Batatasin III alleviates inflammatory bowel disease by suppressing MMP7 and NFκB signaling in macrophages and restoring gut microbial balance

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is characterized by chronic intestinal inflammation, disruption of the mucosal barrier, and immune dysregulation. Recent evidence underscores the role of gut macrophages, microbiota, and proinflammatory mediators in driving disease pathology. This study aimed to investigate the therapeutic potential and underlying mechanisms of Batatasin III, a stilbenoid compound derived from Dendrobium scabrilingue , in a murine model of IBD. A dextran sulfate sodium (DSS)-induced colitis model in mice was used to evaluate the efficacy of Batatasin III. Clinical parameters including body weight, colon length, and disease activity index (DAI) were measured. Histological analysis, cytokines analysis, macrophage polarization assays, gut microbiota sequencing, RNA sequencing, and molecular docking were performed to elucidate the underlying mechanism of Batatasin III. Batatasin III significantly alleviated DSS-induced colitis by improving colon length, reducing DAI, and preserving body weight. It enhanced gut barrier function through increased goblet cell count and upregulated tight junction proteins. The compound reduced proinflammatory cytokines IL-6 and TNF-α, elevated anti-inflammatory IL-10, and shifted macrophage polarization from the M1 to M2 phenotype. Furthermore, Batatasin III favorably modulated the gut microbiota composition and downregulated MMP7 expression. Mechanistically, it inhibited NF-κB activation and MMP7 upregulation in macrophages; pharmacological reactivation of NF-κB with Phorbol 12-myristate 13-acetate attenuated these inhibitory effects on MMP7 activity, MMP7 expression, and inflammatory cytokine expression, supporting an NF-κB-dependent mechanism. Batatasin III exhibits multi-faceted protective effects against colitis by promoting M2 macrophage polarization, reducing pro-inflammatory cytokines and reactive oxygen species, enhancing epithelial integrity, and reshaping gut microbiota. These findings provide a compelling rationale for its further development as a therapeutic agent for IBD.