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Using a DSS-induced colitis mouse model combined with multi-omics analysis and experimental validation, we explored the protective effects and molecular mechanisms of PP against intestinal inflammation. PP mitigated colitis-related symptoms in a dose-dependent manner, inhibited pro-inflammatory cytokines and dose-dependently reversed elevated IL-10 levels to BC group. Multi-omics data revealed that PP intervention was associated with gut microbiota remodeling, enrichment of Akkermansia muciniphila, restoration of bacterial\u2013fungal homeostasis, and improvement of tryptophan and biotin metabolism. By suppressing HMGB1 and RAGE expression, PP blocked the AGE-RAGE-mediated inflammatory cascade. In addition, PP maintained intestinal mucosal integrity through goblet cell protection, MDA reduction, and the regulation of BAX\/Bcl-2, MMP3 and MMP9. Overall, PP relieves UC by regulating gut microecology, host metabolism and the AGE-RAGE pathway, which supports the translational potential of natural polyphenols for inflammatory bowel disease treatment as a gut microecological modulator.<\/jats:p>","DOI":"10.3390\/antiox15091130","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:07:06Z","timestamp":1788768426000},"page":"1130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sphallerocarpus gracilis Polyphenols Alleviate DSS-Induced Colitis by Remodeling Gut Microbiota and Inhibiting the AGE-RAGE\/HMGB1 Pathway"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1211-506X","authenticated-orcid":false,"given":"Xuanjun","family":"Wang","sequence":"first","affiliation":[{"name":"College of Science, Yunnan Agricultural University, Kunming 650051, China"},{"name":"Key Laboratory of 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