Influence of dietary cholesterol on faecal steroid excretion and its impact on the colonic epithelium in mice: implications for colon carcinogenesis

Elevated levels of faecal steroids along with altered patterns of colonic epithelial cell proliferation have been associated with increased risk for the development of colon cancer in humans and experimental animals. In this study, the influence of dietary cholesterol on the faecal excretion of neutral and acid steroids as well as its impact on the colonic epithelium were investigated in two mouse strains. C57BL/6J and BALB/cJ mice, which differ in their metabolism of dietary cholesterol, were fed a semisynthetic diet containing 0% (control), 0.50%, 1.25%, 3.00% or 5.00% cholesterol. Crypt morphometrics were not altered by cholesterol feeding. However, dietary cholesterol significantly increased the number of cells undergoing mitosis (p 0.0001) and DNA synthesis (p 0.0001) in the colonic epithelium of both mouse strains. Changes in the cell proliferative pattern were also noted. Alterations in cell proliferation appeared to be associated with increased lumenal concentrations of neutral steroids and to a lesser extent bile acids. While both acid and neutral steroids concentrations were increased by cholesterol feeding in a dose-dependent manner, neutral steroids were increased to a much greater extent. In animals given the 5% cholesterol diet, neutral steroid concentrations were increased 200 - 400% when compared with controls. Acid steroids were increased by only 12%. The results of this study indicate that high levels of dietary cholesterol may increase risk for development of large bowel cancer through increased lumenal concentrations of neutral steroids with subsequent alterations in cell proliferation