Vitamin E Delta-tocotrienol and Metabolite 13'-carboxychromanol Inhibit Colitis-associated Colon Tumorigenesis and Modulate Gut Microbiota in Mice

The gut microbiota play important roles in colon cancer. Vitamin E δ-tocotrienol (δTE) and its metabolite δTE-13'-carboxychromanol (δTE-13') are known to have cancer-preventive effects, but their impact on gut flora during tumorigenesis and the role of the metabolite in δTE's beneficial effects remain to be determined. In the murine colitis-associated colon cancer (CAC) induced by azoxymethane (AOM) and dextran sulfate sodium (DSS), we show that δTE and δTE-13' inhibited the multiplicity of large adenomas (>2 mm) by 34% (P<.05) and 55% (P<.01), respectively, compared to the control diet. δTE-13' diminished AOM/DSS-increased GM-CSF and MCP-1, and δTE decreased IL-1β. Using 16S rRNA gene sequencing of fecal DNAs, we observe that δTE and δTE-13' modulated the composition but not the richness of gut microbes compared to the control. Both δTE and δTE-13' enhanced potentially beneficial Lactococcus and Bacteroides. The elevation of Lactococcus positively correlated with fecal concentrations of δTE-13' and its hydrogenated metabolite, suggesting that the metabolite may contribute to δTE's modulation of gut microbes. Furthermore, δTE-13' counteracted AOM/DSS-induced depletion of Roseburia that is known to be decreased in patients with inflammatory bowel diseases. δTE uniquely elevated (Eubacterium) coprostanoloigenes. Our study demonstrates that δTE and δTE-13' inhibited tumorigenesis, suppressed pro-inflammatory cytokines and modulated gut microbiota in a murine CAC model. These findings uncover new and distinct activities of δTE and δTE-13' and support the notion that the metabolite may play a role in δTE's anticancer and modulation of gut microbes.