Sulfate Groups Modulate the Protective Effects of Laminaria japonica Fucoidan against High-Fat Diet-Induced Intestinal Mucus Layer Injury via Gut Microbiota Regulation and Metabolic Profiling

Sulfate groups are key to fucoidan’s protection against intestinal mucus barrier damage, but their exact mechanisms remain unclear. This study compared native fucoidan (Fud, sulfate content 26.6%) and desulfated fucoidan (dsFud, sulfate content 2.2%) in a high-fat diet-induced colonic mucus-layer injury mouse model. Both interventions mitigated weight gain, fat accumulation, and dyslipidemia, increased the neutral/acidic mucin ratio and upregulated Muc2 expression, and alleviated colon inflammation as well as NLRP3 inflammasome activation. Compared with dsFud, Fud showed better hepatic lipid regulation and serum triglyceride reduction, upregulated Fut2 more significantly, and more potently inhibited NLRP3 signaling. Fud also markedly reduced the Firmicutes/Bacteroidota ratio and enriched Parabacteroides, Desulfovibrio, and Akkermansia. Metabolomic profiling revealed that they both suppressed primary bile acid metabolism and activated the aryl hydrocarbon receptor. Notably, Fud activated tryptophan metabolism, while dsFud mainly enhanced arginine and proline metabolism. Collectively, sulfation is important for fucoidan’s protective potency on the intestinal mucus layer.