EFFECT OF DIETARY DEOXYCHOLIC-ACID AND CHOLESTEROL ON FECAL STEROID CONCENTRATION AND ITS IMPACT ON THE COLONIC CRYPT CELL-PROLIFERATION INAZOXYMETHANE-TREATED RATS

To elucidate the role of fecal steroids in the malignant tumor formati on of colonic epithelial cells, we examined the effects of dietary deo xycholic acid (DCA) and cholesterol (CHL) on fecal steroid concentrati ons and their impact on colonic crypt cell proliferation. Twenty 5-wee k-old male Fischer 344 rats were provided with either a control semisy nthetic diet or the same diet supplemented with 0.15% DCA and 1% CHL ( steroid diet) over a 5-week period. The effects of these two diets wer e compared among rats that were either injected with azoxymethane (AOM ), a known gastrointestinal carcinogen, or saline. In a 2 x 2 factoria l design, rats fed each of these diets were given two weekly subcutane ous injections of either AOM (15 mg/kg b.w.) or saline at 6 and 7 week s of age. At 9 weeks of age, fecal samples were obtained for analysis of bile acids, CHL and its bacterial metabolites of intestinal microfl ora. At 10 weeks of age, animals were sacrificed and colonic prolifera tion was assessed as vincristine-accumulated mitotic figures per crypt . Rats fed the steroid diet had significantly elevated fecal bile acid (5x, P < 0.001) and neutral steroid (10x, P < 0.01) levels when compa red to those fed the control diet. AOM treatment did not appear to inf luence these levels. However, rats injected with AOM had a significant increase (P < 0.001) in their rate of colonic cell proliferation as c ompared to saline-injected control animals on both diets. Furthermore, rats fed the steroid diet had a significantly higher (P < 0.001) cell proliferation rate than animals fed the control diet. The effects of AOM treatment and the steroid diet on cell proliferation were additive . Our results demonstrate that high concentrations of neutral and acid steroids in the colonic lumen can enhance carcinogen-induced elevated cell proliferation and thus may play a key role in the etiology of co lon cancer. (C) 1998 Elsevier Science Ireland Ltd.