Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis


 Background: Mechanistic data indicate the benefit of short-chain fatty acids (SCFAs) produced by gut microbial fermentation of fiber on colorectal cancer (CRC), but direct epidemiological evidence is limited. A recent study identified single nucleotide polymorphisms (SNPs) for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits. Methods: We conducted a two-sample Mendelian randomization (MR) analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to CRC risk in three large European genetic consortia of 58,131 CRC cases and 67,347 controls. We estimated the risk of overall CRC and conducted subgroup analyses by sex, age, and anatomical subsites of CRC. Results: We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall CRC, CRC by sex, or early-onset CRC (CRC diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD=0.95, 95% CI=0.91-0.99; P=0.03) but it did not surpass multiple testing of subgroup analysis. Conclusions: Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with CRC risk. Impact: Fecal propionate and PWY-5022 may not have a substantial influence on CRC risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on CRC risk.