Abstract
Marine-derived antimicrobial peptides possess both antibacterial and immunomodulatory activities, offering potential advantages for treating complex inflammatory conditions. Meanwhile, the management of inflammatory bowel disease is complicated by the interplay of microbial dysbiosis and bacterial-driven inflammation, which conventional single-target therapies frequently fail to address. In this study, we identified a novel cationic antimicrobial peptide, Scymidgutin8-29, from the mud crab Scylla paramamosain. This 22-residue peptide possesses a calculated molecular mass of 2658.23 Da, an estimated pI of 12.31, and 37.5% hydrophobicity. Scymidgutin8-29 exhibited potent, broad-spectrum membrane-disrupting activity against clinically relevant pathogens, including multidrug-resistant strains, with MBCs of 1.5-3 µM against the tested multidrug-resistant Acinetobacter baumannii isolates and 6-12 µM against MRSA isolates, achieving > 99.9% killing within 20 min. Furthermore, the peptide demonstrated potent anti-inflammatory activity by promoting M2 macrophage polarization in LPS-stimulated RAW264.7 cells, as evidenced by the downregulation of iNOS (to 0.24-fold of LPS control), NO (to 0.47-fold), and pro-inflammatory cytokines (IL-1β, TNF-α, IL-6 to 0.67-0.73-fold), along with the upregulation of Arg-1 (to 1.80-fold) and IL-10 (to 1.38-fold). In a dextran sulfate sodium (DSS)-induced acute colitis mouse model, intrarectal administration of Scymidgutin8-29 (5 mg/kg) significantly reduced the disease activity index (from 7.0 to 3.0), restored colonic histopathology, rebalanced cytokine profiles, and altered gut microbiota composition, notably decreasing colitis-associated Akkermansia and Proteobacteria. These results indicate that Scymidgutin8-29 possesses both direct membrane-disruptive antibacterial activity and immunomodulatory capacity, and demonstrates therapeutic efficacy in the DSS-induced colitis model, positioning it as a potential multi-functional therapeutic candidate for intestinal inflammation.