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Background Human studies investigating the prospective relationship between microbial metabolites and colorectal cancer (CRC) risk are lacking. We tested whether higher serum bile acids (BAs) and lower short-chain fatty acids (SCFAs) were associated with CRC risk. Methods In baseline serum collected ≤30 years prior to CRC diagnosis, we quantified concentrations of 15 BAs and 6 SCFAs using targeted LC-MS/MS assays in 1:1 matched cases and controls from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (men: n = 262 cases; women: n = 233 cases) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (men: n = 598 cases). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for BA and SCFA quartiles and summary measures with CRC overall and by anatomic location using multivariable conditional logistic regression models. PLCO analyses were stratified by sex. Results In PLCO women, seven BAs were strongly associated with increased CRC risk, including the secondary BAs, deoxycholic (ORQ4 v Q1=2.85, 95% CI = 1.45–5.60, Q-trend = 0.011), glycodeoxycholic (OR Q4 v Q1=3.45, 95% CI = 1.79–6.64, Q-trend = 0.006), taurodeoxycholic (OR Q4 v Q1=2.36, 95% CI = 1.22–4.55, Q-trend = 0.023), and glycolithocholic acid (ORQ4 v Q1=2.71, 95% CI = 1.41–5.22, Q-trend = 0.015). Women in the highest, compared to lowest quartile, of total SCFAs had 45% lower risk of CRC (OR = 0.55, 95% CI = 0.31–0.98; P-trend = 0.03). Associations for total BAs and SCFAs were strongest among women with proximal colon cancer. No statistically significant associations were observed for BA or SCFA measures among men. Conclusion Serum concentrations of BAs, particularly downstream microbial metabolites of cholic acid, were strongly associated with increased risk of CRC among women.

Prospective Associations of Circulating Bile Acids and Short-Chain Fatty Acids With Incident Colorectal Cancer