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Helminths serve as principal regulators in modulating host immune responses, and their excretory-secretory proteins are recognized as potential therapeutic agents for inflammatory bowel disease. Nevertheless, our comprehension of the mechanisms underlying immunoregulation remains restricted. This investigation delves into the immunomodulatory role of a secretory protein serpin ( Emu -serpin), within the larval stage of Echinococcus multilocularis . Our observations indicate that Emu -serpin effectively alleviates dextran sulfate sodium-induced colitis, yielding a substantial reduction in immunopathology and an augmentation of anti-inflammatory cytokines. Furthermore, this suppressive regulatory effect is concomitant with the reduction of gut microbiota dysbiosis linked to colitis, as evidenced by a marked impediment to the expansion of the pathobiont taxa Enterobacteriaceae. In vivo experiments demonstrate that Emu -serpin facilitates the expansion of M2 phenotype macrophages while concurrently diminishing M1 phenotype macrophages, alongside an elevation in anti-inflammatory cytokine levels. Subsequent in vitro investigations involving RAW264.7 and bone marrow macrophages reveal that Emu -serpin induces a conversion of M2 macrophage populations from a pro-inflammatory to an anti-inflammatory phenotype through direct inhibition. Adoptive transfer experiments reveal the peritoneal macrophages induced by Emu -serpin alleviate colitis and gut microbiota dysbiosis. In summary, these findings propose that Emu -serpin holds the potential to regulate macrophage polarization and maintain gut microbiota homeostasis in colitis, establishing it as a promising candidate for developing helminth therapy for preventing inflammatory diseases.