Erikka Loftfield

Ph.D., M.P.H.

National Cancer Instiute

Research Fellow

PLCO (Learn more about this study)

2018-1017

Dec 21, 2018

A Prospective Investigation of Microbial Metabolites and Colorectal Cancer

Short chain fatty acids (SCFAs) and secondary bile acids (BAs) are known microbial-metabolites that have been linked to dietary intake, inflammation, and carcinogenesis, but in different ways. High-fiber diets result in higher levels of microbial fermentation products, including the SCFA butyrate, and numerous experimental studies have demonstrated an inhibitory effect of butyrate on carcinogenesis. In addition, dietary fiber intake has been linked to lower risks of incident colorectal adenoma and colorectal cancer, particularly in the distal colon, in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial cohort. High-fat diets, on the other hand, increase BA secretion, and experimental evidence indicates that secondary BAs are carcinogenic to the colon. Furthermore, an earlier untargeted metabolomics case-control study of 254 CRC cases and 254 controls, nested in the PLCO cohort, found a strong positive association between the BA glycochenodeoxycholic acid and colorectal cancer (Q5 v. Q1 OR: 5.34; 95% CI = 2.09-13.68; P = .0001) among women. However, this study did not measure SCFAs, lacked comprehensive assessment of BAs, was only semi-quantitative, and, with a limited number of cases, was unable to explore differences by cancer site (i.e., proximal colon vs. distal colon vs. rectum).

Despite a wealth of experimental evidence, no human studies have prospectively investigated the relationship between systemic concentrations of SCFAs and BAs and colorectal cancer (CRC) risk using a fully quantitative and comprehensive targeted approach. The proposed study will use a case-control study design nested in the prospective PLCO cohort to investigate the hypothesis that lower concentrations of circulating SCFAs and higher concentrations of secondary BAs are associated with higher risk of CRC in humans.

To test our hypothesis, we will use a fully quantitative, liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted platform to quantify the three major SCFAs (i.e., acetate, propionate, butyrate) and the most abundant primary and secondary BAs as well as their glycine and taurine conjugates by means of labeled internal standards. In addition, to increase the statistical power of the proposed targeted metabolomics analyses and to explore potential differences by cancer site, we plan to include 176 additional CRC cases that have been identified since the original case selection was made for the untargeted study, resulting in a total sample size of 430 cases and 430 matched controls. We expect our results to provide insight into the role of key diet-related microbial metabolites and CRC.

1. Specific aim 1: Estimate the prospective associations of serum SCFA and BA concentrations with risk of CRC overall and by cancer site (i.e., proximal colon, distal colon, and rectum) and pathologic aspects (i.e., histology and grade).

2. Specific aim 2: Describe the associations of known risk factors for CRC, including diet, obesity, physical activity, non-steroidal anti-inflammatory drug (NSAID) use, alcohol drinking, and CRC screening variables (e.g. screening abnormalities) with serum SCFA and BA concentrations among controls.