Enteromorpha prolifera Polysaccharide Alleviates Type 2 Diabetes via the Gut Microbiota-Liver Axis to Modulate Cholesterol Metabolism.

Enteromorpha prolifera polysaccharide (EPP), a major bioactive sulfated polysaccharide derived from green algae, possesses potent hypoglycemic and hypolipidemic properties. This study aimed to evaluate the therapeutic efficacy of EPP in a murine model of type 2 diabetes mellitus (T2DM) and elucidate its underlying molecular mechanisms through an integrated multi-omics approach-comprising 16S rRNA microbiomics, untargeted metabolomics, and transcriptomics. Our findings demonstrate that EPP intervention significantly suppressed fasting blood glucose (FBG) levels, attenuated dyslipidemia, and enhanced systemic insulin sensitivity. At the microbiome level, EPP restored intestinal homeostasis by enriching beneficial taxa, specifically Lactobacillus, Ligilactobacillus, and Dubosiella, while depleting the T2DM-associated genus Blautia. These microbial shifts correlated with significantly elevated fecal concentrations of short-chain fatty acids (SCFAs), including acetate, propionate, and branched-chain fatty acids (isobutyrate and isovalerate). Integrated pathway analysis revealed that EPP significantly modulates steroid hormone biosynthesis; integrated pathway analysis suggested that EPP potentially modulates pathways related to steroid hormone biosynthesis, cholesterol metabolism, and primary bile acid synthesis. Quantitative RT-PCR validation confirmed that EPP treatment was accompanied by the upregulation of critical genes involved in bile acid and steroidogenesis (Cyp17a1, Cyp11a1, Hsd3b7, and Stard1) and the downregulation of Srebf2 and Hnf4α, the master transcriptional regulators of cholesterol biosynthesis and hepatic gluconeogenesis, respectively. Correlation analyses further indicated potential links between gut microbiota alterations, SCFA production, and glycemic control. Collectively, these results suggest that EPP may alleviate T2DM symptoms, which is associated with the modulation of the gut microbiota-hepatic cholesterol metabolism axis, positioning it as a promising functional food ingredient or therapeutic candidate for metabolic disorders.