Abstract: This study aimed to investigate the ameliorative effects of Lycium ruthenicum polysaccharides (LRP) on type 2 diabetes mellitus (T2DM) complicated by metabolic dysfunction-associated steatotic liver disease (MASLD) and to elucidate its underlying mechanisms. db/db mice were randomly divided into six groups: control, model, low-, medium-, and high-dose LRP (50, 100, and 200 mg/kg), and simvastatin (10 mg/kg). The intervention period lasted for eight weeks. Metagenomic sequencing and gas chromatography-mass spectrometry (GC-MS) were used to evaluate the effect of LRP on serum biochemical parameters, hepatic histopathology, gut microbiota structure, and short-chain fatty acid (SCFA) profiles in mice. LRP treatment significantly reduced serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, low-density lipoprotein cholesterol, free fatty acids, lipopolysaccharide, and pro-inflammatory cytokine levels, while alleviating hepatic lipid accumulation, inflammation, and fibrosis. Moreover, LRP enhanced the α-diversity of the gut microbiota, increased the relative abundance of beneficial bacteria such as Akkermansia muciniphila and Bacteroides acidifaciens, and decreased that of conditional pathogenic bacteria such as Klebsiella michiganensis and K. oxytoca. LRP also elevated fecal SCFA concentrations (acetate, propionate, and butyrate) and suppressed the hepatic Toll-like receptor 4/NOD-like receptor pyrin domain-containing 3/nuclear factor-κB (TLR4/NLRP3/NF-κB) signaling pathway by downregulating the expression of TLR4, MyD88, NLRP3, caspase-1, and interleukin-1β (IL-1β) and thereby reducing NF-κB phosphorylation. In conclusion, LRP exerts potent protective effects against T2DM-associated MASLD by restoring gut microbiota homeostasis, enhancing SCFA production, and inhibiting the hepatic inflammatory signaling pathway. This finding provides a scientific rationale for developing L. ruthenicum-based functional food products.

Key words: Lycium ruthenicum polysaccharides; type 2 diabetes mellitus; metabolic associated fatty liver disease; gut microbiota; short chain fatty acids; Toll-like receptor 4/NOD-like receptor pyrin domain-containing 3/nuclear factor-κB signaling pathway