Dipsacoside B alleviates experimental colitis by reshaping gut microbiota and metabolically regulating the balance of macrophage polarization.

Gut dysbiosis-driven macrophage polarization plays a critical role in the pathogenesis of ulcerative colitis (UC). Dipsacoside B (DB), a natural saponin, possesses potential anti-inflammatory properties; however, its influence on mucosal immunity and the gut microbiota remains to be elucidated. To evaluate the therapeutic effects of DB, this study employed a DSS-induced colitis model in C57BL/6 mice, testing three different doses. The role of the gut microbiota was investigated through antibiotic-induced depletion and fecal microbiota transplantation (FMT). Both in vivo and in vitro experiments were carried out to assess intestinal barrier function and immune responses, with the latter involving colonic organoid and Caco-2 cells exposed to macrophage-conditioned media. Further mechanistic insights were gained via integrated 16S rRNA sequencing and untargeted metabolomics. In terms of colitis outcomes, DB exerted dose-dependent relief of symptoms and restored intestinal barrier integrity. At the immune level, DB encouraged macrophages within the lamina propria to transition from an M1 to an M2 phenotype. Importantly, the gut microbiota was essential for these effects, when antibiotics were used to deplete the microbiota, the protective effects of DB were abolished, but its protective effects on the mucosa could be transferred via FMT. Omics analyses pointed to increased Akkermansia and activation of the alpha-linolenic acid (ALA) pathway, accompanied by elevated methyl jasmonate (MeJA). In vitro, MeJA was found to regulate macrophage polarization tipping the balance away from M1 and toward M2 and to preserve tight junctions in epithelial cells exposed to inflammatory stress. Collectively, this work reveals that DB ameliorates UC via microbiota-dependent enrichment of MeJA, a microbiota-associated ALA-derived metabolite. Furthermore, this study demonstrates that MeJA exerts immunomodulatory effects by balancing macrophage polarization, thereby providing a novel strategy for targeted therapeutic interventions in UC.