Sulfated Cyclocarya Paliurus Polysaccharide Sorchestrates the Gut Microbiome to Mobilize a Host‐Derived 12‐HEPE Against Ulcerative Colitis

ABSTRACT Despite extensive evidence supporting the therapeutic potential of natural product‐derived compounds in Ulcerative colitis (UC), their precise mechanisms have yet to be fully elucidated. In this study, structurally modified Cyclocarya paliurus polysaccharide (CP) derivatives were evaluated in a dextran sulfate sodium (DSS)‐induced UC mouse model. Among the variants tested, sulfated Cyclocarya paliurus polysaccharide (SCP) emerged as the most therapeutically potent. SCP administration markedly attenuated colitis severity, as evidenced by relieved disease symptoms and reinforced intestinal barrier function. Mechanistically, SCP restored gut microbial homeostasis by enriching beneficial Bacteroidetes and enhancing short‐chain fatty acids (SCFAs) production. This remodeled microbial ecosystem orchestrates the upregulation of host‐derived 12‐hydroxyeicosapentaenoic acid (12‐HEPE), which exerts anti‐inflammatory effects via direct inhibition of Toll‐like receptor 4 (TLR4) signaling. The gut microbiota's functional relevance was substantiated by fecal microbiota transplantation and antibiotic‐mediated exhaustion studies. Notably, the therapeutic benefits of 12‐HEPE were abrogated upon co‐administration of a TLR4 agonist, confirming its target specificity. Elevated serum 12‐HEPE levels were observed in a human UC cohort, implying a potential compensatory immunoregulatory response. Our findings elucidate a novel microbiota–host interaction axis wherein SCP alleviates UC by modulating the gut microbiota to enhance endogenous 12‐HEPE production, thereby suppressing TLR4‐mediated inflammation.