Extracellular Polysaccharides of Eurotium cristatum 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.

ECP administration improved metabolic parameters in T2DM mice induced by high-fat diet combined with streptozotocin.

• T2DM mice were administered ECP at 400 mg/kg·bw for 6 weeks
• The T2DM model was induced by high-fat diet combined with streptozotocin injection
• ECP treatment improved insulin resistance in diabetic mice
• This study was described as the first to explore the antidiabetic activity of crude extracellular polysaccharides of Eurotium cristatum from Fu brick tea

ECP improved gut microbiota dysbiosis by altering the abundance of specific bacterial taxa.

• ECP increased the abundance of norank_f__Muribaculaceae
• ECP decreased the abundances of norank_f__Eubacterium_coprostanoligenes_group and Colidextribacter
• These microbiota compositional changes were correlated with the antidiabetic effects of ECP
• Pseudogerm-free mice supplemented with ECP failed to ameliorate T2DM, indicating gut microbiota dependency

ECP significantly increased colonic levels of acetate and indole-3-propionic acid (IPA) in T2DM mice.

• Acetate is a short-chain fatty acid produced by gut microbiota fermentation
• Indole-3-propionic acid (IPA) is a tryptophan-derived microbial metabolite
• The increase in acetate and IPA was correlated with gut microbiota composition changes induced by ECP
• The formation of acetate and IPA was linked to the downstream activation of the AhR/TSC2/mTORC1 signaling axis

ECP activated the hepatic AhR/TSC2/mTORC1 axis to improve insulin resistance.

• The aryl hydrocarbon receptor (AhR), tuberous sclerosis complex 2 (TSC2), and mechanistic target of rapamycin complex 1 (mTORC1) constitute the signaling axis modulated by ECP
• Activation of this axis was mediated by the gut microbiota-derived metabolites acetate and IPA
• The antidiabetic effects were correlated with gut microbiota composition and formation of acetate and IPA
• Pseudogerm-free mice supplemented with ECP failed to ameliorate T2DM, confirming the gut microbiota-dependent mechanism

ECP modulated multiple gut microbiota-controlled metabolic pathways beyond tryptophan metabolism.

• ECP modulated glycerolipid metabolism pathways
• ECP modulated sphingolipid metabolism pathways
• ECP modulated biosynthesis of unsaturated fatty acids pathways
• ECP modulated pyrimidine metabolism pathways
• All these metabolic pathway modulations were described as gut microbiota-controlled

Gut microbiota was required for ECP's antidiabetic effects, as demonstrated by pseudogerm-free mouse experiments.

• Pseudogerm-free mice supplemented with ECP failed to ameliorate T2DM
• This finding confirmed that ECP's antidiabetic mechanism is gut microbiota-dependent
• The pseudogerm-free mouse model served as a key experimental control to establish causality between gut microbiota remodeling and ECP's effects
• Results highlight that ECP acts through promoting gut microbiota-derived beneficial metabolites rather than through direct host cell effects