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.

MMSC significantly ameliorated DSS-induced colitis as evidenced by reduced disease activity index, preserved colon length, and attenuated histopathological damage in a mouse model.

• A dextran sodium sulfate (DSS)-induced colitis mouse model was used to evaluate MMSC efficacy.
• MMSC is a type II polyketide isolated from the endophytic fungus Aspergillus fumigatus of the mangrove plant Aegiceras corniculatum.
• Outcome measures included disease activity index, colon length preservation, and histopathological assessment of colonic tissue damage.
• Results were evaluated using proteomics analyses, molecular biology techniques, and 16S rDNA gene sequencing.

MMSC concurrently suppressed both the IL-17 and TNF signaling pathways by downregulating key molecular nodes.

• Key downregulated nodes included 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.
• Related pro-inflammatory cytokines downregulated included IL-1β, IL-6, IL-17, and TNF-α.
• Suppression was observed in both colonic tissues from treated mice and in LPS-stimulated NCM460 cells.
• Pathway identification was based on proteomics profiling with subsequent molecular biology validation.

MMSC restored gut microbial diversity and composition in mice with colitis, reversing DSS-induced dysbiosis.

• Gut microbiota was assessed using 16S rDNA gene sequencing.
• MMSC treatment reversed DSS-induced changes in both microbial diversity and community composition.
• Spearman correlation analysis revealed a notable correlation between the IL-17/TNF pathway and MMSC-mediated restoration of the gut microbiota.
• These findings suggest a mechanistic link between the anti-inflammatory signaling effects and microbiota modulation by MMSC.

MMSC, a mangrove-derived natural product, represents a novel therapeutic candidate for ulcerative colitis with a dual mechanism of action.

• MMSC was identified from the endophytic fungus Aspergillus fumigatus associated with the mangrove plant Aegiceras corniculatum.
• Prior to this study, therapeutic effects of MMSC on UC and underlying mechanisms were unclear.
• The dual mechanism encompasses suppression of IL-17/TNF signaling and restoration of gut microbiota homeostasis.
• The study positions mangrove-derived natural products as a promising reservoir for drug discovery in inflammatory bowel disease.