Objective To observe the expression of Toll-like receptor 4 ( TLR4) and nucleotide bindingoligomerization domain protein 2 (NOD2) in the colon of a ulcerative colitis ( UC) rat model, and to explore thetherapeutic mechanism of Sishen pills in the treatment of UC from the perspective of repairing the intestinal mucosal barrier. Methods A UC rat model was prepared by administration of a trinitrobenzenesulfonic acid/ ethanol solution enema. Fortyrats were randomly divided into four groups, a blank group, model group, salazopyrimidine group(0. 36 g/ (kg·d)), andSishen pills group(5 g/ (kg·d)) The mRNA and protein expressions of TLR4 and NOD2 in colon tissue were detected byHE staining, RT-qPCR, SP immunohistochemistry and Western Blot. Results Compared with the blank group, thecolonic mucosal injury score of the model group was significantly greater ( P < 0. 01), and the expressions of TLR4, NOD2mRNA and protein were significantly greater ( P < 0. 01, P < 0. 05); Compared with the model group, the scores ofcolonic mucosal injury in each treatment group were significantly less ( P < 0. 01, v < 0. 05), and the expressions ofTLR4, NOD2 mRNA and protein were significantly less ( P < 0. 01, P < 0. 05). Conclusions Sishen pills can improvethe immune function of rats and inhibit intestinal inflammatory reactions for UC treatment.