Prevention of colitis-associated carcinogenesis in a mouse model by diet supplementation with ursodeoxycholic acid.
Bile acids in the intestinal lumen contribute to the homeostatic regulation of proliferation and death of the colonic epithelial cells: Deoxycholic acid (DCA) appears to enhance and ursodeoxycholic acid (UDCA) to attenuate the process of chemically induced carcinogenesis. We studied the effects of UDCA on colitis-related colorectal carcinogenesis. Three groups of 25 mice were given 0.7% dextran sulphate in drinking water for 7 days and pure water for 10 days and were fed a standard diet containing double iron concentration. In 2 groups, the diet was supplemented with 0.2% cholic acid (CA), the precursor of DCA, or with 0.4% UDCA. After 15 cycles, the histology, the expression of MUC2, beta-catenin, p27 and p16 and the fecal water concentration of DCA and UDCA were investigated. All animals showed colitis with similar severity and histologic as well as immunophenotypic alterations, resembling those of human colitis. Among the animals fed the nonsupplemented diet, 46% developed colorectal adenocarcinomas and 54% anal-rectal squamous cell carcinomas. The prevalence of dysplasia and carcinomas did not change significantly in the animals given CA. Among the mice fed with UDCA, none developed adenocarcinomas and 20% squamous carcinomas. Dysplastic lesions were found in 88%, 67% and 40% of each group, respectively. The prevalence of dysplasia as well as of carcinoma showed an inverse relationship to the UDCA concentration in the fecal water. These data indicate that UDCA suppresses colitis-associated carcinogenesis. This model is suitable for investigation of the mechanism of the anticarcinogenic effect of UDCA in vivo.
Loddenkemper
Christoph
C
Institut für Pathologie, Charité Campus Benjamin Franklin, Berlin, Germany.
Keller
Sylvia
S
Hanski
Marie-Loise
ML
Cao
Minh
M
Jahreis
Gerhard
G
Stein
Harald
H
Zeitz
Martin
M
Hanski
Christoph
C
D000284:Administration, Oral; D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis; D002277:Carcinoma / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic; D002756:Cholagogues and Choleretics / Q000008:administration & dosage / Q000494:pharmacology*; D003092:Colitis / Q000150:complications*; D003106:Colon / Q000737:chemistry / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid