Exploring the complex relationship between gut microbiota and risk of colorectal neoplasia using bidirectional Mendelian Randomization analysis.

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 CRC were derived from a genome-wide association study meta-analysis. In forward MR, we employed genetic instrumental variables (IVs) for 24 gut microbiota taxa and six bacterial metabolites to examine their causal relationship with CRC. We also utilized 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 CRC, adenoma, and polyps, respectively. RESULTS: Forward MR didn't find evidence indicating causal relationship between any of the gut microbiota taxa or six bacterial metabolites tested and CRC 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 odds ratio 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 CRC genetic liability variants changes gut biology by influencing both gut microbiota and CRC risk. IMPACT: This study highlights the need of future complementary studies to explore causal mechanisms linking both host genetic variation with gut microbiome and CRC susceptibility.