Causal relationships between gut microbiota, C-reactive protein levels and colorectal cancer: A Mendelian...

Gut microbiota have been associated with C-reactive protein (CRP) levels and colorectal cancer (CRC), but their causal relationships in humans remain unclear. We performed Mendelian randomization (MR) analyses to investigate causal relationships among gut microbiota, CRP, and CRC using genome-wide association studies (GWAS) summary data. The inverse variance weighted method was prespecified as the primary estimator, with complementary MR methods and sensitivity analyses used to assess robustness. Multiple-testing correction was applied across 209 gut microbial taxa. External validation and targeted replication were conducted using independent CRC GWAS datasets. An exploratory prerequisite-based analysis evaluated whether CRP might represent a potential inflammatory pathway linking CRC-associated gut microbial taxa to CRC. Five gut microbial taxa showed nominal associations with CRC. Genus Eubacterium brachy group id.11296 (odds ratio [OR] = 1.13, 95% confidence intervals [CI] = 1.04-1.22, P = .002) and genus Ruminococcaceae UCG004 id.11362 (OR = 1.15, 95% CI = 1.03-1.29, P = .016) were positively associated with CRC risk. Family Enterobacteriaceae id.3469 (OR = 0.83, 95% CI = 0.69-1.00, P = .048), genus Oscillibacter id.2063 (OR = 0.88, 95% CI = 0.77-1.00, P = .045), and order Enterobacteriales id.3468 (OR = 0.83, 95% CI = 0.69-1.00, P = .048) showed inverse associations. However, none survived Bonferroni or Benjamini-Hochberg false discovery rate correction. Targeted replication provided partial support in BioBank Japan, with 3 taxa showing nominal replication, whereas no nominal replication was observed in FinnGen. For CRP, the weighted median method suggested a nominal inverse association with CRC risk, but this was not supported by the primary inverse variance weighting analysis or other complementary methods. The exploratory pathway analysis did not support CRP as a mediator linking the identified microbial taxa to CRC. This MR study identified 5 gut microbial taxa showing nominal associations with CRC risk, but these findings did not survive multiple-testing correction and should be interpreted as suggestive. Current evidence did not support a robust direct causal effect of CRP on CRC or a CRP-mediated microbiota-CRC pathway. Larger ancestry-matched GWAS datasets, strain-resolved microbiome analyses, and experimental studies are needed.