Ruditapes philippinarum Polysaccharide Alleviates Hyperglycemia by Modulating Gut Microbiota in a Mouse Model of Type 2 Diabetes Mellitus

ABSTRACT Type 2 diabetes mellitus (T2DM), a widespread chronic metabolic disorder, presents a global challenge. Metformin hydrochloride, although widely prescribed, is associated with notable side effects. This study aims to explore safer, more effective alternatives by assessing the impact of Ruditapes philippinarum polysaccharides (RPPs) on glycemic control and modulation of microbiota in T2DM mice. A T2DM mouse model was established through a high‐sucrose/high‐fat diet and intraperitioneal streptozotocin injection. Glycometabolism indicators, histopathological features, and gut microbiota composition in caecum samples were assessed. Following 4 weeks of RPPs intervention, fasting blood glucose (FBG), glycated serum protein (GSP), area under the curve (AUC) of oral glucose tolerance test (OGTT), total cholesterol (TC), triglyceride (TG), and low‐density lipoprotein cholesterol (LDL‐c) levels were reduced in T2DM mice, while AKT‐1 and GLUT‐2 transcription levels were significant increased. Short‐chain fatty acids (SCFAs) concentrations notably increased in the RPP‐L group compared to the Model group, with improvements also observed in medium‐chain fatty acids (MCFAs) and secondary bile acids (SBAs). Regarding gut microbiota, the Firmicutes‐to‐Bacteroidetes (F/B) ratio in RPP‐L was substantially lower than in the Model group. At the genus level, beneficial bacteria, such as Akkermansia , Alloprevotella , Tidjanibacter , and Faecalibaculum demonstrated increased abundance. Correlation analysis identified Muribaculum , Paramuribaculum , Lacrimispora , and Turicibacter as microbial taxa associated with T2DM progression. RPPs significantly alleviated hyperglycemic symptoms in T2DM mice while enhancing the presence of beneficial gut bacteria, leading to a marked improvement in intestinal microbiota composition. This research offers foundational insights for the potential use of R. philippinarum in biomedical and nutraceutical applications.