Lentinan alleviates metabolic dysfunction implicating Parabacteroides goldsteinii-enriched gut microbiota and hepatic lipid metabolism reprogramming through gut-liver axis-associated mechanisms.

Metabolic disorders represent a global health challenge requiring novel therapeutic strategies targeting the gut-liver axis. This study investigates the protective effects and mechanisms of lentinan, a bioactive polysaccharide from Lentinus edodes, against high-fat diet (HFD)-induced metabolic dysfunction. HFD-fed mice were treated with lentinan. Comprehensive phenotypic assessments, metagenome sequencing, hepatic transcriptomics, and correlation analyses were performed to elucidate mechanisms. Lentinan intervention significantly ameliorated dyslipidemia, hepatic steatosis, systemic inflammation, and intestinal barrier dysfunction in HFD-fed mice. Mechanistically, lentinan induced taxonomically selective gut microbiota remodeling, characterized by substantial enrichment of Parabacteroides goldsteinii (positively correlated with hepatic Plppr3 expression) and reduction of Romboutsia ilealis (negatively correlated with Dgkh and Nfat5), while paradoxically decreasing Akkermansia muciniphila despite metabolic improvements. Hepatic transcriptomics revealed significant downregulation of glycerolipid metabolism and oxidative phosphorylation pathways, directly correlating with reduced lipid accumulation and improved serum biochemistry. Unlike conventional prebiotics, lentinan functions as a precision modulator of specific microbial metabolic functions, particularly L-arginine and uridine 5'-monophosphate (UMP) biosynthesis pathways, which interface with host inflammatory and lipid metabolism. These findings establish lentinan as a promising therapeutic candidate for metabolic syndrome management through coordinated gut microbiota-liver axis modulation, providing a conceptual framework for developing precision microbiome-targeted interventions.