物与结直肠癌风险之间存在因果关系。然而，反向 MR 支持结直肠腺瘤的遗传易感性与两种分类群的丰度增加有关：γ变形菌（β=0.027，代表腺瘤风险对数 OR 每增加一个单位时，γ变形菌对数相对丰度值增加 0.027；P=7.06×10-8）和肠杆菌科（β=0.023，P=1.29×10-5）。
我们发现结直肠肿瘤的遗传易感性可能与某些微生物群分类群的丰度有关。更有可能的是，结直肠癌遗传易感性变异的亚组通过影响肠道微生物群和结直肠癌风险来改变肠道生物学。
本研究强调需要进行未来的补充研究，以探索将宿主遗传变异与肠道微生物组和结直肠癌易感性联系起来的因果机制。
