AbstractBackground: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 ofGammaproteobacteriafor 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.