Cell Mol Gastroenterol Hepatol. 2026 Aug 29:101869. doi: 10.1016/j.jcmgh.2026.101869. Online ahead of print.
ABSTRACT
BACKGROUND & AIMS: Trimethylamine N-oxide (TMAO) is a host-microbial co-metabolite that significantly increases following Roux-en-Y gastric bypass (RYGB). While TMAO is associated with cardiovascular diseases, its role in colorectal cancer (CRC) remains unclear.
METHODS: FabplCre;Apc15lox/+ mice, a genetically altered CRC model, together with murine macrophages and human colonic cancer cells (HCT-116) were used to investigate TMAO impact on colonic tumorigenesis.
RESULTS: TMAO supplementation significantly reduced the colonic tumor load in male, but not female mice. Consistently, dietary TMAO resulted in higher retention of circulating TMAO in males, which was significantly and inversely correlated with tumor loads. Furthermore, TNF-α-expressing cell frequencies in the colonic intraepithelial lymphocytes (IEL) were significantly lower in TMAO-supplemented male mice compared to controls, suggesting that circulating TMAO could play a protective effect against colonic tumor growth via down-regulation of TNF-α-expressing cells. This was supported by in vitro observations that TMAO reduced lipopolysaccharides (LPS)-stimulated TNF-α production from macrophages. TMAO exerted no effects on cell proliferation (Ki67) and DNA damage (γH2AX) of HCT-116 cells.
CONCLUSION: Our study leads us to conclude that higher retention of circulating TMAO has a protective effect against CRC in a sex-dependent manner, highlighting the importance of understanding the complex relationship amongst the concentrations of host-microbial cometabolite TMAO, its systemic circulation, and its biological function in modulating CRC risk.
PMID:42668089 | DOI:10.1016/j.jcmgh.2026.101869