Identification of Host Gene-microbiome Associations in Colorectal Cancer Patients Using Mendelian Randomization

Background: There are many studies indicating that alterations in the abundance of certain gut microbiota are associated with colorectal cancer (CRC). However, a causal relationship has not been identified due to confounding factors such as lifestyle, environmental, and possible reverse causal associations between the two. Furthermore, certain host gene mutations can also contribute to the development of CRC. However, the association between genes and gut microbes in patients with CRC has not been extensively studied.

Methods: We conducted a two-sample Mendelian randomization (MR) study to reveal the causal relationship between gut microbiota and CRC. We obtained SNPs associated with gut microbiome abundance as instrumental variables (IVs) from a large-scale, multi-ethnic GWAS study, and extracted CRC-related datasets from an East Asian Population genetic consortia GWAS (AGWAS) study and FinnGen consortium, respectively. We analyzed a total of 166 bacterial features at four taxonomic levels, including order, family, genus, and species. The inverse-variance-weighted (IVW), weighted median, MR-Egger, and simple median methods were applied to the MR analysis, and the robustness of the results were tested using a series of sensitivity analyses. We extracted IVs of gut microbiota with direct causal association with CRC for SNP annotation to identify the genes in which these genetic variants were located to reveal the possible host gene-microbiome associations in CRC patients.

Results: The findings from our MR analysis based on CRC-associated GWAS datasets from AGWAS revealed causal relationships between 6 bacterial taxa and CRC at a locus-wide significance level (P < 1 × 10). The IVW method found that family Porphyromonadaceae, genera Anaerotruncus, Intestinibacter, Slackia, and Ruminococcaceae UCG004, and species Eubacterium coprostanoligenes group were positively associated with CRC risk, which was generally consistent with the results of other complementary analyses. The results of a meta-analysis of the MR estimates from the AGWAS and the FinnGen datasets showed that family Porphyromonadaceae and genera Slackia, Anaerotruncus, and Intestinibacter replicated the same causal association. Sensitivity analysis of all causal associations did not indicate significant heterogeneity, horizontal pleiotropy, or reverse causal associations. We annotated the SNPs at a locus-wide significance level of the above intestinal flora and identified 24 host genes that may be related to pathogenic intestinal microflora in CRC patients.

Conclusion: This study supported the causal relationship of gut microbiota on CRC and revealed a possible correlation between genes and pathogenic microbiota in CRC. These findings suggested that the study of the gut microbiome and its further multi-omics analysis was important for the prevention and treatment of CRC.