| Summary: | Chronic diseases have been a leading cause of death worldwide, and polysaccharide supplementation is an effective therapeutic strategy for chronic diseases without adverse effects. In this study, the beneficial effect of <i>Laminaria japonica</i> fucoidan (LJF) on type 2 diabetes mellitus (T2DM) was evaluated in streptozocin-treated mice. LJF ameliorated the symptoms of T2DM in a dose-dependent manner, involving reduction in weight loss, water intake, triglyceride, blood glucose, cholesterol and free fatty acids, and increases in high-density lipoprotein cholesterol, catalase, glucagon-like peptide-1, and superoxide dismutase. In addition, LJF regulated the balance between insulin resistance and insulin sensitivity, reduced islet necrosis and β-cell damage, and inhibited fat accumulation in T2DM mice. The protective effect of LJF on T2DM can be associated with modulation of the gut microbiota and metabolites, e.g., increases in <i>Lactobacillus</i> and <i>Allobaculum</i>. Untargeted and targeted metabolomics analysis showed that the microbiota metabolite profile was changed with LJF-induced microbiota alterations, mainly involving amino acids, glutathione, and glyoxylate and dicarboxylate metabolism pathways. This study indicates that LJF can be used as a prebiotic agent for the prevention and treatment of diabetes and microbiota-related diseases.
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