Extracellular Polysaccharides of <i>Eurotium cristatum</i> from Fu Brick Tea Ameliorated Type 2 Diabetes in Mice by Remodeling of Gut Microbiota-Dependent Tryptophan Metabolism to Activate the Hepatic AhR/TSC2/mTORC1 Axis

This study was designed to explore, for the first time, the antidiabetic activity of crude extracellular polysaccharides of Eurotium cristatum (ECP) from Fu brick tea and its underlying mechanisms. High-fat diet combined with streptozotocin-induced type 2 diabetes mellitus (T2DM) mice was administrated with ECP (400 mg/kg·bw) for 6 weeks. ECP improved gut microbiota dysbiosis with an increase in norank_f__Muribaculaceae abundance and the decrease in abundances of norank_f__Eubacterium_coprostanoligenes _group and Colidextribacter . Interestingly, ECP significantly increased the colonic levels of acetate and indole-3-propionic acid (IPA), and subsequently activated the aryl hydrocarbon receptor (AhR)/tuberous sclerosis complex 2 (TSC2)/mechanistic target of rapamycin complex 1 (mTORC1) axis to improve insulin resistance, in which the effects were correlated with gut microbiota composition and formation of acetate and IPA, but pseudogerm-free mice supplemented with ECP failed to ameliorate T2DM. ECP also modulated gut microbiota-controlled glycerolipid metabolism, sphingolipid metabolism, biosynthesis of unsaturated fatty acids, and pyrimidine metabolism pathways. These findings highlight a novel antidiabetic mechanism of ECP by promoting gut microbiota-derived beneficial metabolites to trigger the AhR/TSC2/mTORC1 axis.