Multi-omics integrative analysis elucidates the anti-inflammatory effects and underlying mechanisms of Arthrospira platensis-derived peptides in ulcerative colitis.

Inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), remains a global health challenge due to limited therapeutic efficacy and adverse effects of current treatments. Marine-derived peptides, recognized for their structural diversity and bioactivity, hold promise as novel therapeutics. Arthrospira platensis-derived peptide P1 has demonstrated anti-inflammatory potential, warranting exploration of its mechanisms in UC. This study aimed to investigate the therapeutic effects and molecular mechanisms of P1 in a DSS-induced UC mouse model using multi-omics integration. UC was induced in C57BL/6 J mice via 3.5% DSS. P1 or 5-ASA was administered for 7 days. Systemic analyses included gut microbiota profiling (16S rRNA sequencing), transcriptomics, proteomics, histopathology, oxidative stress assays, RT-qPCR, and Western blotting. P1 restored gut microbiota diversity, suppressing Akkermansia while enriching Rikenellaceae and Prevotella. It attenuated oxidative stress by reducing ROS/MDA and enhancing SOD/CAT/GSH-Px activity, mitigated apoptosis via TUNEL assay, and repaired epithelial barrier integrity by upregulating ZO-1/Occludin. Multi-omics integration revealed P1's dual regulation of PPAR and NF-κB pathways: PPARγ activation upregulated lipid metabolism genes (pparγ, hmgcs1) and suppressed NF-κB signaling (nf-κb, tnf-α, il-1β), validated by reduced p-P65 and iNOS alongside elevated IκBα. P1 downregulated pro-inflammatory cytokines (TNF-α, IL-6, IL-17) and increased IL-10. These results showed that P1 alleviated UC through microbiota modulation, oxidative stress reduction, barrier restoration, and PPAR/NF-κB crosstalk regulation, positioning it as a multi-target therapeutic candidate for IBD. This study provides a mechanistic foundation for developing peptide-based strategies in precision colitis management.