Structural elucidation and structure-activity relationship of Porphyra haitanensis polysaccharide for preventing ulcerative colitis: Targeting the immune-microbiota-metabolism axis.

Polysaccharides from Porphyra haitanensis exhibited potential against ulcerative colitis (UC), whereas the mechanism remained unclear. In this study, Porphyra haitanensis polysaccharide (PP) was extracted by high-pressure-assisted hot water method. PP was characterized as a sulfated amorphous polysaccharide mainly consisting of galactose (85.65% ± 0.52 mol%) and fucose (11.24% ± 1.03 mol%), featuring a unique structure of →4)-α-L-Gal-6-S-(1 → 3)-β-D-Gal-(1 → 4)-3,6-anhydro-α-L-Gal-(1 → and a side chain of →6)-α-L-Fuc-(1→. Sulfation and amorphous morphology enabled PP with abundant active moieties and desirable biocompatibility for effective intestinal action. The high content β-galactose residues and fucose side chains endowed PP to exert superior immunomodulatory activity and promote the proliferation of Firmicutes, Lachnospiraceae_NK4A136_group and Ligilactobacillus. The gut microbiota compositional shifts triggered KEGG metabolic alterations, as enriched acid-producing bacteria reciprocally facilitated short-chain fatty acids (SCFAs) synthesis. By remodeling the intestinal microenvironment, SCFAs suppressed the growth of Verrucomicrobia and Akkermansia, thereby downregulated Amino Acid Metabolism. Additionally, SCFAs could alleviated intestinal inflammation and strengthened intestinal epithelial barrier by inhibiting the TLR4/MyD88/NF-κB pathway. This study demonstrated that PP prevented UC by targeting the immune-microbiota-metabolism axis. As a natural polysaccharide, PP could serve as a promising dietary intervention for UC.