Doratha Byrd

Ph.D., M.P.H.

Moffitt Cancer Center

Postdoctoral Fellow (CRTA)

PLCO (Learn more about this study)

2019-1004

Dec 27, 2019

Associations of Serum Trimethylamine N-oxide, Choline, Carnitine, and Betaine with Colorectal Cancer Risk

The overall broad and long-term goal of this project is to clarify the interrelationships among gut microbial metabolites and dietary/lifestyle exposures in relation to colorectal cancer (CRC), the second leading cause of cancer death in the United States (US) among men and women combined. Accumulating evidence supports that the collective activity of the trillions of bacteria residing in the gut, and particularly their metabolites, strongly influence CRC risk. Choline and carnitine undergo catabolism by the gut bacteria to form trimethylamine (TMA), which is then converted to trimethylamine N-oxide (TMAO) primarily by the liver enzyme flavin monooxygenase 3 (FMO3). Choline also can be oxidized to betaine, which has anti-inflammatory properties. Sources of choline include nuts and dairy, which have anti-oxidant and anti-inflammatory properties but also include red/processed meats, which is an established risk factor for colorectal neoplasms. Only two previous prospective studies investigated the associations of circulating concentrations of choline, carnitine, betaine, and TMAO with CRC risk: 1) in a cohort of Finnish male smokers, finding a 3-fold higher CRC risk for those in the highest vs. lowest quartile of choline; and 2) in a cohort of postmenopausal women, finding that those in the highest vs. lowest quartile of TMAO and choline concentrations had a 3.4-fold and 2.9-fold higher rectal cancer risk, respectively; and that that those in the highest vs. lowest quartile of betaine had a 32% lower overall CRC risk. Further exploration of these findings, and their underlying mechanism, are needed in other large, representative, prospective populations. We hypothesize that TMAO and its nutrient precursors, choline and carnitine, will be strongly, directly associated with higher risk for CRC; and that betaine will be strongly, inversely associated with lower risk for CRC. We will comprehensively characterize the etiological interactions between these metabolites in our analyses, and furthermore will investigate whether associations of established CRC risk factors (eg., red/processed meat) with CRC may be mediated by these metabolites.

1. Specific Aim 1: Investigate the prospective associations of serum concentrations of TMAO and its precursors (choline, betaine, and carnitine) 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: Investigate the associations of serum concentrations of TMAO and its precursors (choline, betaine, and carnitine) with established diet/lifestyle risk factors for CRC (e.g., red/processed meat, aspirin use, and obesity)