(LB01-24-25) The Impact of Estrogen on Gut Microbial Metabolites in Colorectal Cancer Development

Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with complex interactions between genetic, environmental, and hormonal factors influencing its onset and progression. The gut microbiota plays a crucial role in CRC development through its metabolites, which affect inflammation and carcinogenesis. Estrogen impacts the microbiota, but its effect on microbial metabolites and CRC progression is unclear. This study explores how estrogen influences microbial metabolites and their potential role in CRC progression using a mouse model. 

Methods: 4 to 5 weeks old male and female FVB/NJ mice received either sham operation  (Males: Msham; Females: Fsham with intact ovaries and normal estrogen levels) or bilateral ovariectomy (Fovx lacking endogenous estrogen). One week post-surgery, all mice were randomly assigned to either a low-fat diet (LFD, 10% fat) or a high-fat diet (HFD, 60% fat). Fovx mice were further divided to subcutaneously injected with either vehicle oil (Fovx+oil) or 17-beta-estradiol (E2, 4 μg/mouse; Fovx+E2) every 4-5 days for 22 weeks. Moreover, all mice received injections of a colon-specific carcinogen azoxymethane (AOM) at a dose of 5 mg/kg in week 1 and 10 mg/kg in weeks 2-6. Colon feces were collected on the last day and metabolites were extracted. UHPLC-MS was utilized to discover microbial metabolites. Tumors collected from the colon were staged using Vienna classification of gastrointestinal tumors.

Results: PLS-DA analysis revealed distinct metabolic profiles between Msham/Fovx+oil and Fsham/Fovx+E2 groups. The latter had similar metabolic patterns, suggesting estrogen's influence on metabolic activity. Tumor stage differences were more pronounced in LFD mice, where adenocarcinoma samples were distinct from low-grade neoplasia. In contrast, the distinction between tumor stages was less clear in HFD mice, indicating dietary effects on metabolic differences.

Conclusions: These findings underscore the complex interaction between diet, estrogen levels, and tumor progression in shaping the metabolic landscape, with potential implications for biomarkers in cancer and metabolic diseases.

Funding Sources: 1) NIH/NCI R15CA274480; 2) Miami University CFR Faculty Research Grants