Trimethylamine N-oxide, a bariatric surgery-associated host-microbial co-metabolite, reduces colonic tumorigenesis in a sex-dependent manner
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Author(s)
Type
Journal Article
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.
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.
Date Issued
2026-08-29
Date Acceptance
2026-08-21
Citation
Cellular and Molecular Gastroenterology and Hepatology, 2026
ISSN
2352-345X
Publisher
Elsevier BV
Journal / Book Title
Cellular and Molecular Gastroenterology and Hepatology
Copyright Statement
© 2026 Published by Elsevier Inc. on behalf of American Gastroenterological Association Institute
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/42668089
PII: S2352-345X(26)00147-5
Subjects
DNA damage
Weight loss surgery
bacterial metabolism
colon cancer risk
cytokines
inflammation
metabolism
microbiota
Publication Status
Published online
Coverage Spatial
United States
Article Number
101869
Date Publish Online
2026-08-29