Abstract: Objective To observe the effects of tauroursodeoxycholic acid (TUDCA) combined with sulfasalazine (SASP) on experimental colitis of mice, and discuss the possible intervention mechanism of TUDCA to colitis model. Methods Experimental colitis model of mice were induced by drinking 5% dextran sulfate sodium (DSS). Mice in drug group were given SASP (500mg/kg), TUDCA (100mg/kg) and TUDCA combined with SASP by gastric gavage. The normal group and model group were administered with correspondingly 0.9 % saline, once per day for 8 days. The general status in mice, disease activity index (DAI), colonic length changes and the score of pathological histology were observed and Hes1, Atoh1 and Cdx2 expression in colons were assessed by immunohistochemistry (SP method). TNF-a and IL-6 expression in serum were assessed by ELISA. Results The DAI of normal group, TUDCA group, SASP group and TUDCA/SASP combined group was (0.10±0.23), (2.37±0.46), (2.17±0.55) and(1.94±0.34), respectively, the score of injury was (0.00±0.00), (6.60±1.71), (6.10±1.45) and (4.5±1.27), respectively, all were lower than those of model group (3.43±0.47), (9.40±1.26) and the differences were statistically significant (P< 0.01). The expression of TNF-a and IL-6 in protein level of normal group was (46.12±8.35) ng/L, (26.89±5.45) ng/L, (56.48±9.02) ng/L, (27.60±4.76) ng/L in TUDCA group, (59.15±11.09) ng/L, (26.42±5.08) ng/L in SASP group, respectively, all were lower than those of model group (70.64±7.93) ng/L, (35.12±3.51) ng/L and the differences were statistically significant (P< 0.05). The expression of Hes1 protein in normal group and TUDCA group was (0.26±0.12) and (0.40±0.10), respectively, which were lower than that of model group (0.82±0.10) with statistically significant differences (P< 0.01). No statistically significant difference was found between model group and SASP group (0.82±0.10) vs (0.73±0.09), P> 0.05. The expression of Atoh1 and Cdx2 at protein level of normal group was (0.48±0.06) and (0.78±0.08), (0.72±0.09) and (0.58±0.09) in TUDCA group, which were lower than those of model group (0.32±0.09), (0.37±0.07) with statistically significant differences (P< 0.01). But, no statistically significant difference was found between model group and SASP group in Atoh1 (0.32±0.09) vs (0.30±0.10), P> 0.05. Conclusion The inflammatory response of the colitis model of mice in both TUDCA and SASP group can be relieved effectively, the combination of them can do better due to the possible synergistic effect. The intervention mechanism of TUDCA may be related to the regulation of inflammatory factors, inhibition of the activity of Hes1 protein and the increase of Cdx2 protein expression.