TY - JOUR
T1 - Exploring the complex relationship between gut microbiota and risk of colorectal neoplasia using bidirectional Mendelian Randomization analysis
AU - Li, Wanxin
AU - Zhou, Xuan
AU - Yuan, Shuai
AU - Wang, Lijuan
AU - Sun, Jing
AU - Chen, Jie
AU - Xiao, Qian
AU - Wan, Zhongxiao
AU - Zheng, Ju-sheng
AU - Zhang, Cai-Xia
AU - Larsson, Susanna C.
AU - Farrington, Susan M
AU - Law, Philip
AU - Houlston, Richard S
AU - Tomlinson, Ian
AU - Ding, Ke-Feng
AU - Dunlop, Malcolm G
AU - Theodoratou, Evropi
AU - Li, Xue
N1 - Funding Information:
regional diagnosis and treatment center of the Health Planning Committee (No. JBZX-201903; to K.F. Ding). This work was also supported by grants from Cancer Research UK (C1298/A25514, C348/A12076, C6199/A16459, C348/A18927). Support was also provided by the DJ Fielding Medical Research Trust.
Funding Information:
This work was supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001; to X. Li) and the National Nature Science Foundation of China (82204019); CRUK Career Development Fellowship (C31250/A22804; to E. Theodoratou); the Swedish Heart Lung Foundation (Hj€art-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsra°det, 2019– 00977), and the Swedish Cancer Society (Cancerfonden; to S.C. Larsson); Natural Science Foundation of Zhejiang Province (LBY20H160002; to Q. Xiao); Project of the
Funding Information:
This work was supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001; to X. Li) and the National Nature Science Foundation of China (82204019); CRUK Career Development Fellowship (C31250/A22804; to E. Theodoratou); the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsradet, 2019–00977), and the Swedish Cancer Society (Cancerfonden; to S.C. Larsson); Natural Science Foundation of Zhejiang Province (LBY20H160002; to Q. Xiao); Project of the regional diagnosis and treatment center of the Health Planning Committee (No. JBZX-201903; to K.F. Ding). This work was also supported by grants from Cancer Research UK (C1298/A25514, C348/A12076, C6199/A16459, C348/A18927). Support was also provided by the DJ Fielding Medical Research Trust. We thank the participants and investigators who participated in the MiBioGen consortium and FINRISK study for providing data.
Publisher Copyright:
©2023 The Authors.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - BACKGROUND: Human gut microbiome has complex relationships with the host, contributing to metabolism, immunity, and carcinogenesis.METHODS: 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.RESULTS: 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).CONCLUSIONS: 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.IMPACT: 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.
AB - BACKGROUND: Human gut microbiome has complex relationships with the host, contributing to metabolism, immunity, and carcinogenesis.METHODS: 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.RESULTS: 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).CONCLUSIONS: 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.IMPACT: 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.
KW - Gut microbiota
KW - Microbial metabolite
KW - Colorectal cancer
KW - Mendelian Randomization
U2 - 10.1158/1055-9965.EPI-22-0724
DO - 10.1158/1055-9965.EPI-22-0724
M3 - Article
C2 - 37012201
SN - 1055-9965
VL - 32
SP - 809
EP - 817
JO - Cancer Epidemiology, Biomarkers & Prevention
JF - Cancer Epidemiology, Biomarkers & Prevention
IS - 6
ER -