Omega-3 Polyunsaturated Fatty Acids, Gut Microbiota, Microbial Metabolites, and Risk of Colorectal Adenomas

SIMPLE SUMMARY: Dietary omega-3 polyunsaturated fatty acids (ω-3 PUFAs) may protect against colorectal adenoma development, and the gut microbiota and microbial metabolites (particularly bile acids) are important in dietary fat metabolism. We aimed to evaluate the impacts of ω-3 PUFAs, gut microbiota, and bile acids (BAs) on colorectal adenoma occurrence in a case–control study (n = 435) with 16s rRNA sequencing and global metabolomics (subset n = 50) measurements. We observed that ω-3 PUFA intake was associated with an 11–55% risk reduction in developing colorectal adenoma, and the association was modified by the gut bacterial evenness level. We also found that three specific gut bacteria and four BAs metabolites that were measured in normal colonic mucosa tissue were positively associated with colorectal adenomas. These findings provide important insights and imply that the improvement of ω-3 PUFA intake and/or alterations in the gut microbial environment may become a potential risk reduction strategy for colorectal cancer prevention. ABSTRACT: Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are thought to protect against colorectal adenoma (CRA) development. We aimed to further understand the underlying mechanisms by examining the relationships between ω-3 PUFAs and the gut microbiota on CRAs. We assessed the mucosal microbiota via bacterial 16S rRNA sequencing among 217 CRA cases and 218 controls who completed PUFA intake questionnaires. The overall microbial composition was assessed by α-diversity measurements (diversity, richness, and evenness). Global metabolomics was conducted using a random subset of case–control pairs (n = 50). We compared microbiota and metabolite signatures between cases and controls according to fold change (FC). Odds ratios (OR) and confidence intervals (CI) were estimated from logistic regression for associations of ω-3 PUFAs and the microbiota with CRAs. We observed an inverse association between overall ω-3 PUFA intake and CRAs, especially for short-chain ω -3 PUFAs (OR = 0.45, 95% CI: 0.21, 0.97). Such inverse associations were modified by bacterial evenness (p(-interaction) = 0.03). Participants with higher levels (FC > 2) of bile acid-relevant metabolites were more likely to have CRAs than the controls, and the correlation between bile acids and bacterial diversity differed by case–control status. Our findings suggest that ω-3 PUFAs are inversely associated with CRA development, and the association may be modified by gut microbiota profiles.