Trimethylamine N-Oxide, a Bariatric Surgery-Associated Host-Microbial Cometabolite, Reduces Colonic Tumorigenesis in a Sex-Dependent Manner.

BACKGROUND & AIMS: Trimethylamine N-oxide is a host-microbial cometabolite that significantly increases following Roux-en-Y gastric bypass. Although trimethylamine N-oxide is associated with cardiovascular diseases, its role in colorectal cancer remains unclear.

METHODS

FabplCre;Apc15lox/+ mice, a genetically altered colorectal cancer model, together with murine macrophages and human colonic cancer cells (HCT-116), were used to investigate the impact of trimethylamine N-oxide on colonic tumorigenesis.

RESULTS

Trimethylamine N-oxide supplementation significantly reduced the colonic tumor load in male, but not female, mice. Consistently, dietary trimethylamine N-oxide resulted in higher retention of circulating trimethylamine N-oxide in males, which was significantly and inversely correlated with tumor loads. Furthermore, tumor necrosis factor-α-expressing cell frequencies in the colonic intraepithelial lymphocytes were significantly lower in trimethylamine N-oxide-supplemented male mice compared with controls, suggesting that circulating trimethylamine N-oxide could play a protective effect against colonic tumor growth via down-regulation of tumor necrosis factor-α-expressing cells. This was supported by in vitro observations that trimethylamine N-oxide reduced lipopolysaccharide-stimulated tumor necrosis factor-α production from macrophages. Trimethylamine N-oxide exerted no effects on cell proliferation (Ki67) and DNA damage (γH2AX) of HCT-116 cells.

CONCLUSIONS

Our study leads us to conclude that higher retention of circulating trimethylamine N-oxide has a protective effect against colorectal cancer in a sex-dependent manner, highlighting the importance of understanding the complex relationship among the concentrations of host-microbial cometabolite trimethylamine N-oxide, its systemic circulation, and its biological function in modulating colorectal cancer risk.