Polysaccharide III from Polygonatum cyrtonema Hua alleviates diabetes-associated MASLD via PPAR pathway-mediated regulation of lipid metabolism and gut microbiota modulation

Type 2 diabetes mellitus (T2DM) frequently coexists with metabolic dysfunction-associated steatotic liver disease (MASLD), and their comorbidity is closely associated with disordered glucose and lipid metabolism. This study evaluated the effects of Polygonatum cyrtonema polysaccharide III (PCP III) on diabetes-associated MASLD and investigated the potential mechanisms involved. A T2DM-MASLD mouse model was established by high-fat diet feeding combined with streptozotocin injection, and mice were treated with PCP III (500 or 1000 mg/kg) for 8 weeks. PCP III significantly reduced body weight, liver weight, and white adipose tissue weight; improved fasting blood glucose, glucose tolerance, and serum lipid profiles; decreased serum alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase activities; and attenuated hepatic steatosis and oxidative stress. In addition, PCP III was associated with remodeling the gut microbiota, as reflected by increased abundances of norank_f__Muribaculaceae, norank_o__Clostridia_UCG-014 , and Dubosiella. Transcriptomic analysis highlighted the PPAR signaling pathway as one of the most significantly affected pathways, which was further supported by the altered expression of genes associated with fatty acid oxidation, bile acid synthesis, and lipid storage. Overall, PCP III showed protective effects against T2DM-associated MASLD, possibly is associated with regulating hepatic lipid metabolism potentially via the PPAR pathway and partially restoring gut microbiota homeostasis. These findings support the potential application of PCP III as a functional food ingredient for metabolic health.