Identification of monomethylsulochrin as a novel agent to ameliorate DSS-induced ulcerative colitis through dual modulation of the IL-17/TNF pathway and gut microbiota

Novel therapeutic agents with improved safety and efficacy are urgently required for ulcerative colitis (UC), a refractory inflammatory bowel disease. Mangrove-derived natural products represent a promising reservoir for drug discovery. Monomethylsulochrin (MMSC) is a type II polyketide isolated from the endophytic fungus Aspergillus fumigatus of the mangrove plant Aegiceras corniculatum . However, its therapeutic effects on UC and the underlying mechanisms remain unclear. Herein, we evaluated the efficacy of MMSC by using a dextran sodium sulfate (DSS)-induced colitis mouse model and elucidated the underlying mechanisms by proteomics analyses, molecular biology techniques, and 16S rDNA gene sequencing. Our results demonstrated that MMSC significantly ameliorated DSS-induced colitis, as evidenced by reduced disease activity index, preserved colon length, and attenuated histopathological damage. Mechanistically, proteomics profiling and subsequent validation confirmed that MMSC concurrently suppressed the interleukin (IL)-17 and tumor necrosis factor (TNF) signaling pathways by downregulating key nodes (matrix metalloproteinase [MMP]-9, S100 calcium-binding protein A8 [S100a8], CCAAT/enhancer-binding protein beta [Cebpb], cAMP responsive element binding protein 1 [Creb1], and Fas) and related pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-17, TNF-α) in both colonic tissues and lipopolysaccharide (LPS)-stimulated NCM460 cells. Furthermore, MMSC restored gut microbial diversity and composition in mice with colitis, reversing DSS-induced dysbiosis. Spearman correlation analysis revealed that the IL-17/TNF pathway exhibited a notable correlation with MMSC-mediated restoration of the gut microbiota. In conclusion, MMSC alleviates UC through a dual mechanism integrating suppression of IL-17/TNF signaling and restoration of gut microbiota homeostasis, highlighting it as a promising candidate for developing novel therapies against UC.