The Novel Sugar Alcohol D-Threitol Alleviates Type 2 Diabetes Mellitus and Modulates Gut Microbiota in Mice

Conventional therapies for type 2 diabetes mellitus (T2DM) are often associated with adverse effects, driving the search for natural alternatives with high safety profiles. This study evaluates the preventive and metabolic‑regulatory potential of D-threitol, a novel sugar alcohol synthesized by engineered Yarrowia lipolytica, in a high-fat diet and streptozotocin-induced T2DM mice model. In vitro, D-threitol acted as a competitive inhibitor of α-glucosidase. After eight weeks of oral administration (500 mg/kg/day), treated mice exhibited reduced weight gain and fat accumulation, improved glucose tolerance and insulin sensitivity, and better lipid profiles, along with attenuated tissue injury in the liver, kidney, and pancreas. Notably, D-threitol intervention significantly reshaped the gut microbiota, enhancing microbial diversity, enriching beneficial genera (e.g., Lactobacillus, Allobaculum), and restoring fecal short-chain fatty acids (SCFAs) levels, particularly acetate, propionate, and butyrate. Molecular docking and dynamics simulations demonstrated stable binding of D-threitol to α-glucosidase, supported by favorable binding energy and hydrogen‑bond formation. D-threitol shows promise as a safe dietary ingredient for the prevention and management of T2DM, mediated through dual mechanisms involving enzymatic inhibition and microbiota modulation.