α-Hemolytic Streptococcus-Derived Mannatide Attenuated DSS-Induced Colitis in Mice Via Reducing Inflammation, Immunomodulatory, and Mucosal Protective Effects.

Mannatide, a glycopeptide derived from the fermentation of α-hemolytic Streptococcus, exhibits diverse immunomodulatory activity. However, clinical evidence regarding its efficacy in colitis remains limited, and its underlying mechanisms are poorly understood. In this study, mannatide was produced via submerged fermentation of α-hemolytic Streptococcus, yielding a concentration of 0.15 mg/mL in the fermentation broth and a molecular weight of 57,401 Da as determined by HPGPC-RID. The effects of mannatide on DSS-induced colitis in mice were also evaluated. The results demonstrated that mannatide alleviated clinical symptoms including weight loss and colon shortening, mitigated pathological damage such as mucosal epithelial disruption and inflammatory cell infiltration, and reduced histological scores from 4.56 to below 2. Additionally, it improved redox profiles by increasing SOD activity to 1.8 times that of the model group at a dosage of 50 mg/kg/BW. Mechanistically, mannatide mediated PI3K/Akt, which was involved in the pathogenesis of colitis in mice through multidirectional transcriptional regulation, including mediating the NF-κB pathway to reduce inflammation, regulating Th17/Treg immune homeostasis, and engaging Akt/eNOS for intestinal mucosal protection. Furthermore, mannatide at 50 mg/kg/BW upregulated the abundance of CAG-485, Muribaculum, and Alistipes-A, affecting P221-PWY, FAO-PWY, REDCITCYC, and PWY-6590 and other colitis-related metabolic pathways via altering gut microbiota composition, ultimately alleviating colitis in mice. Thus, this study provided a foundation for utilizing α-hemolytic Streptococcus and mannatide, as well as offered mechanistic insights for optimizing colitis treatment.