Inflammatory bowel disease (IBD) is an autoimmune disease with increasing incidence rate, and divided into ulcerative colitis (UC) and Crohn's disease (CD). And more and more experimental evidence supports that immune disorder is important in the pathogenesis of IBD. Our previous experiments have confirmed that TsKaSPI and TsAdSPI recombinant proteins could relieve TNBS (2,4,6-Trinitrobenzenesulfonic acid solution)-induced colitis. Therefore, we speculate that macrophages play a certain role in the process of recombinant protein relieving colitis. In this experiment, 96 male BALB/c mice aged 6-8 weeks were randomly divided into two groups: the prevention group and the therapy group. Changes of the ratio of M1/M2 phenotypic macrophages in spleens and MLNs, key factors in the IL-33/ST2 and IL-6/JAK2/STAT3 signaling pathway were detected. The purpose is to analyze the specific role played by macrophages and their secreted cytokines in the immunomodulation of colitis by Trichinella spiralis (T. spiralis) Serine protease inhibitors. The results showed that the percentage of M1 phenotypic macrophages was decreased and M2 phenotypic macrophages was increased in the TsKaSPI + TNBS, TsAdSPI + TNBS group compared with the PBS + TNBS group in the prevention group. Meanwhile, the expression of IL-33 and ST2 were significantly decreased. The key factors of IL-6/JAK2/STAT3 signaling pathway were all significantly increased. In addition, in the therapy group, we found similar results. This experiment demonstrated that macrophages have a certain impact during this process of recombinant protein relieving mouse CD model.